Regulation of Injury-Induced Neurogenesis by Nitric Oxide

Carreira, Bruno P.; Carvalho, Caetana M.; Araújo, Inês M.

doi:https://doi.org/10.1155/2012/895659

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Volume 2012 | Article ID 895659 | https://doi.org/10.1155/2012/895659

Regulation of Injury-Induced Neurogenesis by Nitric Oxide

Bruno P. Carreira,¹Caetana M. Carvalho,¹and Inês M. Araújo^2,3

Academic Editor: Oscar Gonzalez-Perez

Received01 Jun 2012

Accepted19 Jul 2012

Published10 Sept 2012

Abstract

The finding that neural stem cells (NSCs) are able to divide, migrate, and differentiate into several cellular types in the adult brain raised a new hope for restorative neurology. Nitric oxide (NO), a pleiotropic signaling molecule in the central nervous system (CNS), has been described to be able to modulate neurogenesis, acting as a pro- or antineurogenic agent. Some authors suggest that NO is a physiological inhibitor of neurogenesis, while others described NO to favor neurogenesis, particularly under inflammatory conditions. Thus, targeting the NO system may be a powerful strategy to control the formation of new neurons. However, the exact mechanisms by which NO regulates neural proliferation and differentiation are not yet completely clarified. In this paper we will discuss the potential interest of the modulation of the NO system for the treatment of neurodegenerative diseases or other pathological conditions that may affect the CNS.

1. Introduction

Neurogenesis is not limited to embryonic development as previously thought and occurs throughout the entire adult life of mammals, including humans. New neurons are continuously added to neural circuits and originate at two principal brain regions: the subventricular zone (SVZ) of the lateral ventricles, which generates olfactory bulb (OB) neurons, and the subgranular zone (SGZ) of the dentate gyrus (DG) of the hippocampus. Both regions harbor neural stem cells (NSCs) that can be isolated and cultured in vitro in the presence of growth factors, such as basic fibroblast growth factor (bFGF), epidermal growth factor (EGF), or both. The absence of growth factors results in the differentiation of cells into neurons, astrocytes, or oligodendrocytes as discussed in [1]. Neurogenesis has been exhaustively studied over the past years, and despite the great progress that has been achieved, the knowledge of the multiple aspects controlling proliferation, differentiation, or survival of NSCs is far from being known or understood. It was shown that neurogenesis decreases with aging and is impaired in several pathological conditions affecting the brain. Whether the insult is acute, such as ischemic brain stroke, traumatic brain injury, or epileptic seizures, or is a slow-progressing disease like Alzheimer’s disease, Huntington’s disease, or Parkinson’s disease, all these conditions are accompanied by an inflammatory response in the brain [2]. Furthermore, the blockade of neuroinflammation restores adult neurogenesis [3, 4]. When an inflammatory response in the brain appears following an injury, activation of the brain immune cells takes place, particularly microglial cells. In inflammatory conditions, microglial cells become “activated”, and among a plethora of morphological and immunological alterations, they are able to express the inducible nitric oxide synthase (iNOS), producing high levels of nitric oxide (NO).

NO is a multifaceted gaseous signaling molecule with several distinct functions in the central nervous system (CNS) [5]. This molecule is simultaneously involved in neuroprotection and in neurotoxicity, being also involved in inflammatory mechanisms in the CNS [6, 7]. NO was shown to modulate neurogenesis in the adult CNS as reviewed in [8]. In physiological conditions, NO tonically inhibits neurogenesis in the brain, while in pathophysiological conditions it exerts a proneurogenic effect on the dividing population of neuronal precursors. Moreover, the physiological effect of NO is mostly mediated by the neuronal nitric oxide synthase (nNOS), which is constitutively expressed, while pathophysiological levels of NO are attained following expression of iNOS [9–12]. Depending on the insult and on its source, NO can act as an antiproliferative agent [9–11] or stimulate neuronal precursor proliferation and differentiation [12]. However, the exact mechanisms by which NO regulates neuronal proliferation and differentiation are not yet clarified, and further investigation on this matter is needed. Since neuroinflammation is detrimental for adult neurogenesis, it would be of great interest to elucidate the role of inflammatory NO on the ongoing neurogenesis in these conditions. Therefore, the main goal of this paper is to elucidate the potential of the NO system modulation for the treatment of neurodegenerative diseases or other pathological conditions that may affect the CNS.

2. Neurogenesis following Brain Injury

Adult neurogenesis is implicated in many forms of plasticity in the CNS. The neurogenic process can be summarized in five main stages: (a) precursor cell proliferation, (b) fate determination, (c) migration, (d) differentiation and integration, and (e) survival.

Various models of injury in the rodent brain have been used to demonstrate that proliferation of stem cells is particularly enhanced in the SVZ and DG after an insult, which has been suggested to be a repair attempt from the lesioned brain, as reviewed in [13]. It has been observed that injury and pathological conditions affect adult neurogenesis, having a particular impact in neurogenic regions, but also in areas that are not normally considered as classical neurogenic regions, as discussed in [14, 15].

Regarding the type of insult to the brain, this may be acute, as ischemic brain stroke, traumatic brain injury or prolonged seizures, or a slow-progressing neurodegenerative disease. Neurogenesis decreases with aging and is impaired in several neurodegenerative disorders, such as Huntington’s disease [16, 17] or Alzheimer’s disease [18]. All these conditions are accompanied by an inflammatory response in the brain. However, the factors that attract neural progenitors to the lesioned areas are still under investigation. Another matter of hot debate is whether these new neurons are functionally integrated and survive in the existing neuronal circuitry.

3. Injury and Neuroinflammation

Inflammation is, by definition, a complex biological response to certain noxious stimuli such as stress, injury, or infection by external agents [19, 20]. After injury or exposure to pathogens, an inflammatory response takes place, with the involvement of two major groups of immune cells: (a) CNS resident microglial cells and astrocytes and (b) infiltrating lymphocytes, monocytes, and macrophages from the hematopoietic system [21, 22]. Therefore, the neuroinflammatory response attempts to protect the affected organism by removing harmful stimuli or removing dead and damaged cells, thereby initiating the healing process and return the tissue to homeostasis. When activated, immune cells release different regulating substances, such as complement molecules, cytokines-like interferon (IFN)-gamma, tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, IL-18 and IL-6, chemokines such as stromal-derived factor (SDF)-1alpha and monocytes chemoattractant protein-1 (MCP-1), glutamate, reactive oxygen species (ROSs), and reactive nitrogen species (RNSs) like NO, as extensively reviewed in [23]. These inflammatory mediators are responsible for the recruitment of resident microglia, stimulation of astrogliosis, but also for the disruption of the blood-brain barrier (BBB) and further recruitment of monocytes and lymphocytes from the hematopoietic system to the site of inflammation [24–26].

Although inflammation in the CNS should be considered as a process that seeks to protect, we also must take into account its harmful properties as reported in [27]. The activation of recruited cells to the site of inflammation leads to the release of inflammatory factors that contribute to create a positive feedback loop of inflammatory activation, resulting ultimately in neuronal loss and/or neuronal damage. Thus, the inflammatory response may have a dual effect on the cellular environment, beneficial and/or detrimental. The severity of neuroinflammation can range from mild acute to uncontrolled chronic inflammation, resulting in different activation states of inflammatory cells and distinct biological outcomes [28]. It is believed that neuroinflammation may be involved in the mechanisms that lead to various CNS diseases, also affecting the process by which new neurons are generated in the brain [29].

3.1. Neurodegeneration

Neurodegeneration is characterized by the slow progressive dysfunction and loss of neurons in the CNS. Immune activation within the CNS is a classical event following infections, ischemia, trauma, and neurodegenerative diseases. The inflammatory response often contributes to collateral CNS injury, which is characterized essentially by neuronal loss and atrophy in different brain regions. Neuronal susceptibility to cell death [30, 31] and concomitant failure in self-repair mechanisms [32], combined with inhibition of axonal growth and limited repopulation by neuronal precursor cells are singled out as the main causes for neurodegenerative events that follow brain inflammation [33, 34]. However, not all immune response in the CNS should be considered harmful, and in many cases they actually are an important aid for cell repair and regeneration. Particularly, microglial cells seem to play an important role in facilitating the reorganization of neuronal circuits and in triggering repair [35]. Thus, like inflammation, microglial activation also appears to play a dual role in neurodegeneration, acting either as detrimental or beneficial, as reported in [36].

The relationship between neuroinflammation and neurodegeneration is being studied in numerous models of CNS disorders such as Alzheimer’s and Parkinson’s disease, suggesting neuroinflammation as a critical process, if not the primary cause, for CNS lesions seen in these diseases, as extensively reviewed in [23, 37]. However, these studies also revealed complex neuroimmune interactions, both at cellular and molecular levels, thus demonstrating that immune cells secrete both neurotoxic and neuroprotective molecules [2]. Although different triggering events could occur, a common feature for the neurodegenerative event seems to be the chronic activation of microglial cells.

3.2. Neuroinflammation and Production of New Neurons

As mentioned in previous sections, neuroinflammation is a complex process with different outcomes in neurogenesis, which can be enhanced or suppressed [38]. Besides differences between mild acute and uncontrolled chronic inflammation, the shift from pro- to antineurogenic inflammatory status appears to be dependent on (a) the mechanism by which microglia, macrophages, and/or astrocytes are activated, (b) the type of inflammatory mediators released, and (c) for how long inflammatory cells, particularly microglia, are activated [36].

3.2.1. Impaired Formation of New Neurons

Inflammation and microglia activation were initially thought to inhibit adult neurogenesis [3, 4], while recent studies indicate that microglia can also support neurogenic events, as described in [39]. It was shown that lipopolysaccharide-(LPS-) induced activation of microglia impairs neurogenesis in rats [4], apparently through the increased production of TNF-alpha [40]. Additional evidences corroborating the detrimental effect of LPS-activated microglia was provided by another study, which showed that acute activation of microglia with LPS reduces NSC survival and neuronal differentiation [41]. Furthermore, suppression of microglial activation with an antibiotic, such as minocycline, was also used to demonstrate increased neurogenesis in the hippocampus, thus indicating that the severity of impaired neurogenesis correlates with the number of activated microglial cells [4]. Several other authors reported that the mechanism by which microglia exert these effects involves the release of proinflammatory mediators, such as IL-1, IL-6, IFN-gamma, and TNF-alpha, which seem to play an essential role in suppressing neurogenesis [42–45] (Table 1). It has also been suggested that ROS and RNS, particularly NO, can inhibit adult neurogenesis in inflammatory conditions [3, 46, 47]. In addition, several studies demonstrated that neurogenesis could be restored following treatment with anti-inflammatory drugs [3, 4, 48, 49]. Neurogenesis was restored after treatment with indomethacin, a nonsteroidal anti-inflammatory drug (NSAID), after irradiation-induced inflammation [3] or focal cerebral ischemia [49]. Other studies also reported an increased survival of newly generated neuroblasts in the striatum after stroke [49], or in the DG after middle cerebral artery occlusion (MCAO) [50] when the activation of microglia is inhibited by indomethacin or minocycline, respectively.

3.2.2. Enhancement of Neurogenesis

Contrary to what was initially thought that neuroinflammation is detrimental to adult neurogenesis, recent evidence indicates that under certain circumstances inflammation can also benefit the neurogenic process (Table 1). Apparently, neural stem cells become “activated” following brain injury and migrate into the lesioned areas, thus suggesting the inflammatory microenvironment as an important trigger for the migration of newborn cells [64, 65]. Microglia was reported to play a dual role on neurogenesis, suggesting neurogenesis inhibition to be caused by microglial activation under inflammatory conditions [53]. Other studies showed a persistent production of neurons from adult NSC, even after the inhibition of acute microglial activation, during recovery after stroke [66, 67]. Moreover, it was demonstrated that long-term survival of newborn neurons after status epilepticus (SE), with concomitant chronic activation of microglia [68]. In vitro studies have also showed an important role for microglia in directing the replacement of damaged or lost cells [52, 69–71]. LPS-activated microglia and inflammation increase the integration of newly generated neurons into the adult rat hippocampus [72]. More recently, long-term accumulation of activated microglia, although with a downregulated inflammatory profile, was shown to be concomitant with persistent neurogenesis in the adult SVZ after stroke [73]. Other inflammatory mediators have also been implicated in the improvement of migration and proliferation of new neurons following brain damage, such as SDF-1alpha and its receptor CXCR4 [62, 66] or trophic factors such as GDNF and BDNF, who are involved in the removal of damaged synapses [73]. In summary, all these studies suggest a neuroprotective role of microglia for newborns cells. Although microglia may have a detrimental action in early stages of the inflammatory response that follows acute insults, it could be converted into a protective state during chronic activation.

3.2.3. Dual Role of Inflammation in Neurogenesis

It is now widely accepted that microglia have a dual role in neurogenesis by favoring it or, alternatively, hindering neurogenesis. Apparently, microglial cells and the inflammatory factors they release, like NO (to be discussed below), seem to have opposite roles in neurogenesis under inflammatory conditions [38, 74]. However, it is important to reinforce the idea that inflammation, essentially characterized by activation of microglia, has distinct roles in various stages of neurogenesis, this effect being dependent on the degree of activation of immune cells, type of inflammatory mediator released, and duration of the inflammatory response [38]. Nevertheless, there are lines of evidence for some of the most important inflammatory mediators in the regulation of neurogenesis and/or neuroprotection [23, 75, 76].

As noted, further studies should be conducted to assess the interaction between neuroinflammation and neurogenesis, particularly how neuroinflammation modulates self-renewal, proliferation, migration, differentiation, integration in the neuronal network, and, more importantly, survival of newborn cells. As different authors have reported that chronic inflammation can stimulate one or more stages of neurogenesis, such as migration, proliferation, or differentiation, the problem remains in the reduced long-term survival of newborn neurons [23]. Moreover, since different microglial phenotypes and morphologies can be identified during inflammation, an extensive genetic and proteomic characterization will be of great interest to understand more accurately this complex crosstalk.

4. Nitric Oxide

Nitric oxide, a short-lived gaseous-free radical, is synthesized by the nitric oxide synthase (NOS) family of enzymes present in most of the cells of the body. NO is implicated in a wide range of physiological processes within the cardiovascular, immune, and nervous system, where it can act as a non-canonical neurotransmitter [77], but it can also be an important player in pathophysiological events. Different members of the NOS family control different functions of NO. The discovery of NO in the CNS was a breakthrough in the concept of neuronal communication. NO was characterized in the CNS for the first time as an intracellular messenger to increase cyclic guanosine 3′,5′-monophosphate (cGMP) levels, after the activation of glutamate receptors [78]. Later, the same authors also described NO as a neuromodulator, particularly due to its diffusible properties [79], thus acting not only in cells that release NO, but also in neighboring cells where it can therefore trigger its autocrine and/or paracrine functions. Unlike other neurotransmitters, NO is synthesized on demand, diffusing from nerve terminals since it is not stored in vesicles nor released by exocytosis [5]. In the CNS, NO is also associated with cognitive function, having an important role in synaptic plasticity, and controls biological functions, including body temperature, sleep-wake cycle, appetite, and modulation of hormone release, as reviewed in [7]. Another distinctive feature from classical neurotransmitters is that, unlike them, NO ends its action after reacting with a substrate and not by enzymatic degradation or reuptake. In addition, the key mechanism to regulate the activity of NO is the control of its synthesis.

Physiologically, NO interacts with several intracellular targets activating different signaling pathways with a stimulatory or inhibitory response. However, NO can also be toxic to cells, in a mechanism dependent on the formation of RNS [80, 81]. Oxidative stress and nitrosative stress, a consequence of high levels of NO and RNS, have been implicated in the pathogenesis of several neurodegenerative disorders [80, 82, 83], which will be explored in Section 4.2.

4.1. NO as an Inflammatory Mediator

The NOS family of enzymes is responsible for the synthesis of NO. Three different enzyme isoforms have been identified in mammalian cells: (a) neuronal NOS (nNOS, type I), which is constitutively expressed in brain neurons and is activated by calcium/calmodulin, particularly following stimulation of NMDA-type glutamate receptors; (b) endothelial NOS (eNOS, type III), constitutively expressed in endothelial cells and astrocytes and is regulated by calcium/calmodulin and phosphorylation/dephosphorylation; (c) inducible NOS (iNOS, type II) which is calcium-independent and its regulation depends on de novo synthesis [80, 84, 85]. iNOS is not normally expressed in the “healthy” brain but is induced in glial and endothelial cells by proinflammatory stimuli such as cytokines, bacterial/viral agents, and/or hypoxia [80]. iNOS is mainly expressed in macrophages, astrocytes, and microglial cells, upon neurotoxic, traumatic, and inflammatory damage [7, 84, 86, 87], but it could also be found in neurons [88, 89]. Once expressed, iNOS continuously produces high amounts of NO, even for several days [31, 87, 90–92]. The massive production of NO by iNOS is toxic, since it inactivates the mitochondrial respiratory chain enzymes that ultimately induce apoptosis in target cells. Moreover, NO has been described as an important activator of cyclooxygenase-II (COX-2) in glial cells, also regulating leukocyte adhesion in vessels [80]. The concentration achieved by NO seems to be a determining factor for the effects observed locally in the brain. Thus, in physiological concentrations, which are believed to range from 0.1 to 100 nM, NO is relatively nonreactive, and its actions are mainly mediated by binding to the heme group of soluble guanylate cyclase (sGC), leading to its activation and subsequent production of cGMP [93].

NO can also be converted into more reactive species commonly refereed as RNS. In high concentrations, NO reacts directly with oxygen () to produce nitrogen dioxide (), which in turn further reacts with NO originating dinitrogen trioxide (). In addition, may oxidize or nitrate, by adding a nitro () group to a great variety of molecules, being a classic example the nitration of tyrosine to 3-nitrotyrosine [94]. Moreover, NO reacts with superoxide () to produce peroxynitrite (), an extremely reactive molecule which can oxidize or nitrate other molecules or, instead, decay forming other damaging species, such as and/or the hydroxyl radical (). On the other hand, can add a nitrosonium ion () to thiols or amines, an event also designated as nitrosation/nitrosylation, being a good example cysteine than can be nitrosated to S-nitrosocysteine [94]. Both S-nitrosylation and nitration typically lead to alterations in protein function [94].

4.2. Neuronal Death

According to the literature, the role of NO in the brain could be summed up in two radically different outcomes: (a) as an intracellular signaling messenger, regulating a wide variety of physiological events, such as synaptic plasticity, blood flow, and neuronal development [95] and (b) as a cytotoxic agent killing indiscriminately both pathogenic and “healthy” host cells in disease [96, 97]. Strong evidence has been reported in the literature supporting a role of NO in the pathogenesis of neurodegenerative disorders, including autoimmune and chronic neurodegenerative diseases. As stated in previous sections, the role of NO seems to be dependent on the concentration attained locally in tissues. When produced in excess, NO shifts from a physiological to a neurotoxic effector. NO overproduction may be due to nNOS activation following persistent glutamate excitatory input and/or iNOS expression, upon an inflammatory response. Activated inflammatory cells generate increased levels of ROS such as superoxide, hydrogen peroxide, and hydroxyl radical. Moreover, NO can also induce the production of superoxide by mitochondria [7]. NO and superoxide readily react to form , an extremely reactive molecule [81].

Likewise, the excessive release of both glutamate and NO, coupled to oxidative stress and mitochondrial dysfunction, appears to be involved in the majority of neurodegenerative diseases. NO from inflammatory origin has been reported as an important contributing factor to the vulnerability of neurons, causing neuronal death both in vivo and in vitro in rodents [98, 99]. Some authors have suggested this neurotoxic effect as a consequence of enzymatic inhibition of the respiratory chain, resulting in hypoxia, excitotoxicity, and elevated levels of , as reviewed in [81]. Furthermore, the excessive NO release by glial cells leads to the formation of , which appears to be involved in the mechanisms of neuronal death, some of them linked to protein dysfunction due to nitration or s-nitrosylation [100]. Protein nitration is an irreversible chemical modification affecting tyrosine phosphorylation or dephosphorylation, which seriously affects several signaling pathways involved in the control of cell survival, proliferation, or programmed cell death, as reviewed in [101].

Although it has been implicated in acute injury events, particularly due to a massive release during an inflammatory response, NO has also been associated to slow progressive disorders that can be genetically inherited or sporadic. Parkinson’s disease, Alzheimer’s disease, Huntington’s disease, multiple sclerosis, and amyotrophic lateral sclerosis are all neurodegenerative disorders in which NO has been suggested to be involved, since all of them show evidence of oxidative and nitrosative stress [80, 102]. ROS and RNS are important factors in neuroinflammation-mediated neurotoxicity [103]. Furthermore, the presence of 3-nitrotyrosine has been reported in several neurodegenerative diseases linked to oxidative stress such as Alzheimer’s [104] or Parkinson’s disease [105]. Thus, understanding the involvement of NO in the etiology of these disorders may highlight an eventual beneficial potential role of selective NOS inhibitors.

4.3. Nitric Oxide and Neurogenesis

The role of NO as a modulator of neurogenesis is a matter of strong debate. Depending on the source, NO has a dual influence in the neurogenic process both by inhibiting or stimulating neurogenesis (Table 2).

The role of NO in neurogenesis has not been identified until recently [9, 10, 110]. The authors of these contributions had also described a cytostatic function of NO in the CNS, demonstrating that nNOS-derived NO is involved in the regulation of neurogenesis, particularly neural stem cell function [9, 10, 110]. Since blood vessels are part of the SVZ and dentate gyrus SGZ niches, which are also surrounded by differentiated neurons expressing nNOS, NO is produced in close proximity to NSCs. Several authors have described another function for NO in the rostral migratory stream (RMS), where SVZ-derived progenitor cells migrate into the olfactory bulb and differentiate into neurons [119]. These authors demonstrated that nitrergic neurons are in close vicinity to the RMS and that the NO generated regulates the migration and proliferation of progenitors that could also express nNOS [119]. Other groups have demonstrated NO production to be induced by neurotrophic factors, which in turn act in target cells inducing cell cycle arrest and/or exit favoring differentiation [111, 120, 121].

It should be noted here that the majority of the studies on the effect of NO in adult neurogenesis are focused mainly on the modulation of proliferation. In this context, the evaluation of survival rates of newly formed neurons is also important, since NO is known to be a regulator of apoptosis [118]. Several studies have shown that NO inhibits apoptosis by preventing increases in caspase-3 activity [122], which has been described to increase short-term survival of progenitor-cell progeny in the adult rat DG following SE [123].

Production of NO via nNOS has been demonstrated to have an important antiproliferative effect both in vitro and in vivo, but also as being involved in neuronal differentiation, survival, and synaptic plasticity [9, 10, 107, 113, 124]. It was shown that chronic nNOS inhibition enhances neurogenesis. Indeed, the selective inhibition of nNOS with 7-nitroindazole (7-NI) greatly increased cell proliferation in the SVZ, RMS, and OB, but not in the DG, in adult mice [10]. This antiproliferative effect of NO has been confirmed by others, that have shown that when NO production is inhibited either by using an intraventricular infusion of an NOS inhibitor in the rat brain or by using an nNOS-knockout mouse model, proliferation is greatly increased in the olfactory subependymal zone and in the DG [9, 108, 113, 125]. Moreover, the inhibitory role of nNOS-derived NO on SVZ and DG neurogenesis has also been demonstrated in the context of cerebral ischemia [126]. Other authors suggested NO to be a negative regulator of SVZ neurogenesis by modulating the activity of the EGF receptor [107], via nitrosylation of specific cysteine residues [127] (Table 3). Accordingly to these studies, the antiproliferative effect can be partially explained by the inhibition of the EGF receptor and the phosphoinositide-3-kinase (PI3-K)/Akt signaling pathway [107, 127]. Moreover, these authors described the antimitotic effect of NO to correlate with the nuclear presence of the cyclin-dependent kinase inhibitor [127].

On the contrary, by using pharmacological or genetic approaches, an opposite role has been found for NO synthesized by eNOS in the SVZ and iNOS in the DG following focal ischemia, which seems to stimulate neurogenesis [12, 128]. Moreover, increased immunoreactivity against iNOS following transient ischemia was shown to correlate with a decrease of nNOS in the hippocampus, which is concomitant with an increased neurogenesis [116, 129]. Numerous works showed that ischemia-induced neurogenesis in DG involves the activation of NMDA receptors [130], which is simultaneous to increased iNOS expression [131, 132] (Table 3). However, in a study regarding the effects of NO in cell proliferation, both nNOS- and iNOS-derived NO increases neurogenesis following seizures in the DG of adult rats [133]. Other authors reported that NO released under inflammatory conditions is involved in NSC differentiation into astrocytes by a mechanism dependent on the activation of the JAK/STAT-1 signal transduction pathway [112]. Recently we showed that supraphysiological levels of NO induce the proliferation of SVZ-derived neural stem cells through the activation of two signaling pathways, in a biphasic manner. Thus, the mitotic effect of NO is initially mediated by the direct activation of signaling pathway downstream of the EGF receptor, but bypassing the EGF receptor [74]. Downstream of the EGF receptor, there is an increased activation of the mitogen-activated protein (MAP) kinase ERK pathway following exposure to NO, which activates several downstream targets, namely p90RSK, and further decreases nuclear levels of , thus allowing cell cycle progression [74]. Furthermore, the proliferative effect of supraphysiological levels of NO, following longer periods of exposure (24 h), is mediated by increased signaling through the cGMP/cGMP-dependent kinase (PKG) pathway [115]. In addition, we also showed that NO from iNOS origin promotes proliferation of NSC in the hippocampus of adult mice following SE [74].

Altogether these findings illustrate that NO is a modulator of neurogenesis in diverse ways, and the different NO synthases are important players in this effect on neurogenesis [11, 139, 140]. NO effects on neurogenesis are dependent on the developmental period and source of NO (Table 3). Furthermore, NO can have concentration-dependent effects, depending on the local concentration and surrounding molecular environment. Apparently, under physiological conditions NO acts as a negative regulator of neurogenesis [9, 10, 110], while in inflammatory conditions a decrease in nNOS and increase in iNOS may act as a mechanism to enhance neurogenesis [12, 74, 107, 141, 142]. However, the exact molecular mechanisms underlying this dual effect of NO on neurogenesis, are not fully clarified and more studies need to be conducted.

5. Potential Neurogenic Targets in Nitrergic Pathways

Repair of damaged tissues and organs is essential for the survival of organisms. Although the CNS has pools of neural stem cells, these have a limited ability for repair and endogenous cell replacement. Some strategies have been studied over the past years to promote brain repair, particularly: (a) neural precursor or stem cell transplantation or (b) stimulation of endogenous neurogenesis. Moreover, excessive proliferation of NSCs associated with tumor formation is a major concern in the clinical application of both these strategies. Since most brain disorders that could benefit from enhanced neurogenesis are normally accompanied by neuroinflammation, understanding how the inflammatory response affects the neurogenic process is of major importance for the design of safe and efficient therapeutic strategies.

As discussed previously, NO was described to have a dual role on the regulation of adult neurogenesis. NO synthesized from nNOS appears to decrease neurogenesis or to act as an antiproliferative agent [9, 10, 107, 108, 110, 113, 127], whereas NO from iNOS and eNOS origin seems to stimulate neurogenesis [12, 74, 128, 142]. Taking this evidence into account, the modulation of the NO system may be a good target for the development of strategies to improve brain repair. Next, some of the most relevant therapeutic strategies for brain repair using the modulation of the nitrergic system will be discussed.

5.1. Nitric Oxide-Releasing Drugs

Nitric oxide-releasing drugs are pharmacologically active substances that release NO in vivo or in vitro. Two large groups of NO-releasing drugs can be found today: (a) NO donors and (b) NO-releasing nonsteroidal anti-inflammatory drugs. Although the clinical application of these drugs to improve brain repair seems remote, their potential application in the treatment of CNS disorders is a matter of great interest. Several studies have been carried out in order to understand how these drugs control neurogenesis. In fact, there seem to exist good reasons to believe that the use of these drugs may be advantageous in the treatment of brain disorders.

5.1.1. Nitric Oxide Donors

Nitric oxide-releasing compounds are clinically used for the treatment of patients with coronary heart disease [143]. Different types of NO-releasing agents have been developed and are commercially available, such as sodium nitroprusside (SNP), firstly described as a vasodilator, which is used to manage acute hypertensive crisis; or molsidomine, used in the therapy of angina pectoris and heart failure. SIN-1, another NO donor, is known as both NO and donor mainly because during NO release from SIN-1 superoxide is also generated [144, 145]. A wide range of NO-releasing drug classes have been developed recently. Among them are diazeniumdiolates, also known as NONOates (such as DEA/NO, SPER/NO, or DETA/NO) that release NO spontaneously under physiological conditions. Preclinical studies have shown a potential application for NONOate in cardiovascular disease, but further studies need to be conducted for their use in the clinic [145]. Chemically distinct NO donors differ in their half-life time and amounts of NO released in vitro. Moreover, depending on pH value, temperature, presence of cofactors, and light, the amount of NO released could be altered [144–146].

These compounds have also been useful to study physiological processes and molecular mechanisms in which NO is involved. NO was described to act as an antiproliferative agent in the CNS under physiological conditions, thus affecting neurogenesis [127]. Interestingly, in this work the authors described NO to be antiproliferative through the inhibition of the EGF receptor by S-nitrosylation [127]. Moreover, other authors have also described NO physiological levels to be antiproliferative in the brain [11, 107].

Numerous studies have used NO donors to investigate the effect of high concentrations of NO on neurogenesis, thus mimicking NO concentrations that can be achieved locally in the brain following an inflammatory response. Several groups reported nitric oxide-releasing drugs to enhance recovery after brain injury, partly by increasing neurogenesis in the DG and SVZ [147–150], following ischemic stroke [147, 151] and traumatic brain injury [148]. One study found that exogenous administration of NO using DETA/NO increases cell proliferation and survival in mice hippocampus [117]. We have shown that high concentrations of NO, which could be attained locally in the brain following an inflammatory response, have a dual effect on the proliferation of SVZ-derived NSCs [74, 115]. In fact, the effect of NO on the proliferation appears to be dependent on the period of exposure and concentration of NO achieved. Thus, a slight elevation on NO levels above the physiological range has a proliferative effect in an initial stage (1 day). On the contrary, continuous release of NO overtime (for 2 days) had an antiproliferative effect in SVZ-derived NSCs [74, 115]. This evidence is important to realize that controlling neuroinflammation, thus controlling NO production, will improve the outcome from the neurogenic process following brain injury. Other groups have shown that high concentrations of NO could also modulate other neurogenic stages, such as migration [136, 152] or differentiation [112].

In fact, the studies published in the literature about the effect of high levels of NO in neurogenesis, using NO donors, seem to bring contradictory evidence. However, it should be noted that in most of these works the NO donors used are chemically distinct and/or have distinct kinetics on NO release. Therefore, the evidence should be carefully interpreted to prevent misleading conclusions. Nevertheless, all these studies appear to be consensual on the following: NO is an important modulator of neurogenesis.

5.1.2. Nitric Oxide-Releasing Nonsteroidal Anti-Inflammatory Drugs

Nitric oxide-releasing nonsteroidal anti-inflammatory drugs (NO-NSAIDs) are a group of compounds with potential therapeutic applications in several clinical conditions. These drugs are synthesized by grafting a NO-donating moiety to classical NSAID, such as aspirin (NO-aspirin), flurbiprofen (NO-flurbiprofen), naproxen (NO-naproxen), diclofenac (NO-diclofenac), and ibuprofen (NO-ibuprofen) [143, 153, 154]. At present, NSAIDs are used for the treatment of a variety of inflammatory conditions. However, NSAIDs have a limited therapeutic application in chronic conditions, mainly due to their significant side effects in the gastrointestinal (GI) tract and kidneys. In the last decades, a great effort has been done to improve NSAID safety. Therefore, NO-NSAID may be considered as an important therapeutic attempt to overcome the side effects by NSAID. The release of NO from these drugs mimics the physiological production of NO by constitutive NOS, which appears to reduce the toxicity when compared to the parent NSAID [153, 155]. Moreover, this modification strongly reduces the side effects of NSAID, without affecting the anti-inflammatory effectiveness [153].

Since NSAIDs are primarily used as anti-inflammatory drugs, many of the studies with NO-NSAID have been essentially about its anti-inflammatory effects. Numerous studies in the literature have reported the anti-inflammatory effect of NO-NSAID in animal models of acute or chronic inflammation. More recently, there has been increasing concern about the potential application of these drugs in CNS disorders, particularly in neurodegenerative diseases, such as Alzheimer’s disease. Numerous reports suggested NO-NSAID to be a suitable approach for the treatment of Alzheimer’s disease, since they are less toxic to the GI tract than NSAID following chronic ingestion. Moreover, NO-NSAID also inhibit caspase activity thus protecting neurons against cytokine-induced apoptosis during Alzheimer’s disease [153]. As reported by Hauss-Wegrzyniak and coworkers, chronic ingestion of NO-flurbiprofen reduced the activity state of microglial cells in a rat model of Alzheimer’s disease, when comparing to animals treated with aspirin [156]. Other authors also described NO-flurbiprofen to reduce brain beta-amyloid in a mice model of Alzheimer’s disease, which was associated with activation of microglial cells, the presumed responsible for clearing beta-amyloid deposits [157]. Interestingly, these authors reported NO-aspirin to be more efficacious than ibuprofen or celecoxib, a selective COX-2 inhibitor [157]. The neuroprotective effect of different NO-NSAID has additionally been described in other animal models of brain damage. Treatment with NO-aspirin was shown to be more neuroprotective than aspirin, following MCAO [158]. In fact, the results from these experiments are of great interest since they strongly suggest that NO release is determinant for the protective action of NO-aspirin in this animal model. Although the mechanism underlying this effect is still unclear, NO improved blood flow to the ischemic region, thereby reducing the lesioned area. Moreover, the ability of NO-NSAID to inhibit caspase activity is also important for this effect [159].

Given the ability of NSAID in crossing the BBB [160], the use of NO-NSAID in the treatment of CNS disorders can be a very useful tool, in particular for the control of neuroinflammation that, as noted above, may affect neurogenesis [155]. Therefore, it is important to conduct more studies to understand the mechanisms and levels within which NO released by NO-NSAID may promote neurogenesis.

5.2. PDE Inhibitors

The main cellular signaling pathway stimulated by NO is the activation of sGC, subsequent production of cGMP, and further activation of protein kinases that regulate various physiological events [161]. Neurons synthesize cGMP in response to NO by activation of sGC, a heterodimeric heme-containing enzyme. NO reacts with the heme group of the sGC, which undergoes a conformational change, converting GTP into the second messenger cGMP [93, 162]. Some studies suggest that NO can also downregulate sGC activity, particularly in neuroinflammatory conditions [163]. cGMP-dependent kinases, which are serine/threonine kinases, are activated by cGMP and are involved in several physiological phenomena including long-term potentiation in the hippocampus and long-term depression in the cerebellum [93, 162]. In physiological conditions, intracellular cGMP levels are controlled by cyclic nucleotide phosphodiesterases (PDEs) [94]. PDEs are enzymes that hydrolyze the 3′-phosphodiester bound of cyclic adenosine monophosphate (cAMP) or cGMP, originating their corresponding monophosphates, 5′-AMP or 5′-GMP, respectively. cGMP-related physiological functions can be regulated by controlling the levels of PDE type 5 (PDE5) enzymes, which specifically hydrolyze cGMP. Moreover, cGMP also modulates the activity of PDE [164].

The use of selective PDE inhibitors has been proven to be useful in the clinic, particularly PDE5 inhibitors, which are drugs used to treat erectile dysfunction and pulmonary arterial hypertension [164–166]. Sildenafil, commercially available as Viagra, is classically considered as a PDE5 inhibitor; however, it also inhibits PDE1 and PDE6 [166–168]. Similarly to sildenafil, two other inhibitors with higher selectivity for PDE5 were developed for the treatment of erectile dysfunction: tadalafil (Cialis) and vardenafil (Levitra). More recently, a new compound was developed, T0156, which potently inhibits PDE5 [169]. In fact, T0156 inhibits PDE5 with higher potency than sildenafil also presenting higher selectivity for PDE5 in comparison to PDE6 [169]. In erectile dysfunction, PDE5 inhibition enhances relaxation of the cavernosal smooth muscle by NO and cGMP, thus allowing blood flow and stimulating penile erection [170, 171]. In the lung, PDE5 inhibitors act as vasodilators, increasing blood supply, antagonizing the vasoconstriction of smooth muscle, and decreasing pulmonary arterial resistance, thus treating pulmonary hypertension (for comprehensive review see [172–174]).

In the CNS, neurogenesis generally declines with aging and is correlated with the emergence of neurodegenerative diseases. Moreover, the levels of NO gradually decrease in aging, which is concomitant with a decrease in cGMP levels. As demonstrated in aged rats, cGMP levels are decreased as a consequence of the increasing phosphodiesterase activity when compared to young adult rats [175]. Several authors described NO and cGMP to be important effectors in the regulation of different events related with the neurogenic process, particularly proliferation, migration, differentiation, growth, axon guidance, and cell survival [115, 136, 152, 176, 177]. Furthermore, brain PDE5 was reported to have a role in learning and memory, physiological events that are closely dependent on neurogenesis. Therefore, targeting PDE5 activity as a strategy to reverse the deleterious effects on neurogenesis, and thus enhancing it, seems to be a promising strategy to be applied in clinic. However it should be noted that the use of PDE5 inhibitors as an effective therapy for neurodegenerative diseases is dependent on their permeability to the BBB. For instance, sildenafil is known to cross the BBB and can be easily administered.

The administration of PDE5 inhibitors as a possible therapy for Alzheimer’s disease has been studied, due to their ability to reverse deficits in long-term memory caused by pharmacological agents or aging. Different authors have described that the administration of sildenafil enhances memory and restores learning ability in animal models [178–184]. Beyond this important role, PDE5 inhibitors appear to stimulate neuronal plasticity, particularly through the enhancement of endogenous neurogenesis in the adult brain. In addition, the administration of PDE5 inhibitors, such as sildenafil, but also tadalafil, positively affected neurogenesis in the OB, SVZ, and the DG of rats by a mechanism involving the intracellular increase of cGMP levels [185–187]. Moreover, the administration of PDE5 inhibitors has also been associated to neuronal function recovery in rats following a stroke [188] or after ischemic injury either in young adult rats as in aged rats [187, 189]. Furthermore, PDE5 inhibition by sildenafil stimulated cell proliferation in rat SVZ cultures [190]. In a recent report, it was shown that sildenafil has a neuroprotective role, improving the clinical symptoms and neuropathology in a mouse model of multiple sclerosis, thus suggesting PDE5 as an important target for the therapy of this disease [151].

In summary, this evidence supports the idea that the use of PDE5 inhibitors merits further investigation in order to clarify their involvement on neurogenesis, but also to understand the mechanisms underlying these effects.

6. Future Prospects

Stimulation of endogenous adult neurogenesis and modulation of injury-induced neurogenesis is presently being considered as a potential therapeutic approach for neuronal repair in neurodegenerative disorders, as opposed to the more invasive approach of transplantation of exogenous stem cells. Understanding how the inflammatory response affects neurogenesis is fundamental to better design therapeutic strategies for safe and efficient regulation of endogenous neurogenesis. Therefore, the knowledge of the inflammatory agents that modulate proliferation and/or differentiation of NSCs is of great usefulness if its action could be correctly targeted and controlled, for instance, with selective drugs for the agent of interest.

Nitric oxide, which acts as a nonspecific cytotoxic mediator and a biological messenger, in immunological response, has been attracting increasing importance from pharmaceutical companies. Indeed, several nonsteroidal anti-inflammatory NO-releasing drugs (NO-NSAID) are currently under investigation and were shown to be beneficial in models of several neurodegenerative conditions accompanied by inflammation [153, 191]. As an alternative to conventional NSAIDs with significant side effects, pharmacologically improved and therapeutically enhanced NO releasing nonsteroidal anti-inflammatory drugs with less side effects are being developed as reviewed in [192]. Moreover, besides the clinical applications of PDE5 inhibitors, they appear to be a good strategy for the treatment of certain CNS disorders and further improve neurogenesis. These drugs have already been shown to be important modulators of the nitrergic system, preventing neurodegeneration and favoring neurogenesis.

In light of these facts, the modulation of the NO system seems to be a good target for the development of strategies to improve brain repair. However, despite all good evidence that drugs that modulate the NO system have given, further studies are necessary. In fact, a full understanding of how inflammation affects neurogenesis is essential to the development of therapeutic strategies that can induce neurogenesis from endogenous neural precursor cells, and further investigation needs to be conducted to better understand the mechanisms underlying the effect of neuroinflammation in cellular regeneration in the diseased brain.

Acknowledgments

This work was supported by the Foundation for Science and Technology, (FCT, Portugal), COMPETE and FEDER (project PTDC/SAU-NEU/102612/2008). B. P. Carreira is supported by FCT (fellowship SFRH/BPD/78901/2011).

References

H. Suh, W. Deng, and F. H. Gage, “Signaling in adult neurogenesis,” Annual Review of Cell and Developmental Biology, vol. 25, pp. 253–275, 2009.
View at: Publisher Site | Google Scholar
S. Amor, F. Puentes, D. Baker, and P. Van Der Valk, “Inflammation in neurodegenerative diseases,” Immunology, vol. 129, no. 2, pp. 154–169, 2010.
View at: Publisher Site | Google Scholar
M. L. Monje, H. Toda, and T. D. Palmer, “Inflammatory blockade restores adult hippocampal neurogenesis,” Science, vol. 302, no. 5651, pp. 1760–1765, 2003.
View at: Publisher Site | Google Scholar
C. T. Ekdahl, J. H. Claasen, S. Bonde, Z. Kokaia, and O. Lindvall, “Inflammation is detrimental for neurogenesis in adult brain,” Proceedings of the National Academy of Sciences of the United States of America, vol. 100, no. 23, pp. 13632–13637, 2003.
View at: Publisher Site | Google Scholar
S. Moncada and J. P. Bolaños, “Nitric oxide, cell bioenergetics and neurodegeneration,” Journal of Neurochemistry, vol. 97, no. 6, pp. 1676–1689, 2006.
View at: Publisher Site | Google Scholar
B. Liu, H. M. Gao, J. Y. Wang, G. H. Jeohn, C. L. Cooper, and J. S. Hong, “Role of nitric oxide in inflammation-mediated neurodegeneration,” Annals of the New York Academy of Sciences, vol. 962, pp. 318–331, 2002.
View at: Google Scholar
V. Calabrese, C. Mancuso, M. Calvani, E. Rizzarelli, D. A. Butterfield, and A. M. Stella, “Nitric oxide in the central nervous system: neuroprotection versus neurotoxicity,” Nature Reviews Neuroscience, vol. 8, no. 10, pp. 766–775, 2007.
View at: Publisher Site | Google Scholar
A. Contestabile and E. Ciani, “Role of nitric oxide in the regulation of neuronal proliferation, survival and differentiation,” Neurochemistry International, vol. 45, no. 6, pp. 903–914, 2004.
View at: Publisher Site | Google Scholar
M. A. Packer, Y. Stasiv, A. Benraiss et al., “Nitric oxide negatively regulates mammalian adult neurogenesis,” Proceedings of the National Academy of Sciences of the United States of America, vol. 100, no. 16, pp. 9566–9571, 2003.
View at: Publisher Site | Google Scholar
B. Moreno-López, C. Romero-Grimaldi, J. A. Noval, M. Murillo-Carretero, E. R. Matarredona, and C. Estrada, “Nitric oxide is a physiological inhibitor of neurogenesis in the adult mouse subventricular zone and olfactory bulb,” Journal of Neuroscience, vol. 24, no. 1, pp. 85–95, 2004.
View at: Publisher Site | Google Scholar
E. R. Matarredona, M. Murillo-Carretero, B. Moreno-López, and C. Estrada, “Role of nitric oxide in subventricular zone neurogenesis,” Brain Research Reviews, vol. 49, no. 2, pp. 355–366, 2005.
View at: Publisher Site | Google Scholar
D. Y. Zhu, S. H. Liu, H. S. Sun, and Y. M. Lu, “Expression of inducible nitric oxide synthase after focal cerebral ischemia stimulates neurogenesis in the adult rodent dentate gyrus,” Journal of Neuroscience, vol. 23, no. 1, pp. 223–229, 2003.
View at: Google Scholar
D. H. Lowenstein and J. M. Parent, “Brain, heal thyself,” Science, vol. 283, no. 5405, pp. 1126–1127, 1999.
View at: Publisher Site | Google Scholar
G. L. Ming and H. Song, “Adult neurogenesis in the mammalian central nervous system,” Annual Review of Neuroscience, vol. 28, pp. 223–250, 2005.
View at: Publisher Site | Google Scholar
G. L. Ming and H. Song, “Adult neurogenesis in the mammalian brain: significant answers and significant questions,” Neuron, vol. 70, no. 4, pp. 687–702, 2011.
View at: Publisher Site | Google Scholar
J. M. A. C. Gil, P. Mohapel, I. M. Araújo et al., “Reduced hippocampal neurogenesis in R6/2 transgenic Huntington's disease mice,” Neurobiology of Disease, vol. 20, no. 3, pp. 744–751, 2005.
View at: Publisher Site | Google Scholar
S. E. Lazic, H. Grote, R. J. E. Armstrong et al., “Decreased hippocampal cell proliferation in R6/I Huntington's mice,” NeuroReport, vol. 15, no. 5, pp. 811–813, 2004.
View at: Publisher Site | Google Scholar
Y. Tatebayashi, M. H. Lee, L. Li, K. Iqbal, and I. Grundke-Iqbal, “The dentate gyrus neurogenesis: a therapeutic target for Alzheimer's disease,” Acta Neuropathologica, vol. 105, no. 3, pp. 225–232, 2003.
View at: Google Scholar
P. Nencini, C. Sarti, R. Innocenti, G. Pracucci, and D. Inzitari, “Acute inflammatory events and ischemic stroke subtypes,” Cerebrovascular Diseases, vol. 15, no. 3, pp. 215–221, 2003.
View at: Publisher Site | Google Scholar
O. I. Schmidt, C. E. Heyde, W. Ertel, and P. F. Stahel, “Closed head injury—an inflammatory disease?” Brain Research Reviews, vol. 48, no. 2, pp. 388–399, 2005.
View at: Publisher Site | Google Scholar
G. Stollg and S. Jander, “The role of microglia and macrophages in the pathophysiology of the CNS,” Progress in Neurobiology, vol. 58, no. 3, pp. 233–247, 1999.
View at: Publisher Site | Google Scholar
W. J. Streit, S. A. Walter, and N. A. Pennell, “Reactive microgliosis,” Progress in Neurobiology, vol. 57, no. 6, pp. 563–581, 1999.
View at: Publisher Site | Google Scholar
N. P. Whitney, T. M. Eidem, H. Peng, Y. Huang, and J. C. Zheng, “Inflammation mediates varying effects in neurogenesis: relevance to the pathogenesis of brain injury and neurodegenerative disorders,” Journal of Neurochemistry, vol. 108, no. 6, pp. 1343–1359, 2009.
View at: Publisher Site | Google Scholar
W. F. Hickey, “Leukocyte traffic in the central nervous system: the participants and their roles,” Seminars in Immunology, vol. 11, no. 2, pp. 125–137, 1999.
View at: Publisher Site | Google Scholar
P. Taupin, “Adult neurogenesis, neuroinflammation and therapeutic potential of adult neural stem cells,” International Journal of Medical Sciences, vol. 5, no. 3, pp. 127–132, 2008.
View at: Google Scholar
A. S. Lossinsky and R. R. Shivers, “Structural pathways for macromolecular and cellular transport across the blood-brain barrier during inflammatory conditions. Review,” Histology and Histopathology, vol. 19, no. 2, pp. 535–564, 2004.
View at: Google Scholar
T. Wyss-Coray and L. Mucke, “Inflammation in neurodegenerative disease—a double-edged sword,” Neuron, vol. 35, no. 3, pp. 419–432, 2002.
View at: Publisher Site | Google Scholar
G. Stoll, S. Jander, and M. Schroeter, “Detrimental and beneficial effects of injury-induced inflammation and cytokine expression in the nervous system,” Advances in Experimental Medicine and Biology, vol. 513, pp. 87–113, 2002.
View at: Google Scholar
S. Das and A. Basu, “Inflammation: a new candidate in modulating adult neurogenesis,” Journal of Neuroscience Research, vol. 86, no. 6, pp. 1199–1208, 2008.
View at: Publisher Site | Google Scholar
K. M. Boje and P. K. Arora, “Microglial-produced nitric oxide and reactive nitrogen oxides mediate neuronal cell death,” Brain Research, vol. 587, no. 2, pp. 250–256, 1992.
View at: Publisher Site | Google Scholar
C. C. Chao, S. Hu, T. W. Molitor, E. G. Shaskan, and P. K. Peterson, “Activated microglia mediate neuronal cell injury via a nitric oxide mechanism,” Journal of Immunology, vol. 149, no. 8, pp. 2736–2741, 1992.
View at: Google Scholar
A. Björklund and O. Lindvall, “Self-repair in the brain,” Nature, vol. 405, no. 6789, pp. 892–895, 2000.
View at: Publisher Site | Google Scholar
J. L. Goldberg and B. A. Barres, “The relationship between neuronal survival and regeneration,” Annual Review of Neuroscience, vol. 23, pp. 579–612, 2000.
View at: Publisher Site | Google Scholar
A. E. Fournier and S. M. Strittmatter, “Regenerating nerves follow the road more traveled,” Nature Neuroscience, vol. 5, no. 9, pp. 821–822, 2002.
View at: Publisher Site | Google Scholar
H. Neumann, M. R. Kotter, and R. J. M. Franklin, “Debris clearance by microglia: an essential link between degeneration and regeneration,” Brain, vol. 132, no. 2, pp. 288–295, 2009.
View at: Publisher Site | Google Scholar
C. T. Ekdahl, Z. Kokaia, and O. Lindvall, “Brain inflammation and adult neurogenesis: the dual role of microglia,” Neuroscience, vol. 158, no. 3, pp. 1021–1029, 2009.
View at: Publisher Site | Google Scholar
S. Lehnardt, “Innate immunity and neuroinflammation in the CNS: the role of microglia in toll-like receptor-mediated neuronal injury,” GLIA, vol. 58, no. 3, pp. 253–263, 2010.
View at: Publisher Site | Google Scholar
C. T. Ekdahl, “Microglial activation—tuning and pruning adult neurogenesis,” Front Pharmacol, vol. 3, article 41, 2012.
View at: Google Scholar
U. K. Hanisch and H. Kettenmann, “Microglia: active sensor and versatile effector cells in the normal and pathologic brain,” Nature Neuroscience, vol. 10, no. 11, pp. 1387–1394, 2007.
View at: Publisher Site | Google Scholar
Y. P. Liu, H. I. Lin, and S. F. Tzeng, “Tumor necrosis factor-α and interleukin-18 modulate neuronal cell fate in embryonic neural progenitor culture,” Brain Research, vol. 1054, no. 2, pp. 152–158, 2005.
View at: Publisher Site | Google Scholar
E. Cacci, M. A. Ajmone-Cat, T. Anelli, S. Biagioni, and L. Minghetti, “In vitro neuronal and glial differentiation from embryonic or adult neural precursor cells are differently affected by chronic or acute activation of microglia,” GLIA, vol. 56, no. 4, pp. 412–425, 2008.
View at: Publisher Site | Google Scholar
T. Ben-Hur, O. Ben-Menachem, V. Furer, O. Einstein, R. Mizrachi-Kol, and N. Grigoriadis, “Effects of proinflammatory cytokines on the growth, fate, and motility of multipotential neural precursor cells,” Molecular and Cellular Neuroscience, vol. 24, no. 3, pp. 623–631, 2003.
View at: Publisher Site | Google Scholar
E. Cacci, J. H. Claasen, and Z. Kokaia, “Microglia-derived tumor necrosis factor-α exaggerates death of newborn hippocampal progenitor cells in vitro,” Journal of Neuroscience Research, vol. 80, no. 6, pp. 789–797, 2005.
View at: Publisher Site | Google Scholar
R. E. Iosif, C. T. Ekdahl, H. Ahlenius et al., “Tumor necrosis factor receptor 1 is a negative regulator of progenitor proliferation in adult hippocampal neurogenesis,” Journal of Neuroscience, vol. 26, no. 38, pp. 9703–9712, 2006.
View at: Publisher Site | Google Scholar
J. W. Koo and R. S. Duman, “IL-1β is an essential mediator of the antineurogenic and anhedonic effects of stress,” Proceedings of the National Academy of Sciences of the United States of America, vol. 105, no. 2, pp. 751–756, 2008.
View at: Publisher Site | Google Scholar
L. Valliéres, I. L. Campbell, F. H. Gage, and P. E. Sawchenko, “Reduced hippocampal neurogenesis in adult transgenic mice with chronic astrocytic production of interleukin-6,” Journal of Neuroscience, vol. 22, no. 2, pp. 486–492, 2002.
View at: Google Scholar
B. F. Liu, E. J. Gao, X. Z. Zeng et al., “Proliferation of neural precursors in the subventricular zone after chemical lesions of the nigrostriatal pathway in rat brain,” Brain Research, vol. 1106, no. 1, pp. 30–39, 2006.
View at: Publisher Site | Google Scholar
A. R. Simard and S. Rivest, “Role of inflammation in the neurobiology of stem cells,” NeuroReport, vol. 15, no. 15, pp. 2305–2310, 2004.
View at: Publisher Site | Google Scholar
B. D. Hoehn, T. D. Palmer, and G. K. Steinberg, “Neurogenesis in rats after focal cerebral ischemia is enhanced by indomethacin,” Stroke, vol. 36, no. 12, pp. 2718–2724, 2005.
View at: Publisher Site | Google Scholar
Z. Liu, Y. Fan, S. J. Won et al., “Chronic treatment with minocycline preserves adult new neurons and reduces functional impairment after focal cerebral ischemia,” Stroke, vol. 38, no. 1, pp. 146–152, 2007.
View at: Publisher Site | Google Scholar
X. Wang, S. Fu, Y. Wang et al., “Interleukin-1β mediates proliferation and differentiation of multipotent neural precursor cells through the activation of SAPK/JNK pathway,” Molecular and Cellular Neuroscience, vol. 36, no. 3, pp. 343–354, 2007.
View at: Publisher Site | Google Scholar
M. Nakanishi, T. Niidome, S. Matsuda, A. Akaike, T. Kihara, and H. Sugimoto, “Microglia-derived interleukin-6 and leukaemia inhibitory factor promote astrocytic differentiation of neural stem/progenitor cells,” European Journal of Neuroscience, vol. 25, no. 3, pp. 649–658, 2007.
View at: Publisher Site | Google Scholar
O. Butovsky, Y. Ziv, A. Schwartz et al., “Microglia activated by IL-4 or IFN-γ differentially induce neurogenesis and oligodendrogenesis from adult stem/progenitor cells,” Molecular and Cellular Neuroscience, vol. 31, no. 1, pp. 149–160, 2006.
View at: Publisher Site | Google Scholar
G. Wong, Y. Goldshmit, and A. M. Turnley, “Interferon-γ but not TNFα promotes neuronal differentiation and neurite outgrowth of murine adult neural stem cells,” Experimental Neurology, vol. 187, no. 1, pp. 171–177, 2004.
View at: Publisher Site | Google Scholar
J. H. Song, X. W. Chen, D. K. Song, P. Wang, A. Shuaib, and C. Hao, “Interferon γ induces neurite outgrowth by up-regulation of p35 neuron-specific cyclin-dependent kinase 5 activator via activation of ERK1/2 pathway,” Journal of Biological Chemistry, vol. 280, no. 13, pp. 12896–12901, 2005.
View at: Publisher Site | Google Scholar
R. Baron, A. Nemirovsky, I. Harpaz, H. Cohen, T. Owens, and A. Monsonego, “IFN-γ enhances neurogenesis in wild-type mice and in a mouse model of Alzheimer's disease,” FASEB Journal, vol. 22, no. 8, pp. 2843–2852, 2008.
View at: Publisher Site | Google Scholar
D. Widera, I. Mikenberg, M. Elvers, C. Kaltschmidt, and B. Kaltschmidt, “Tumor necrosis factor α triggers proliferation of adult neural stem cells via IKK/NF-κB signaling,” BMC Neuroscience, vol. 7, article 64, 2006.
View at: Publisher Site | Google Scholar
J. P. Wu, J. S. Kuo, Y. L. Liu, and S. F. Tzeng, “Tumor necrosis factor-alpha modulates the proliferation of neural progenitors in the subventricular/ventricular zone of adult rat brain,” Neuroscience Letters, vol. 292, no. 3, pp. 203–206, 2000.
View at: Publisher Site | Google Scholar
R. E. Iosif, H. Ahlenius, C. T. Ekdahl et al., “Suppression of stroke-induced progenitor proliferation in adult subventricular zone by tumor necrosis factor receptor 1,” Journal of Cerebral Blood Flow and Metabolism, vol. 28, no. 9, pp. 1574–1587, 2008.
View at: Publisher Site | Google Scholar
U. Heldmann, P. Thored, J. H. Claasen, A. Arvidsson, Z. Kokaia, and O. Lindvall, “TNF-α antibody infusion impairs survival of stroke-generated neuroblasts in adult rat brain,” Experimental Neurology, vol. 196, no. 1, pp. 204–208, 2005.
View at: Publisher Site | Google Scholar
L. Bernardino, F. Agasse, B. Silva, R. Ferreira, S. Grade, and J. O. Malva, “Tumor necrosis factor-α modulates survival, proliferation, and neuronal differentiation in neonatal subventricular zone cell cultures,” Stem Cells, vol. 26, no. 9, pp. 2361–2371, 2008.
View at: Publisher Site | Google Scholar
J. Imitola, K. Raddassi, K. I. Park et al., “Directed migration of neural stem cells to sites of CNS injury by the stromal cell-derived factor 1α/CXC chemokine receptor 4 pathway,” Proceedings of the National Academy of Sciences of the United States of America, vol. 101, no. 52, pp. 18117–18122, 2004.
View at: Publisher Site | Google Scholar
H. Peng, R. Kolb, J. E. Kennedy, and J. Zheng, “Differential expression of CXCL12 and CXCR4 during human fetal neural progenitor cell differentiation,” Journal of Neuroimmune Pharmacology, vol. 2, no. 3, pp. 251–258, 2007.
View at: Publisher Site | Google Scholar
A. Arvidsson, T. Collin, D. Kirik, Z. Kokaia, and O. Lindvall, “Neuronal replacement from endogenous precursors in the adult brain after stroke,” Nature Medicine, vol. 8, no. 9, pp. 963–970, 2002.
View at: Publisher Site | Google Scholar
H. Nakatomi, T. Kuriu, S. Okabe et al., “Regeneration of hippocampal pyramidal neurons after ischemic brain injury by recruitment of endogenous neural progenitors,” Cell, vol. 110, no. 4, pp. 429–441, 2002.
View at: Publisher Site | Google Scholar
P. Thored, A. Arvidsson, E. Cacci et al., “Persistent production of neurons from adult brain stem cells during recovery after stroke,” Stem Cells, vol. 24, no. 3, pp. 739–747, 2006.
View at: Publisher Site | Google Scholar
Z. Kokaia, P. Thored, A. Arvidsson, and O. Lindvall, “Regulation of stroke-induced neurogenesis in adult brain—recent scientific progress,” Cerebral Cortex, vol. 16, supplement 1, pp. i162–i167, 2006.
View at: Google Scholar
S. Bonde, C. T. Ekdahl, and O. Lindvall, “Long-term neuronal replacement in adult rat hippocampus after status epilepticus despite chronic inflammation,” European Journal of Neuroscience, vol. 23, no. 4, pp. 965–974, 2006.
View at: Publisher Site | Google Scholar
J. Aarum, K. Sandberg, S. L. B. Haeberlein, and M. A. A. Persson, “Migration and differentiation of neural precursor cells can be directed by microglia,” Proceedings of the National Academy of Sciences of the United States of America, vol. 100, no. 26, pp. 15983–15988, 2003.
View at: Publisher Site | Google Scholar
S. C. Morgan, D. L. Taylor, and J. M. Pocock, “Microglia release activators of neuronal proliferation mediated by activation of mitogen-activated protein kinase, phosphatidylinositol-3-kinase/Akt and delta-Notch signalling cascades,” Journal of Neurochemistry, vol. 90, no. 1, pp. 89–101, 2004.
View at: Publisher Site | Google Scholar
N. M. Walton, B. M. Sutter, E. D. Laywell et al., “Microglia instruct subventricular zone neurogenesis,” GLIA, vol. 54, no. 8, pp. 815–825, 2006.
View at: Publisher Site | Google Scholar
K. Jakubs, S. Bonde, R. E. Iosif et al., “Inflammation regulates functional integration of neurons born in adult brain,” Journal of Neuroscience, vol. 28, no. 47, pp. 12477–12488, 2008.
View at: Publisher Site | Google Scholar
P. Thored, U. Heldmann, W. Gomes-Leal et al., “Long-term accumulation of microglia with proneurogenic phenotype concomitant with persistent neurogenesis in adult subventricular zone after stroke,” GLIA, vol. 57, no. 8, pp. 835–849, 2009.
View at: Publisher Site | Google Scholar
B. P. Carreira, M. I. Morte, A. Inacio et al., “Nitric oxide stimulates the proliferation of neural stem cells bypassing the epidermal growth factor receptor,” Stem Cells, vol. 28, no. 7, pp. 1219–1230, 2010.
View at: Publisher Site | Google Scholar
O. Gonzalez-Perez, F. Jauregui-Huerta, and A. Y. Galvez-Contreras, “Immune system modulates the function of adult neural stem cells,” Current Immunology Reviews, vol. 6, no. 3, pp. 167–173, 2010.
View at: Publisher Site | Google Scholar
O. Gonzalez-Perez, A. Quiñones-Hinojosa, and J. M. Garcia-Verdugo, “Immunological control of adult neural stem cells,” Journal of Stem Cells, vol. 5, no. 1, pp. 23–31, 2010.
View at: Google Scholar
W. K. Alderton, C. E. Cooper, and R. G. Knowles, “Nitric oxide synthases: structure, function and inhibition,” Biochemical Journal, vol. 357, no. 3, pp. 593–615, 2001.
View at: Publisher Site | Google Scholar
J. Garthwaite, S. L. Charles, and R. Chess-Williams, “Endothelium-derived relaxing factor release on activation of NMDA receptors suggests role as intercellular messenger in the brain,” Nature, vol. 336, no. 6197, pp. 385–388, 1988.
View at: Google Scholar
J. Garthwaite and C. L. Boulton, “Nitric oxide signaling in the central nervous system,” Annual Review of Physiology, vol. 57, pp. 683–706, 1995.
View at: Google Scholar
F. X. Guix, I. Uribesalgo, M. Coma, and F. J. Muñoz, “The physiology and pathophysiology of nitric oxide in the brain,” Progress in Neurobiology, vol. 76, no. 2, pp. 126–152, 2005.
View at: Publisher Site | Google Scholar
P. Pacher, J. S. Beckman, and L. Liaudet, “Nitric oxide and peroxynitrite in health and disease,” Physiological Reviews, vol. 87, no. 1, pp. 315–424, 2007.
View at: Publisher Site | Google Scholar
R. Sultana, H. F. Poon, J. Cai et al., “Identification of nitrated proteins in Alzheimer's disease brain using a redox proteomics approach,” Neurobiology of Disease, vol. 22, no. 1, pp. 76–87, 2006.
View at: Publisher Site | Google Scholar
R. Sultana, T. Reed, M. Perluigi, R. Coccia, W. M. Pierce, and D. A. Butterfield, “Proteomic identification of nitrated brain proteins in amnestic mild cognitive impairment: a regional study,” Journal of Cellular and Molecular Medicine, vol. 11, no. 4, pp. 839–851, 2007.
View at: Publisher Site | Google Scholar
D. S. Bredt, “Endogenous nitric oxide synthesis: biological functions and pathophysiology,” Free Radical Research, vol. 31, no. 6, pp. 577–596, 1999.
View at: Google Scholar
T. M. Dawson and S. H. Snyder, “Gases as biological messengers: nitric oxide and carbon monoxide in the brain,” Journal of Neuroscience, vol. 14, no. 9, pp. 5147–5159, 1994.
View at: Google Scholar
M. L. Simmons and S. Murphy, “Induction of nitric oxide synthase in glial cells,” Journal of Neurochemistry, vol. 59, no. 3, pp. 897–905, 1992.
View at: Google Scholar
S. Murphy, “Production of nitric oxide by glial cells: regulation and potential roles in the CNS,” GLIA, vol. 29, no. 1, pp. 1–13, 2000.
View at: Google Scholar
M. T. Heneka and D. L. Feinstein, “Expression and function of inducible nitric oxide synthase in neurons,” Journal of Neuroimmunology, vol. 114, no. 1-2, pp. 8–18, 2001.
View at: Publisher Site | Google Scholar
M. J. Serou, M. A. DeCoster, and N. G. Bazan, “Interleukin-1 beta activates expression of cyclooxygenase-2 and inducible nitric oxide synthase in primary hippocampal neuronal culture: platelet-activating factor as a preferential mediator of cyclooxygenase-2 expression,” Journal of Neuroscience Research, vol. 58, pp. 593–598, 1999.
View at: Google Scholar
E. Galea, D. L. Feinstein, and D. J. Reis, “Induction of calcium-independent nitric oxide synthase activity in primary rat glial cultures,” Proceedings of the National Academy of Sciences of the United States of America, vol. 89, no. 22, pp. 10945–10949, 1992.
View at: Publisher Site | Google Scholar
S. Murphy, M. L. Simmons, L. Agullo et al., “Synthesis of nitric oxide in CNS glial cells,” Trends in Neurosciences, vol. 16, no. 8, pp. 323–328, 1993.
View at: Publisher Site | Google Scholar
C. Nathan and Q. W. Xie, “Nitric oxide synthases: roles, tolls, and controls,” Cell, vol. 78, no. 6, pp. 915–918, 1994.
View at: Publisher Site | Google Scholar
J. Schlossmann and F. Hofmann, “cGMP-dependent protein kinases in drug discovery,” Drug Discovery Today, vol. 10, no. 9, pp. 627–634, 2005.
View at: Publisher Site | Google Scholar
K. A. Hanafy, J. S. Krumenacker, and F. Murad, “NO, nitrotyrosine, and cyclic GMP in signal transduction,” Medical Science Monitor, vol. 7, no. 4, pp. 801–819, 2001.
View at: Google Scholar
H. Prast and A. Philippu, “Nitric oxide as modulator of neuronal function,” Progress in Neurobiology, vol. 64, no. 1, pp. 51–68, 2001.
View at: Publisher Site | Google Scholar
G. C. Brown, “Nitric oxide produced by activated astrocytes rapidly and reversibly inhibits cellular respiration,” Neuroscience Letters, vol. 193, no. 3, pp. 201–204, 1995.
View at: Publisher Site | Google Scholar
V. L. Dawson and T. M. Dawson, “Nitric oxide neurotoxicity,” Journal of Chemical Neuroanatomy, vol. 10, no. 3-4, pp. 179–190, 1996.
View at: Publisher Site | Google Scholar
S. Y. Lee, T. Andoh, D. L. Murphy, and C. C. Chiueh, “17beta-estradiol activates ICI 182,780-sensitive estrogen receptors and cyclic GMP-dependent thioredoxin expression for neuroprotection,” The FASEB Journal, vol. 17, no. 8, pp. 947–948, 2003.
View at: Google Scholar
G. A. Cunningham, N. H. McClenaghan, P. R. Flatt, and P. Newsholme, “L-alanine induces changes in metabolic and signal transduction gene expression in a clonal rat pancreatic β-cell line and protects from pro-inflammatory cytokine-induced apoptosis,” Clinical Science, vol. 109, no. 5, pp. 447–455, 2005.
View at: Publisher Site | Google Scholar
P. Mander, V. Borutaite, S. Moncada, and G. C. Brown, “Nitric oxide from inflammatory-activated glia synergizes with hypoxia to induce neuronal death,” Journal of Neuroscience Research, vol. 79, no. 1-2, pp. 208–215, 2005.
View at: Publisher Site | Google Scholar
H. P. Monteiro, R. J. Arai, and L. R. Travassos, “Protein tyrosine phosphorylation and protein tyrosine nitration in redox signaling,” Antioxidants and Redox Signaling, vol. 10, no. 5, pp. 843–889, 2008.
View at: Publisher Site | Google Scholar
V. Calabrese, C. Cornelius, E. Rizzarelli, J. B. Owen, A. T. Dinkova-Kostova, and D. A. Butterfield, “Nitric oxide in cell survival: a Janus molecule,” Antioxidants and Redox Signaling, vol. 11, no. 11, pp. 2717–2739, 2009.
View at: Publisher Site | Google Scholar
R. B. Rock, G. Gekker, S. Hu et al., “Role of microglia in central nervous system infections,” Clinical Microbiology Reviews, vol. 17, no. 4, pp. 942–964, 2004.
View at: Publisher Site | Google Scholar
P. F. Good, P. Werner, A. Hsu, C. W. Olanow, and D. P. Perl, “Evidence for neuronal oxidative damage in Alzheimer's disease,” American Journal of Pathology, vol. 149, no. 1, pp. 21–28, 1996.
View at: Google Scholar
P. F. Good, A. Hsu, P. Werner, D. P. Perl, and C. W. Olanow, “Protein nitration in Parkinson's disease,” Journal of Neuropathology and Experimental Neurology, vol. 57, no. 4, pp. 338–342, 1998.
View at: Google Scholar
C. Romero-Grimaldi, B. Moreno-López, and C. Estrada, “Age-dependent effect of nitric oxide on subventricular zone and olfactory bulb neural precursor proliferation,” Journal of Comparative Neurology, vol. 506, no. 2, pp. 339–346, 2008.
View at: Publisher Site | Google Scholar
A. Torroglosa, M. Murillo-Carretero, C. Romero-Grimaldi, E. R. Matarredona, A. Campos-Caro, and C. Estrada, “Nitric oxide decreases subventricular zone stem cell proliferation by inhibition of epidermal growth factor receptor and phosphoinositide-3-kinase/Akt pathway,” Stem Cells, vol. 25, no. 1, pp. 88–97, 2007.
View at: Publisher Site | Google Scholar
S. Fritzen, A. Schmitt, K. Köth, C. Sommer, K. P. Lesch, and A. Reif, “Neuronal nitric oxide synthase (NOS-I) knockout increases the survival rate of neural cells in the hippocampus independentlyof BDNF,” Molecular and Cellular Neuroscience, vol. 35, no. 2, pp. 261–271, 2007.
View at: Publisher Site | Google Scholar
E. Ciani, V. Calvanese, C. Crochemore, R. Bartesaghi, and A. Contestabile, “Proliferation of cerebellar precursor cells is negatively regulated by nitric oxide in newborn rat,” Journal of Cell Science, vol. 119, no. 15, pp. 3161–3170, 2006.
View at: Publisher Site | Google Scholar
E. R. Matarredona, M. Murillo-Carretero, B. Moreno-López, and C. Estrada, “Nitric oxide synthesis inhibition increases proliferation of neural precursors isolated from the postnatal mouse subventricular zone,” Brain Research, vol. 995, no. 2, pp. 274–284, 2004.
View at: Publisher Site | Google Scholar
A. Cheng, S. Wang, J. Cai, M. S. Rao, and M. P. Mattson, “Nitric oxide acts in a positive feedback loop with BDNF to regulate neural progenitor cell proliferation and differentiation in the mammalian brain,” Developmental Biology, vol. 258, no. 2, pp. 319–333, 2003.
View at: Publisher Site | Google Scholar
R. Covacu, A. I. Danilov, B. S. Rasmussen et al., “Nitric oxide exposure diverts neural stem cell fate from neurogenesis towards astrogliogenesis,” Stem Cells, vol. 24, no. 12, pp. 2792–2800, 2006.
View at: Publisher Site | Google Scholar
X. J. Zhu, Y. Hua, J. Jiang et al., “Neuronal nitric oxide synthase-derived nitric oxide inhibits neurogenesis in the adult dentate gyrus by down-regulating cyclic AMP response element binding protein phosphorylation,” Neuroscience, vol. 141, no. 2, pp. 827–836, 2006.
View at: Publisher Site | Google Scholar
Q. G. Zhou, Y. Hu, Y. Hua et al., “Neuronal nitric oxide synthase contributes to chronic stress-induced depression by suppressing hippocampal neurogenesis,” Journal of Neurochemistry, vol. 103, no. 5, pp. 1843–1854, 2007.
View at: Publisher Site | Google Scholar
B. P. Carreira, M. I. Morte, A. S. Lourenco et al., “Differential contribution of the guanylyl cyclase-cyclic GMP-protein kinase g pathway to the proliferation of neural stem cells stimulated by nitric oxide,” Neurosignals. In press.
View at: Publisher Site | Google Scholar
C. X. Luo, X. J. Zhu, Q. G. Zhou et al., “Reduced neuronal nitric oxide synthase is involved in ischemia-induced hippocampal neurogenesis by up-regulating inducible nitric oxide synthase expression,” Journal of Neurochemistry, vol. 103, no. 5, pp. 1872–1882, 2007.
View at: Publisher Site | Google Scholar
Y. Hua, X. Y. Huang, L. Zhou et al., “DETA/NONOate, a nitric oxide donor, produces antidepressant effects by promoting hippocampal neurogenesis,” Psychopharmacology, vol. 200, no. 2, pp. 231–242, 2008.
View at: Publisher Site | Google Scholar
Z. Kokaia and O. Lindvall, “Neurogenesis after ischaemic brain insults,” Current Opinion in Neurobiology, vol. 13, no. 1, pp. 127–132, 2003.
View at: Publisher Site | Google Scholar
B. Moreno-López, J. A. Noval, L. G. González-Bonet, and C. Estrada, “Morphological bases for a role of nitric oxide in adult neurogenesis,” Brain Research, vol. 869, no. 1-2, pp. 244–250, 2000.
View at: Publisher Site | Google Scholar
N. Peunova and G. Enikolopov, “Nitric oxide triggers a switch to growth arrest during differentiation of neuronal cells,” Nature, vol. 375, no. 6526, pp. 68–73, 1995.
View at: Publisher Site | Google Scholar
W. Poluha, C. M. Schonhoff, K. S. Harrington et al., “A novel, nerve growth factor-activated pathway involving nitric oxide, p53, and p21(WAF1) regulates neuronal differentiation of PC12 cells,” Journal of Biological Chemistry, vol. 272, no. 38, pp. 24002–24007, 1997.
View at: Publisher Site | Google Scholar
Y. M. Kim, R. V. Talanian, and T. R. Billiar, “Nitric oxide inhibits apoptosis by preventing increases in caspase-3- like activity via two distinct mechanisms,” Journal of Biological Chemistry, vol. 272, no. 49, pp. 31138–31148, 1997.
View at: Publisher Site | Google Scholar
C. T. Ekdahl, P. Mohapel, E. Elmér, and O. Lindvall, “Caspase inhibitors increase short-term survival of progenitor-cell progeny in the adult rat dentate gyrus following status epilepticus,” European Journal of Neuroscience, vol. 14, no. 6, pp. 937–945, 2001.
View at: Publisher Site | Google Scholar
C. Hölscher, “Nitric oxide, the enigmatic neuronal messenger: its role in synaptic plasticity,” Trends in Neurosciences, vol. 20, no. 7, pp. 298–303, 1997.
View at: Publisher Site | Google Scholar
C. Park, M. Kang, Y. Kim-Kwon, J. Kim, H. Ahn, and Y. Huh, “Inhibition of neuronal nitric oxide synthase increases adrenalectomy-induced granule cell death in the rat dentate gyrus,” Brain Research, vol. 933, no. 1, pp. 81–84, 2002.
View at: Publisher Site | Google Scholar
Y. Sun, K. Jin, J. T. Childs, L. Xie, X. O. Mao, and D. A. Greenberg, “Neuronal nitric oxide synthase and ischemia-induced neurogenesis,” Journal of Cerebral Blood Flow and Metabolism, vol. 25, no. 4, pp. 485–492, 2005.
View at: Publisher Site | Google Scholar
M. Murillo-Carretero, A. Torroglosa, C. Castro, A. Villalobo, and C. Estrada, “S-nitrosylation of the epidermal growth factor receptor: a regulatory mechanism of receptor tyrosine kinase activity,” Free Radical Biology and Medicine, vol. 46, no. 4, pp. 471–479, 2009.
View at: Publisher Site | Google Scholar
A. Reif, A. Schmitt, S. Fritzen et al., “Differential effect of endothelial nitric oxide synthase (NOS-III) on the regulation of adult neurogenesis and behaviour,” European Journal of Neuroscience, vol. 20, no. 4, pp. 885–895, 2004.
View at: Publisher Site | Google Scholar
L. Corsani, E. Bizzoco, F. Pedata, M. Gianfriddo, M. S. Faussone-Pellegrini, and M. G. Vannucchi, “Inducible nitric oxide synthase appears and is co-expressed with the neuronal isoform in interneurons of the rat hippocampus after transient ischemia induced by middle cerebral artery occlusion,” Experimental Neurology, vol. 211, no. 2, pp. 433–440, 2008.
View at: Publisher Site | Google Scholar
A. Arvidsson, Z. Kokaia, and O. Lindvall, “N-methyl-D-aspartate receptor-mediated increase of neurogenesis in adult rat dentate gyrus following stroke,” European Journal of Neuroscience, vol. 14, no. 1, pp. 10–18, 2001.
View at: Publisher Site | Google Scholar
A. Cárdenas, M. A. Moro, O. Hurtado et al., “Implication of glutamate in the expression of inducible nitric oxide synthase after oxygen and glucose deprivation in rat forebrain slices,” Journal of Neurochemistry, vol. 74, no. 5, pp. 2041–2048, 2000.
View at: Publisher Site | Google Scholar
S. Jander, M. Schroeter, and G. Stoll, “Role of NMDA receptor signaling in the regulation of inflammatory gene expression after focal brain ischemia,” Journal of Neuroimmunology, vol. 109, no. 2, pp. 181–187, 2000.
View at: Publisher Site | Google Scholar
W. Jiang, L. Xiao, J. C. Wang, Y. G. Huang, and X. Zhang, “Effects of nitric oxide on dentate gyrus cell proliferation after seizures induced by pentylenetrazol in the adult rat brain,” Neuroscience Letters, vol. 367, no. 3, pp. 344–348, 2004.
View at: Publisher Site | Google Scholar
C. Park, K. S. Shin, J. H. Ryu et al., “The inhibition of nitric oxide synthase enhances PSA-NCAM expression and CREB phosphorylation in the rat hippocampus,” NeuroReport, vol. 15, no. 2, pp. 231–234, 2004.
View at: Publisher Site | Google Scholar
J. Chen, A. Zacharek, C. Zhang et al., “Endothelial nitric oxide synthase regulates brain-derived neurotrophic factor expression and neurogenesis after stroke in mice,” Journal of Neuroscience, vol. 25, no. 9, pp. 2366–2375, 2005.
View at: Publisher Site | Google Scholar
M. A. Tegenge, T. D. Rockel, E. Fritsche, and G. Bicker, “Nitric oxide stimulates human neural progenitor cell migration via cGMP-mediated signal transduction,” Cellular and Molecular Life Sciences, vol. 68, no. 12, pp. 2089–2099, 2011.
View at: Publisher Site | Google Scholar
L. Shen and J. Zhang, “NMDA receptor and iNOS are involved in the effects of ginsenoside Rg1 on hippocampal neurogenesis in ischemic gerbils,” Neurological Research, vol. 29, no. 3, pp. 270–273, 2007.
View at: Publisher Site | Google Scholar
C. X. Luo, X. J. Zhu, A. X. Zhang et al., “Blockade of L-type voltage-gated Ca2+ channel inhibits ischemia-induced neurogenesis by down-regulating iNOS expression in adult mouse,” Journal of Neurochemistry, vol. 94, no. 4, pp. 1077–1086, 2005.
View at: Publisher Site | Google Scholar
A. Cárdenas, M. A. Moro, O. Hurtado, J. C. Leza, and I. Lizasoain, “Dual role of nitric oxide in adult neurogenesis,” Brain Research Reviews, vol. 50, no. 1, pp. 1–6, 2005.
View at: Publisher Site | Google Scholar
C. Estrada and M. Murillo-Carretero, “Nitric oxide and adult neurogenesis in health and disease,” Neuroscientist, vol. 11, no. 4, pp. 294–307, 2005.
View at: Publisher Site | Google Scholar
A. R. Álvaro, J. Martins, I. M. Araújo, J. Rosmaninho-Salgado, A. F. Ambrósio, and C. Cavadas, “Neuropeptide Y stimulates retinal neural cell proliferation—involvement of nitric oxide,” Journal of Neurochemistry, vol. 105, no. 6, pp. 2501–2510, 2008.
View at: Publisher Site | Google Scholar
R. L. Zhang, Z. G. Zhang, L. Zhang, and M. Chopp, “Proliferation and differentiation of progenitor cells in the cortex and the subventricular zone in the adult rat after focal cerebral ischemia,” Neuroscience, vol. 105, no. 1, pp. 33–41, 2001.
View at: Publisher Site | Google Scholar
J. L. Burgaud, E. Ongini, and P. Del Soldato, “Nitric oxide-releasing drugs: a novel class of effective and safe therapeutic agents,” Annals of the New York Academy of Sciences, vol. 962, pp. 360–371, 2002.
View at: Google Scholar
M. Feelisch and M. Kelm, “Biotransformation of organic nitrates to nitric oxide by vascular smooth muscle and endothelial cells,” Biochemical and Biophysical Research Communications, vol. 180, no. 1, pp. 286–293, 1991.
View at: Publisher Site | Google Scholar
I. L. Megson and D. J. Webb, “Nitric oxide donor drugs: current status and future trends,” Expert Opinion on Investigational Drugs, vol. 11, no. 5, pp. 587–601, 2002.
View at: Publisher Site | Google Scholar
J. Saraiva, S. S. Marotta-Oliveira, S. A. Cicillini, O. E. Jde, and J. M. Marchetti, “Nanocarriers for nitric oxide delivery,” Journal of Drug Delivery, vol. 2011, Article ID 936438, 16 pages, 2011.
View at: Publisher Site | Google Scholar
R. Zhang, L. Zhang, Z. Zhang et al., “A nitric oxide donor induces neurogenesis and reduces functional deficits after stroke in rats,” Annals of Neurology, vol. 50, no. 5, pp. 602–611, 2001.
View at: Publisher Site | Google Scholar
D. Lu, A. Mahmood, R. Zhang, Y. Li, and M. Chopp, “Upregulation of neurogenesis and reduction in functional deficits following administration of DETA/NONOate, a nitric oxide donor, after traumatic brain injury in rats,” Journal of Neurosurgery, vol. 99, no. 2, pp. 351–361, 2003.
View at: Google Scholar
H. Chen, S. M. Zhang, M. A. Hernán et al., “Nonsteroidal anti-inflammatory drugs and the risk of Parkinson disease,” Archives of Neurology, vol. 60, no. 8, pp. 1059–1064, 2003.
View at: Publisher Site | Google Scholar
R. G. Keynes and J. Garthwaite, “Nitric oxide and its role in ischaemic brain injury,” Current Molecular Medicine, vol. 4, no. 2, pp. 179–191, 2004.
View at: Publisher Site | Google Scholar
P. Pifarre, J. Prado, M. A. Baltrons et al., “Sildenafil (Viagra) ameliorates clinical symptoms and neuropathology in a mouse model of multiple sclerosis,” Acta Neuropathologica, vol. 121, no. 4, pp. 499–508, 2011.
View at: Publisher Site | Google Scholar
M. A. Tegenge and G. Bicker, “Nitric oxide and cGMP signal transduction positively regulates the motility of human neuronal precursor (NT2) cells,” Journal of Neurochemistry, vol. 110, no. 6, pp. 1828–1841, 2009.
View at: Publisher Site | Google Scholar
J. E. Keeble and P. K. Moore, “Pharmacology and potential therapeutic applications of nitric oxide-releasing non-steroidal anti-inflammatory and related nitric oxide-donating drugs,” British Journal of Pharmacology, vol. 137, no. 3, pp. 295–310, 2002.
View at: Publisher Site | Google Scholar
P. Geusens, “Naproxcinod, a new cyclooxygenase-inhibiting nitric oxide donator (CINOD),” Expert Opinion on Biological Therapy, vol. 9, no. 5, pp. 649–657, 2009.
View at: Publisher Site | Google Scholar
M. A. Ajmone-Cat, E. Cacci, and L. Minghetti, “Non steroidal anti-inflammatory drugs and neurogenesis in the adult mammalian brain,” Current Pharmaceutical Design, vol. 14, no. 14, pp. 1435–1442, 2008.
View at: Publisher Site | Google Scholar
B. Hauss-Wegrzyniak, P. Vraniak, and G. L. Wenk, “The effects of a novel NSAID on chronic neuroinflammation are age dependent,” Neurobiology of Aging, vol. 20, no. 3, pp. 305–313, 1999.
View at: Publisher Site | Google Scholar
P. T. Jantzen, K. E. Connor, G. DiCarlo et al., “Microglial activation and β-amyloid deposit reduction caused by a nitric oxide-releasing nonsteroidal anti-inflammatory drug in amyloid precursor protein plus presenilin-1 transgenic mice,” Journal of Neuroscience, vol. 22, no. 6, pp. 2246–2254, 2002.
View at: Google Scholar
S. Fredduzzi, G. Mariucci, M. Tantucci, P. Del Soldato, and M. V. Ambrosini, “Nitro-aspirin (NCX4016) reduces brain damage induced by focal cerebral ischemia in the rat,” Neuroscience Letters, vol. 302, no. 2-3, pp. 121–124, 2001.
View at: Publisher Site | Google Scholar
S. Fiorucci, E. Antonelli, L. Santucci et al., “Gastrointestinal safety of nitric oxide-derived aspirin is related to inhibition of ICE-like cysteine proteases in rats,” Gastroenterology, vol. 116, no. 5, pp. 1089–1106, 1999.
View at: Publisher Site | Google Scholar
J. M. R. Parepally, H. Mandula, and Q. R. Smith, “Brain uptake of nonsteroidal anti-inflammatory drugs: ibuprofen, flurbiprofen, and indomethacin,” Pharmaceutical Research, vol. 23, no. 5, pp. 873–881, 2006.
View at: Publisher Site | Google Scholar
W. P. Arnold, C. K. Mittal, S. Katsuki, and F. Murad, “Nitric oxide activates guanylate cyclase and increases guanosine 3':5'-cyclic monophosphate levels in various tissue preparations,” Proceedings of the National Academy of Sciences of the United States of America, vol. 74, no. 8, pp. 3203–3207, 1977.
View at: Google Scholar
S. Jurado, J. Sánchez-Prieto, and M. Torres, “Expression of cGMP-dependent protein kinases (I and II) and neuronal nitric oxide synthase in the developing rat cerebellum,” Brain Research Bulletin, vol. 65, no. 2, pp. 111–115, 2005.
View at: Publisher Site | Google Scholar
T. Sardón, M. A. Baltrons, and A. García, “Nitric oxide-dependent and independent down-regulation of NO-sensitive guanylyl cyclase in neural cells,” Toxicology Letters, vol. 149, no. 1–3, pp. 75–83, 2004.
View at: Publisher Site | Google Scholar
J. S. Krumenacker, K. A. Hanafy, and F. Murad, “Regulation of nitric oxide and soluble guanylyl cyclase,” Brain Research Bulletin, vol. 62, no. 6, pp. 505–515, 2004.
View at: Publisher Site | Google Scholar
A. L. Burnett, B. Musicki, L. Jin, and T. J. Bivalacqua, “Nitric oxide/redox-based signalling as a therapeutic target for penile disorders,” Expert Opinion on Therapeutic Targets, vol. 10, no. 3, pp. 445–457, 2006.
View at: Publisher Site | Google Scholar
A. R. Hemnes and H. C. Champion, “Sildenafil, a PDE5 inhibitor, in the treatment of pulmonary hypertension,” Expert Review of Cardiovascular Therapy, vol. 4, no. 3, pp. 293–300, 2006.
View at: Publisher Site | Google Scholar
S. Uthayathas, S. S. Karuppagounder, B. M. Thrash, K. Parameshwaran, V. Suppiramaniam, and M. Dhanasekaran, “Versatile effects of sildenafil: recent pharmacological applications,” Pharmacological Reports, vol. 59, no. 2, pp. 150–163, 2007.
View at: Google Scholar
S. A. Ballard, C. J. Gingell, K. Tang, L. A. Turner, M. E. Price, and A. M. Naylor, “Effects of sildenafil on the relaxation of human corpus cavernosum tissue in vitro and on the activities of cyclic nucleotide phosphodiesterase isozymes,” Journal of Urology, vol. 159, no. 6, pp. 2164–2171, 1998.
View at: Google Scholar
H. Mochida, M. Takagi, H. Inoue et al., “Enzymological and pharmacological profile of T-0156, a potent and selective phosphodiesterase type 5 inhibitor,” European Journal of Pharmacology, vol. 456, no. 1–3, pp. 91–98, 2002.
View at: Publisher Site | Google Scholar
J. D. Corbin, “Mechanisms of action of PDE5 inhibition in erectile dysfunction,” International Journal of Impotence Research, vol. 16, supplement 1, pp. S4–S7, 2004.
View at: Publisher Site | Google Scholar
R. C. Rosen and J. B. Kostis, “Overview of phosphodiesterase 5 inhibition in erectile dysfunction,” American Journal of Cardiology, vol. 92, no. 9, pp. 9M–18M, 2003.
View at: Publisher Site | Google Scholar
G. D. Lewis and M. J. Semigran, “Type 5 phosphodiesterase inhibition in heart failure and pulmonary hypertension,” Current Heart Failure Reports, vol. 1, no. 4, pp. 183–189, 2004.
View at: Google Scholar
M. D. Patel and S. D. Katz, “Phosphodiesterase 5 inhibition in chronic heart failure and pulmonary hypertension,” American Journal of Cardiology, vol. 96, no. 12, 2005.
View at: Publisher Site | Google Scholar
M. K. Steiner, I. R. Preston, J. R. Klinger, and N. S. Hill, “Pulmonary hypertension: inhaled nitric oxide, sildenafil and natriuretic peptides,” Current Opinion in Pharmacology, vol. 5, no. 3, pp. 245–250, 2005.
View at: Publisher Site | Google Scholar
M. Chalimoniuk and J. B. Strosznajder, “Aging modulates nitric oxide synthesis and cGMP levels in hippocampus and cerebellum: effects of amyloid β peptide,” Molecular and Chemical Neuropathology, vol. 35, no. 1–3, pp. 77–95, 1998.
View at: Google Scholar
U. Gómez-Pinedo, R. Rodrigo, O. Cauli et al., “cGMP modulates stem cells differentiation to neurons in brain in vivo,” Neuroscience, vol. 165, no. 4, pp. 1275–1283, 2010.
View at: Publisher Site | Google Scholar
K. S. Madhusoodanan and F. Murad, “NO-cGMP signaling and regenerative medicine involving stem cells,” Neurochemical Research, vol. 32, no. 4-5, pp. 681–694, 2007.
View at: Publisher Site | Google Scholar
C. M. Baratti and M. M. Boccia, “Effects of sildenafil on long-term retention of an inhibitory avoidance response in mice,” Behavioural Pharmacology, vol. 10, no. 8, pp. 731–737, 1999.
View at: Google Scholar
B. D. Devan, J. L. Bowker, K. B. Duffy et al., “Phosphodiesterase inhibition by sildenafil citrate attenuates a maze learning impairment in rats induced by nitric oxide synthase inhibition,” Psychopharmacology, vol. 183, no. 4, pp. 439–445, 2006.
View at: Publisher Site | Google Scholar
S. Erceg, P. Monfort, M. Hernández-Viadel, R. Rodrigo, C. Montoliu, and V. Felipo, “Oral administration of sildenafil restores learning ability in rats with hyperammonemia and with portacaval shunts,” Hepatology, vol. 41, no. 2, pp. 299–306, 2005.
View at: Publisher Site | Google Scholar
K. Rutten, J. de Vente, A. Şik, M. M. Ittersum, J. Prickaerts, and A. Blokland, “The selective PDE5 inhibitor, sildenafil, improves object memory in Swiss mice and increases cGMP Levels in hippocampal slices,” Behavioural Brain Research, vol. 164, no. 1, pp. 11–16, 2005.
View at: Publisher Site | Google Scholar
J. Prickaerts, W. C. G. Van Staveren, A. Şik et al., “Effects of two selective phosphodiesterase type 5 inhibitors, sildenafil and vardenafil, on object recognition memory and hippocampal cyclic GMP levels in the rat,” Neuroscience, vol. 113, no. 2, pp. 351–361, 2002.
View at: Publisher Site | Google Scholar
N. Singh and M. Parle, “Sildenafil improves acquisition and retention of memory in mice,” Indian Journal of Physiology and Pharmacology, vol. 47, no. 3, pp. 318–324, 2003.
View at: Google Scholar
B. D. Devan, D. Sierra-Mercado Jr., M. Jimenez et al., “Phosphodiesterase inhibition by sildenafil citrate attenuates the learning impairment induced by blockade of cholinergic muscarinic receptors in rats,” Pharmacology Biochemistry and Behavior, vol. 79, no. 4, pp. 691–699, 2004.
View at: Publisher Site | Google Scholar
R. Zhang, Y. Wang, L. Zhang et al., “Sildenafil (Viagra) induces neurogenesis and promotes functional recovery after stroke in rats,” Stroke, vol. 33, no. 11, pp. 2675–2680, 2002.
View at: Publisher Site | Google Scholar
R. Zhang, L. Wang, L. Zhang et al., “Nitric oxide enhances angiogenesis via the synthesis of vascular endothelial growth factor and cGMP after stroke in the rat,” Circulation Research, vol. 92, no. 3, pp. 308–313, 2003.
View at: Publisher Site | Google Scholar
L. Zhang, Z. Zhang, R. L. Zhang et al., “Tadalafil, a long-acting type 5 phosphodiesterase isoenzyme inhibitor, improves neurological functional recovery in a rat model of embolic stroke,” Brain Research, vol. 1118, no. 1, pp. 192–198, 2006.
View at: Publisher Site | Google Scholar
L. Zhang, R. L. Zhang, Y. Wang et al., “Functional recovery in aged and young rats after embolic stroke: treatment with a phosphodiesterase type 5 inhibitor,” Stroke, vol. 36, no. 4, pp. 847–852, 2005.
View at: Publisher Site | Google Scholar
R. L. Zhang, Z. Zhang, L. Zhang, Y. Wang, C. Zhang, and M. Chopp, “Delayed treatment with sildenafil enhances neurogenesis and improves functional recovery in aged rats after focal cerebral ischemia,” Journal of Neuroscience Research, vol. 83, no. 7, pp. 1213–1219, 2006.
View at: Publisher Site | Google Scholar
L. Wang, Z. G. Zhang, R. L. Zhang, and M. Chopp, “Activation of the PI3-K/Akt pathway mediates cGMP enhanced-neurogenesis in the adult progenitor cells derived from the subventricular zone,” Journal of Cerebral Blood Flow and Metabolism, vol. 25, no. 9, pp. 1150–1158, 2005.
View at: Publisher Site | Google Scholar
C. Napoli and L. J. Ignarro, “Nitric oxide-releasing drugs,” Annual Review of Pharmacology and Toxicology, vol. 43, pp. 97–123, 2003.
View at: Publisher Site | Google Scholar
E. Koc and S. G. Kucukguzel, “Medicinal chemistry and anti-inflammatory activity of nitric oxide-releasing NSAI drugs,” Mini-Reviews in Medicinal Chemistry, vol. 9, no. 5, pp. 611–619, 2009.
View at: Publisher Site | Google Scholar

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Copyright © 2012 Bruno P. Carreira et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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