Review Article | Open Access
P2 Receptors in Neurological and Cardiovascular Disorders
P2X receptors are ATP-gated cation channels that mediate fast excitatory transmission in diverse regions of the brain and spinal cord. Several P2X receptor subtypes, including P2, have the unusual property of changing their ion selectivity during prolonged exposure to ATP, which results in a channel pore permeable to molecules as large as 900 daltons. The P2 receptor was originally described in cells of hematopoietic origin, and mediates the influx of and and and ions as well as the release of proinflammatory cytokines. P2 receptors may affect neuronal cell death through their ability to regulate the processing and release of interleukin-1, a key mediator in neurodegeneration, chronic inflammation, and chronic pain. Activation of P2, a key mediator in neurodegeneration, chronic inflammation, and chronic pain. Activation of P2 receptors provides an inflammatory stimulus, and P2 receptor-deficient mice have substantially attenuated inflammatory responses, including models of neuropathic and chronic inflammatory pain. Moreover, P2 receptor activity, by regulating the release of proinflammatory cytokines, may be involved in the pathophysiology of depression. Apoptotic cell death occurs in a number of vascular diseases, including atherosclerosis, restenosis, and hypertension, and may be linked to the release of ATP from endothelial cells, P2 receptor activation, proinflammatory cytokine production, and endothelial cell apoptosis. In this context, the P2 receptor may be viewed as a gateway of communication between the nervous, immune, and cardiovascular systems.
The role of extracellular ATP and purinoceptors in cytokine regulation and neurological disorders is the focus of a rapidly expanding area of research. ATP can act as a neurotransmitter, while the presence of the purinergic receptor subclass P2 on immune cells suggests that it also regulates immune function and inflammatory responses. In addition, activation of this receptor has dramatic cytotoxic properties which, together with its ability to regulate cytokine production and release, propose that it can act as an important regulator of cell death in response to pathological insults in both nervous and other (e.g., cardiovascular) tissues.
Neurodegeneration is the underlying basis of many disorders including cerebral ischemia, brain trauma, multiple sclerosis, Parkinson’s, Alzheimer’s, and Huntington’s diseases. Neuroinflammation in disorders such as Alzheimer’s disease (AD) has previously been viewed as an epiphenomenon, with inflammation occurring when damaged neurons provoke an activation response from glia. Accumulating evidence now challenges this perspective and points to a more active role of neuroinflammation in pathophysiology onset and progression. In the central nervous system (CNS), glial cells (microglia, astroglia, and oligodendroglia) not only serve supportive and nutritive roles for neurons but also in the healthy brain often respond to stress and insults by transiently upregulating inflammatory processes. These processes are kept in check by other endogenous anti-inflammatory and neuroprotective responses that return the brain to homeostasis. Otherwise “normal” glial functions can sometimes result in a more severe and chronic neuroinflammatory cycle that actually promotes or propagates neurodegenerative disease . The delicate balance in this homeostasis can be disturbed, resulting in disease or exacerbation of initiating factors that result in disease (i.e., the neuroinflammation hypothesis) (Figure 1) .
Clinical evidence in support of neuroinflammation as a pharmacological target for chronic neurodegenerative diseases, such as AD, comes from epidemiological and genetic linkage data. For example, long-term use of nonsteroidal anti-inflammatory drugs is correlated with a protective effect against AD , and certain polymorphisms in the genes for proinflammation mediators are associated with increased risk . Postmortem brain tissue from patients with AD has expressed an array of inflammatory mediators, including cytokines and chemokines in those regions most affected in the disorder . Neuroinflammation has been documented also in the affected brain regions of individuals suffering from Parkinson’s disease, multiple sclerosis, human immunodeficiency virus type 1-associated dementia, and various prion diseases [6–9], as well as cerebral ischemia , spinal cord injury , and traumatic brain injury . The ability of P2 receptor activation to regulate cytokine production and cellular vitality has implications for other neurological disorders, for example, pain and depression, as well as within the cardiovascular system. Collectively these observations propose that excessive P2 receptor activation on both glia and vascular cells constitutes a viable target for the discovery and development of novel disease therapeutics. This review will discuss the current biology and cellular signaling pathways of P2 receptor function, as well as insights into the role for this receptor in neurological/psychiatric and cardiovascular diseases, and the therapeutic potential of P2 receptor antagonism.
2. P2 Receptor Biology
Virtually all cell types express plasma membrane receptors for extracellular nucleotides, named P2 receptors. Presently, 15 members have been cloned and are classified into two subfamilies: the G protein-coupled P2Y receptors and P2X receptors [13, 14]. P2X receptors function as ATP-gated nonselective cationic channels permeable to , , and . The ability of P2X receptors to act as direct conduits for influx or indirect activators of voltage-gated channels underlies their multiple roles in -based signaling responses in those tissues. The channels are oligomeric complexes composed of protein subunits encoded by seven different P2X receptor genes ( through ) expressed in mammalian and other vertebrate genomes. The minimum stoichiometric conformation of the P2 receptor channel appears to be a trimer [13, 16]. Whether pore formation results from intrinsic dilation of the channel  or P2 receptor-mediated downstream signaling remains to be fully resolved.
All functional P2X receptor subtypes display a very high selectivity for ATP over other physiological nucleotides . The P2 receptor is unusual among the P2X receptor family in that sustained activation by extracellular ATP causes the formation of a reversible plasma membrane pore permeable to hydrophilic solutes up to 900 Da . This property is likely due to the receptor’s extended carboxy terminal domain . The P2 receptor activates a diverse range of cellular responses including phospholipase , phospholipase D, mitogen-activated protein kinase (MAPK), and nuclear factor-kappa B (NF-B) (Figure 2) .
P2 receptors are selectively expressed on cells of hematopoietic lineage including mast cells, erythrocytes, monocytes, peripheral macrophages, dendritic cells, T- and B-lymphocytes, and epidermal Langerhans cells . Within the CNS, functional P2 receptors are localized on microglia and Schwann cells as well as on astrocytes [19, 20]. The existence of functional P2 receptors on peripheral or central neurons remains controversial owing to the poor selectivity of both antibodies and ligands targeting the rat P2 receptor . In rat peripheral sensory ganglia (dorsal root), P2 receptors appear to be selectively localized on glial cells, but not neurons . The best characterized activity of the P2 receptor is its role in interleukin-1 (IL-1) release from macrophages and microglia that have been primed with substances such as bacterial endotoxin (lipopolysaccharide, LPS) . Protracted activation of P2 receptors in some cell types results in the induction of apoptosis [13, 24]. However, the physiological significance of this “highly stimulated" state of the P2 receptor is unclear.
The only known physiological activator of the P2 receptor is ATP. It is remarkable that activation of the P2 receptor requires near millimolar concentrations of ATP (M). Since the cytoplasmic ATP concentration is in the millimolar range, acute cell injury or death will cause massive ATP release into the extracellular milieu. Indeed, activated immune cells , macrophages , microglia , platelets , and dying cells may release high concentrations of nucleotide di- and tri-phosphates into the extracellular space . Extracellular ATP concentrations increase significantly under inflammatory conditions in vivo  and in response to tissue trauma , suggesting that ATP levels sufficient to activate the P2 receptor may be reached in the pericellular space . In addition, proinflammatory cytokines and bacterial products up-regulate P2 receptor expression and increase its sensitivity to extracellular ATP [32, 33].
Deletion of abolishes the ability of extracellular ATP to induce IL-1 release from isolated macrophages . P2 receptor-deficient mice are protected against symptom development and cartilage destruction in anticollagen antibody-induced arthritis . Disruption of the P2 receptor gene abolishes chronic inflammatory and neuropathic pain , and may play a role in the pathophysiology of AD . Recent studies suggest a link between the P2 receptor gene and both neuropsychiatric  and cardiovascular diseases . These topics will be covered in detail in later sections.
3. P2 Receptor Signaling
In macrophages/monocytes, P2 receptor stimulation rapidly activates c-Jun N-terminal kinases 1 and 2 (JNK-1/2) , extracellular signal-regulated kinase (ERK-1/2), and p38 MAPK . The P2 receptor agonist -O -(4-benzoyl-benzoyl)ATP (BzATP) activates the same pathways in mouse N9 microglia , and increases the nuclear translocation of NF-B in mouse BV-2 microglia . Dephosphorylation of NFAT (nuclear factor of activated T cells) by calcineurin exposes a nuclear localization sequence, permitting nuclear translocation and transcriptional activation . In N9 cells, ATP activates NFAT via the P2 receptors in a calcineurin-dependent fashion . The cyclic AMP response element- (CRE-) binding protein (CREB), a member of the ATF-1 (activating transcription factor 1) family of transcription factors, is involved in cytokine gene regulation . P2 receptor-dependent induction of CREB and ATF-1 phosphorylation occurs in BV-2 cells via an MAPK kinase (MEK)/ERK-dependent pathway . Activation of activator protein-1 (AP-1) is another transcription factor associated with regulation of inflammatory genes . Multiple members of the c-Fos and c-Jun families dimerize to form AP-1. In serum-starved Jurkat T-cells, activation of P2 receptors induced AP-1 DNA binding activity as a result of increased c-Jun and c-Fos expression . ATP treatment also increased the phosphorylation of ERK-1/2 and JNK-1/2, but not p38 MAPK, providing a potential mechanism for these effects (Figure 3).
Stimulation of P2 receptors increases protein tyrosine phosphorylation [48, 49] ultimately leading to MAPK pathway activation. Many events downstream of P2 receptor activation are dependent upon extracellular calcium influx [13, 44], and activation of MAPK pathways by P2 receptors may involve calcium signaling. In RAW 264.7 macrophages, the calcium-dependent kinase Pyk2, which facilitates Ras activation, is tyrosine phosphorylated in response to treatment with BzATP [48, 50], potentially linking calcium fluxes, Ras activation, and MAPK pathways with P2 receptors. P2 receptors also induce the activation of other small molecular weight G-proteins. For example, the Rho/p38 pathway may be involved in the shedding of IL-1-containing vesicles  through actin filament reorganization and membrane blebbing [51, 52], conceivably providing a mechanism whereby MAPKs can mediate increased microglial proinflammatory cytokine release.
4. P2 Receptors and Neurological/Psychiatric Diseases
4.1. Neurodegenerative Disorders
P2 receptors may affect neuronal cell death through their ability to regulate the processing and release of IL-1, a key mediator in neurodegeneration . Deletion of the P2 receptor did not affect neuronal cell death induced by transient or permanent middle cerebral artery occlusion or by excitotoxic injury . In another study, organotypic mouse hippocampal slice cultures were incubated for 3 hours to LPS, followed by a 3-hour coincubation with ATP or a P2 receptor agonist. A pronounced activation and apoptotic-like death of microglia was associated with a massive release of IL-1, together with exacerbated CA3 pyramidal cell loss induced by subsequent exposure to the glutamatergic agonist -amino-3-hydroxyl-5-methyl-4-isoxazole propionate in an IL-1-dependent manner . In rats subjected to spinal cord injury, areas surrounding the traumatic lesion displayed an abnormally high and sustained pattern of ATP release, and delivery of P2 antagonist after acute impact injury improved functional recovery and diminished cell death in the peritraumatic zone . Acute spinal cord injuries produce highly inflammatory environments , and P2 receptor activation of local microglial cells may have adverse effects for neighboring neuronal cells. P2 may be involved in the generation of in rat primary microglia [37, 57]. P2 receptor-like immunoreactivity was upregulated around -amyloid plaques in Tg2576 mice (which overexpress the human amyloid precursor protein harboring the Swedish familial mutation (K670N, M671L)) and was regionally localized with activated microglia and astrocytes . Upregulation of the P2 receptor subtype on microglia has been observed also after ischemia in the cerebral cortex of rats , and previous work has demonstrated immunoreactivity for the P2 receptor on reactive astrocytes in multiple sclerosis autopsy brain tissue .
Whether P2 receptor over-expression is driving microglial activation or, conversely, P2 receptor over-expression is a consequence of microglial activation is not known. Using cocultures of rat cortical neurons and microglia, Skaper et al.  have recently shown that ATP and BzATP cause neuronal cell injury. Treatment with the selective P2 antagonist Brilliant Blue G prevented the deleterious effects of BzATP-treated microglia (Figure 4). Neuronal cell injury was attenuated by a superoxide dismutase mimetic and by a peroxynitrite decomposition catalyst, suggesting a role for reactive oxide species . Cocultures composed of wild-type cortical neurons and microglia from P2 receptor-deficient mice failed to exhibit neuronal cell injury in the presence of BzATP but retained sensitivity to injury when microglia were derived from genotypically matched normal (P2 mice) . P2 receptor activation on microglia thus appears necessary for microglial cell–mediated injury of neurons.
A marked decline of intracellular ATP levels with a concomitant efflux of ATP into the extracellular space occurs in the rat brain during the first few minutes after oxygen depletion in vivo , and low concentrations of ATP can act as a chemoattractant for microglia , directing them to a site of injury. ATP released from activated astrocytes activates microglia , and microglial cells could encounter high levels of ATP near dying and disintegrating cells. These observations indicate that ATP and ATP analogues do act via the P2 receptor on microglia to affect neuronal cell health and that the P2 receptor can serve as an important component of a neuroinflammatory response (Figure 5(a)). Receptor antagonists of the P2 receptor could have therapeutic utility in the treatment of AD and cerebral ischemia and neuroinflammatory conditions by regulating pathologically activated glial cells.
ATP is recognized as one of the keys for the relay of sensory information from the periphery to the CNS , and is also one of several important mediators involved in immune-neural interactions . Both sensory neurons and glial cells inside and outside of the CNS release ATP to affect surrounding cells [64, 65]. Particularly intriguing is the gathering body of literature linking activated microglia and astrocytes to central sensitization and the development and maintenance of neuropathic pain [65–67]. Both the localization of P2 receptors on pro-inflammatory cells, and the fact that ATP acting at P2 receptors serves as an efficient secondary stimulus for the generation and release of IL-1 from proinflammatory cells  have implicated a role for P2 receptors in inflammatory diseases  (Figure 5(a)).
Labasi et al.  observed a lower incidence and severity of monoclonal anticollagen-induced arthritis in P2 receptor knockout mice compared with wild-type, suggesting a pathological role for P2 receptors in inflammatory-/immune-mediated disease. Deletion of the gene abolished the ability of ATP to induce IL-1 release from macrophages isolated from these mice . Local administration of a P2 receptor antagonist had antihyperalgesic effects in the complete Freund’s adjuvant-induced mechanical hyperalgesia (paw pressure) model . More recently, Chessell et al.  demonstrated that in mice lacking the P2 receptor, inflammatory and neuropathic hypersensitivity is completely absent to both mechanical and thermal stimuli, while normal nociceptive processing is preserved. In these knockout animals, systemic cytokine analysis showed reductions in adjuvant-induced increases in IL-1, IL-6, IL-10, and macrophage chemoattractant protein-1. Moreover, P2 receptor was upregulated in human dorsal root ganglia and injured nerves obtained from chronic neuropathic pain patients . Endogenous IL-1 levels are increased in the nervous system in response to trauma associated with mechanical damage, ischemia, seizures, and hyperexcitability . At the level of the spinal cord, blockage of IL-1 receptors results in reduced nociception in animal models of inflammation and nerve injury-induced pain [71, 72].
Much recent research has focused on the development of novel, selective, and potent small molecule inhibitors of the P2 receptor [73–77]. A-740003 and A-438079 are structurally unrelated P2 antagonists, and both exhibit therapeutic efficacy on neuropathy-induced mechanical allodynia [78, 79]. A-740003 also has antihyperalgesic effects in the carrageenan- and adjuvant-induced thermal hyperalgesia models of inflammatory pain . These data are consistent with a study of an adamantane P2 antagonist (AACBA; GSK314181A) that is structurally dissimilar from A-740003 and A-438079, which showed dose-dependent antinociception in an inflammatory pain model . The preclinical testing of P2 antagonists strongly suggests therapeutic potential in pathological pain and inflammation.
Intriguingly, cytokines like IL-1 are suggested to be involved in the pathophysiology of depression. This neuropsychiatric disorder is recognized as having high prevalence in several clinical settings including infectious, autoimmune, and neurodegenerative disorders, conditions associated with a proinflammatory status, and it has been proposed that excessive secretion of macrophage cytokines, for example, IL-1, TNF-, and IFN-, could be a potential causative factor . Central and systemic administration of proinflammatory cytokines (IL-1, TNF-, IL-6) to animals induces what has been described as “sickness behavior," which is characterized by many of the physiological and behavioral changes associated with depression [82, 83]. A similarity and functional linkage between symptoms of sickness behavior in animals and those of depression in humans has been suggested . In addition, cytokines can induce neuroendocrine and neurochemical changes akin to a depressive syndrome , and clinical use of cytokines (e.g., IFN-) produces depressive-like symptoms that can be attenuated with antidepressant treatment . Not only do patients suffering from major depression, who are otherwise medically healthy, often have significant elevations in the density of microglia  and elevated levels of circulating proinflammatory cytokines [87–89] but also mice lacking functional type 1 or type 2 TNF- receptors display an antidepressant phenotype . Cytokines may thus be involved in the etiopathogenesis of depression (Figure 5(a)).
Linkage studies have shown that the gene may be involved in some neuropsychiatric conditions. Genetic analysis of a French population indicated a Gln640Arg single nucleotide polymorphism of the P2 receptor gene as a potential susceptibility gene for bipolar effective disorder  and major depression [92, 93]. This Gln640Arg polymorphism is located at the C-terminal domain of the P2 receptor, which is essential for its normal function. Identified polymorphisms in the P2 receptor of lymphocytes are known to produce a loss of function or to alter trafficking of the receptor to the membrane surface, thus decreasing its membrane expression . The functional consequences for cytokine release of polymorphisms in the P2 receptor have been investigated in some cases, which result in reduction in TNF- release from LPS stimulated leukocytes in the presence of ATP . Basso et al.  have recently described the behavioral profile of P2 receptor gene knockout mice in animal models of depression and anxiety, and found an antidepressant-like phenotype together with a higher responsiveness to a subefficacious dose of the antidepressant imipramine. Further research will be necessary to elucidate the specific mechanism(s) underlying the antidepressant-like characteristics of P2 receptor knockout genotype and how inactivation of the P2 gene is physiologically translated into the expression of this behavioral profile.
Activation of the inflammatory response in the etiology of depression would lead one to predict that antidepressant drugs display negative immunoregulatory effects . Indeed, a number of antidepressants that exhibit distinct mechanisms of action, at therapeutically effective concentrations, limit the release of proinflammatory cytokines both in vitro  and in vivo [99, 100]. In addition, antidepressants attenuate the behavioral and emotional disturbances elicited by immunostimulation and cytokine administration to humans and rodents [86, 100] and the abnormal increased production of proinflammatory cytokines seen in depressed patients [89, 101]. Antagonism of P2 receptors may thus constitute a novel target for the treatment of depression.
5. P2 Receptors and Cardiovascular Disease
ATP is an important neurotransmitter being released with noradrenaline and neuropeptide Y from perivascular sympathetic nerves; it acts at postjunctional P2X receptors to evoke vascular smooth muscle contraction. The relative contributions of ATP and noradrenaline as functional cotransmitters varies with species, age, type, and size of blood vessel, the tone/pressure of the blood vessel, and in disease . In the vascular system, short-term purinergic signaling events are associated with the control of blood vessel tone/pressure influenced by ATP released from perivascular nerves, smooth muscle, and endothelial cells [102, 103]. In the rat vascular system, P2 receptor immunoreactivity was detected in all arteries, with the exception of small renal arteries . In general, P2 receptor-specific immunoreactivity was seen in the outer adventitial layer with a predominantly vesicular distribution. In the large coronary and cerebral arteries, weak diffuse P2 receptor immunoreactivity was also detected in the smooth muscle layer . P2 receptors are involved in sympathetic nerve-mediated vasoconstriction in small arteries of the rat hepatic mesentery . Smooth muscle layers of placental and umbilical blood vessels express functional P2 receptors , suggesting their participation in the humoral regulation of placental blood flow. This is novel, since the umbilical cord lacks sympathetic innervation , a documented source of ATP. In addition, ATP is capable of increasing contractile tension in cardiac tissue via P2X receptors , although the receptor subtype was not identified. While ATP can also induce vasodilation in isolated aortic preparations, the nature of the purinergic receptor site responsible was not characterized [109–111].
Apoptotic cell death is recognized to occur in a number of vascular diseases, including atherosclerosis, restenosis, and hypertension [112, 113]. Vascular endothelial cells are continuously exposed to variations in blood flow, and the shear stress that occurs during changes in blood flow causes a substantial release of ATP from endothelial cells , which might mediate alterations in the balance between proliferation and apoptosis . Occupancy of P2 receptors leads to the production of proinflammatory cytokines, and TNF- promotes endothelial cell apoptosis via the activation of caspase 3  which, conceivably, play a role in vascular remodeling in hypertension . Stimulation of P2 receptors on human dendritic cells induces the release of tissue factor-bearing microparticles , which may have implications for triggering and propagating coagulation either in healthy or atherosclerotic vessels. P2 receptor activation reportedly amplifies LPS-induced vascular hyporeactivity, due to IL-1 release from endothelial cells, in turn inducing downstream nitric oxide production . Thus, the P2 receptor may be an important regulator for vascular hypotensive responses in inflammation or inflammatory-related disease (Figure 5(b)). Intriguingly, evidence suggests that ambulatory blood pressure is associated with polymorphic variation in the P2 receptor gene .
In cutaneous vessels where purinergic neurotransmission is more prominent compared with deep vessels, physiological and pathological roles of nerve-released ATP have been described . P2 receptors expressed in human saphenous vein myocytes contribute to the contractile effect of ATP , and venous diseases may offer conditions allowing P2 receptor activation to cause lysis of venous myocytes. ATP released after hypoxia, stress, and inflammation, or membrane damage, conditions found in the vessel wall of varicose veins , as well as that generated by reduced ecto-ATPase activity , may lead to P2 receptor-induced pore formation, the disorganization and loss of contractile myocytes in the muscle layers of the media of varicose veins, and venous disease.
It is well established that both ATP and noradrenaline are coreleased from sympathetic nerve varicosities . Although in a range of muscular arteries both neurotransmitters contribute to neurally evoked contraction , ATP is the predominant sympathetic neurotransmitter in rat mesenteric arteries at high intraluminal pressure . The increased responses produced by ATP at higher pressures could contribute to or exacerbate the raised pressure observed in hypertension.
Fibroblasts are a key structural element of the arterial wall, major producers of extracellular matrix, and an active source of inflammatory mediators [127, 128]. In human pathology, fibroblast dysfunction is implicated in chronic degenerative diseases such as atherosclerosis and diabetic angiopathy . In the atheromatous lesion, fibroblasts are a source of mediators that stimulate endothelial cells and promote recruitment of leukocytes, thus accelerating damage of the arterial intima and media . In diabetes, the arterial wall undergoes accelerated degenerative changes , the pathogenesis of which is incompletely understood but that undoubtedly implicates profound modifications of fibroblast reactivity. In diabetic patients, fibroblast responses might be inherently aberrant , thus rendering these cells sensitive to inflammatory factors released into the blood or the arterial wall. It is likely that ATP is released at the site of atherosclerotic lesions or during platelet adhesion to the endothelium . It is interesting to note a recent study demonstrating that fibroblasts from type-2 diabetes patients are characterized by a hyperactive purinergic loop based either on a higher level of ATP release or an enhanced P2 receptor reactivity, together with an increased pericellular concentration of ATP, and a higher basal level of fibronectin secretion and spontaneous rate of apoptosis at least in part dependent on autocrine stimulation of P2 receptors by secreted ATP  (Figure 5(b)). Accumulation of fibronectin in the interstitial space (e.g., arterial wall) in diabetes is believed to play a major role in the pathogenesis of diabetic tissue damage . In another report, P2 receptor activation in diabetic rabbits led to a marked reduction in retinal blood velocity and function .
6. Concluding Remarks
It is now generally accepted that high levels of extracellular nucleotides such as ATP may be released under pathological conditions such as inflammation, trauma, and stress. Interestingly, a number of neurodegenerative conditions exhibit enhanced P2 receptor expression in the neuroinflammatory loci where activated microglia are a coexisting feature. Recent findings suggest that increased P2 receptor numbers drive microglial activation, rather than P2 receptor over-expression being a consequence of microglial activation . Signaling via P2 receptors may thus allow cells to sense and respond to events occurring in the extracellular environment, modulate the transcription of genes involved in cellular inflammatory processes, and to thus regulate cytokine responses. Given the distribution of P2 receptors and the fact that high concentrations of ATP are required to activate the receptor, this P2X receptor may be viewed as a ‘danger’ sensor. The therapeutic exploitation of P2 receptors is now under way because of their potential role, not only in such disorders as AD, spinal cord injury, and sensory neuropathies  but also in multiple sclerosis , inflammatory neuropathic pain , rheumatoid arthritis , as well as depressive illness. The discovery of P2 receptor-selective antagonists has provided data demonstrating that the acute blockage of P2 receptors significantly reduces nociception in animal models of persistent neuropathic and inflammatory pain, while there is growing appreciation for the role of P2 receptor modulation of proinflammatory IL-1 processing , the analgesic activity of P2 receptor antagonists [78, 79] indicates a specific role for P2 receptors in neuronal-glial cell interactions associated with ongoing pain . P2 receptors are expressed with some selectivity on different types of cells in the cardiovascular system, and drugs affecting P2 receptor signaling may have promise as clinical antihypertensive and antithrombotic agents . In this context, the P2 receptor may be viewed as a key point of communication between the nervous, immune, and cardiovascular systems. Further investigation of the P2 receptor with receptor subselective antagonists in preclinical studies as well as in disease-specific clinical trials will help to evaluate this target’s potential therapeutic use.
The authors wish to thank Stefano Lovison for excellent graphics design assistance.
- W. S. T. Griffin, J. G. Sheng, M. C. Royston et al., “Glial-neuronal interactions in Alzheimer's disease: the potential role of a ‘cytokine cycle’ in disease progression,” Brain Pathology, vol. 8, no. 1, pp. 65–72, 1998.
- J. M. Craft, D. M. Watterson, and L. J. van Eldik, “Neuroinflammation: a potential therapeutic target,” Expert Opinion on Therapeutic Targets, vol. 9, no. 5, pp. 887–900, 2005.
- P. L. McGeer, M. Schulzer, and E. G. McGeer, “Arthritis and anti-inflammatory agents as possible protective factors for Alzheimer's disease: a review of 17 epidemiologic studies,” Neurology, vol. 47, no. 2, pp. 425–432, 1996.
- P. L. McGeer and E. G. McGeer, “Polymorphisms in inflammatory genes and the risk of Alzheimer disease,” Archives of Neurology, vol. 58, no. 11, pp. 1790–1792, 2001.
- P. Eikelenboom and W. A. van Gool, “Neuroinflammatory perspectives on the two faces of Alzheimer's disease,” Journal of Neural Transmission, vol. 111, no. 3, pp. 281–294, 2004.
- P. L. McGeer and E. G. McGeer, “Inflammation and the degenerative diseases of aging,” Annals of the New York Academy of Sciences, vol. 1035, pp. 104–116, 2004.
- D. Langford and E. Masliah, “Crosstalk between components of the blood brain barrier and cells of the CNS in microglial activation in AIDS,” Brain Pathology, vol. 11, no. 3, pp. 306–312, 2001.
- V. H. Perry, C. Cunningham, and D. Boche, “Atypical inflammation in the central nervous system in prion disease,” Current Opinion in Neurology, vol. 15, no. 3, pp. 349–354, 2002.
- P. Teismann and J. B. Schulz, “Cellular pathology of Parkinson's disease: astrocytes, microglia and inflammation,” Cell and Tissue Research, vol. 318, no. 1, pp. 149–161, 2004.
- G. H. Danton and W. D. Dietrich, “Inflammatory mechanisms after ischemia and stroke,” Journal of Neuropathology and Experimental Neurology, vol. 62, no. 2, pp. 127–136, 2003.
- R. W. Keane, A. R. Davis, and W. D. Dietrich, “Inflammatory and apoptotic signaling after spinal cord injury,” Journal of Neurotrauma, vol. 23, no. 3-4, pp. 335–344, 2006.
- H. M. Bramlett and W. D. Dietrich, “Pathophysiology of cerebral ischemia and brain trauma: similarities and differences,” Journal of Cerebral Blood Flow and Metabolism, vol. 24, no. 2, pp. 133–150, 2004.
- R. A. North, “Molecular physiology of P2X receptors,” Physiological Reviews, vol. 82, no. 4, pp. 1013–1067, 2002.
- G. Burnstock, “Introduction: P2 receptors,” Current Topics in Medicinal Chemistry, vol. 4, no. 8, pp. 793–803, 2004.
- B. S. Khakh and R. A. North, “P2X receptors as cell-surface ATP sensors in health and disease,” Nature, vol. 442, no. 7102, pp. 527–532, 2006.
- R. A. North and A. Surprenant, “Pharmacology of cloned P2X receptors,” Annual Review of Pharmacology and Toxicology, vol. 40, pp. 563–580, 2000.
- A. Surprenant, F. Rassendren, E. Kawashima, R. A. North, and G. Buell, “The cytolytic receptor for extracellular ATP identified as a receptor (P2),” Science, vol. 272, no. 5262, pp. 735–738, 1996.
- T. M. Egan, D. S. K. Samways, and Z. Li, “Biophysics of P2X receptors,” Pflügers Archiv European Journal of Physiology, vol. 452, no. 5, pp. 501–512, 2006.
- G. Collo, S. Neidhart, E. Kawashima, M. Kosco-Vilbois, R. A. North, and G. Buell, “Tissue distribution of the P2 receptor,” Neuropharmacology, vol. 36, no. 9, pp. 1277–1283, 1997.
- J. A. Sim, M. T. Young, H.-Y. Sung, R. A. North, and A. Surprenant, “Reanalysis of P2 receptor expression in rodent brain,” The Journal of Neuroscience, vol. 24, no. 28, pp. 6307–6314, 2004.
- C. M. Anderson and M. Nedergaard, “Emerging challenges of assigning P2 receptor function and immunoreactivity in neurons,” Trends in Neurosciences, vol. 29, no. 5, pp. 257–262, 2006.
- X.-F. Zhang, P. Han, C. R. Faltynek, M. F. Jarvis, and C.-C. Shieh, “Functional expression of P2 receptors in non-neuronal cells of rat dorsal root ganglia,” Brain Research, vol. 1052, no. 1, pp. 63–70, 2005.
- D. Ferrari, P. Chiozzi, S. Falzoni, S. Hanau, and F. Di Virgilio, “Purinergic modulation of interleukin-1 release from microglial cells stimulated with bacterial endotoxin,” Journal of Experimental Medicine, vol. 185, no. 3, pp. 579–582, 1997.
- C. Virginio, A. MacKenzie, R. A. North, and A. Surprenant, “Kinetics of cell lysis, dye uptake and permeability changes in cells expressing the rat P2 receptor,” The Journal of Physiology, vol. 519, no. 2, pp. 335–346, 1999.
- A. Filippini, R. E. Taffs, T. Agui, and M. V. Sitkovsky, “Ecto-ATPase activity in cytolytic T-lymphocytes. Protection from the cytolytic effects of extracellular ATP,” The Journal of Biological Chemistry, vol. 265, no. 1, pp. 334–340, 1990.
- A. Sikora, J. Liu, C. Brosnan, G. Buell, I. Chessel, and B. R. Bloom, “Cutting edge: purinergic signaling regulates radical-mediated bacterial killing mechanisms in macrophages through a P2-independent mechanism,” The Journal of Immunology, vol. 163, no. 2, pp. 558–561, 1999.
- D. Ferrari, P. Chiozzi, S. Falzoni et al., “ATP-mediated cytotoxicity in microglial cells,” Neuropharmacology, vol. 36, no. 9, pp. 1295–1301, 1997.
- R. Beigi, E. Kobatake, M. Aizawa, and G. R. Dubyak, “Detection of local ATP release from activated platelets using cell surface-attached firefly luciferase,” American Journal of Physiology, vol. 276, no. 1, pp. C267–C278, 1999.
- G. R. Dubyak and C. el-Moatassim, “Signal transduction via P2-purinergic receptors for extracellular ATP and other nucleotides,” The American Journal of Physiology, vol. 265, no. 3, pp. C577–C606, 1993.
- E. R. Lazarowski, R. C. Boucher, and T. K. Harden, “Constitutive release of ATP and evidence for major contribution of ecto-nucleotide pyrophosphatase and nucleoside diphosphokinase to extracellular nucleotide concentrations,” The Journal of Biological Chemistry, vol. 275, no. 40, pp. 31061–31068, 2000.
- K. Nieber, D. Eschke, and A. Brand, “Brain hypoxia: effects of ATP and adenosine,” Progress in Brain Research, vol. 120, pp. 287–297, 1999.
- B. D. Humphreys and G. R. Dubyak, “Modulation of P2 nucleotide receptor expression by pro- and anti-inflammatory stimuli in THP-1 monocytes,” Journal of Leukocyte Biology, vol. 64, no. 2, pp. 265–273, 1998.
- L. Narcisse, E. Scemes, Y. Zhao, S. C. Lee, and C. F. Brosnan, “The cytokine IL-1 transiently enhances P2 receptor expression and function in human astrocytes,” GLIA, vol. 49, no. 2, pp. 245–258, 2005.
- M. Solle, J. Labasi, D. G. Perregaux et al., “Altered cytokine production in mice lacking P2 receptors,” The Journal of Biological Chemistry, vol. 276, no. 1, pp. 125–132, 2001.
- J. M. Labasi, N. Petrushova, C. Donovan et al., “Absence of the P2 receptor alters leukocyte function and attenuates an inflammatory response,” The Journal of Immunology, vol. 168, no. 12, pp. 6436–6445, 2002.
- I. P. Chessell, J. P. Hatcher, C. Bountra et al., “Disruption of the P2 purinoceptor gene abolishes chronic inflammatory and neuropathic pain,” Pain, vol. 114, no. 3, pp. 386–396, 2005.
- L. K. Parvathenani, S. Tertyshnikova, C. R. Greco, S. B. Roberts, B. Robertson, and R. Posmantur, “P2 mediates superoxide production in primary microglia and is up-regulated in a transgenic mouse model of Alzheimer's disease,” The Journal of Biological Chemistry, vol. 278, no. 15, pp. 13309–13317, 2003.
- A. M. Basso, N. A. Bratcher, R. R. Harris, M. F. Jarvis, M. W. Decker, and L. E. Rueter, “Behavioral profile of P2 receptor knockout mice in animal models of depression and anxiety: relevance for neuropsychiatric disorders,” Behavioural Brain Research, vol. 198, no. 1, pp. 83–90, 2009.
- G. D. Eslick, B. V. Thampan, M. Nalos, A. S. McLean, and R. Sluyter, “Circulating interleukin-18 concentrations and a loss-of-function P2X7 polymorphism in heart failure,” International Journal of Cardiology. In press.
- B. D. Humphreys, J. Rice, S. B. Kertesy, and G. R. Dubyak, “Stress-activated protein kinase/JNK activation and apoptotic induction by the macrophage P2X7 nucleotide receptor,” The Journal of Biological Chemistry, vol. 275, no. 35, pp. 26792–26798, 2000.
- M. Aga, C. J. Johnson, A. P. Hart et al., “Modulation of monocyte signaling and pore formation in response to agonists of the nucleotide receptor P2,” Journal of Leukocyte Biology, vol. 72, no. 1, pp. 222–232, 2002.
- Y. D. Potucek, J. M. Crain, and J. J. Watters, “Purinergic receptors modulate MAP kinases and transcription factors that control microglial inflammatory gene expression,” Neurochemistry International, vol. 49, no. 2, pp. 204–214, 2006.
- A. Rao, C. Luo, and P. G. Hogan, “Transcription factors of the NFAT family: regulation and function,” Annual Review of Immunology, vol. 15, pp. 707–747, 1997.
- D. Ferrari, C. Stroh, and K. Schulze-Osthoff, “P2/P2Z purinoreceptor-mediated activation of transcription factor NFAT in microglial cells,” The Journal of Biological Chemistry, vol. 274, no. 19, pp. 13205–13210, 1999.
- B. Mayr and M. Montminy, “Transcriptional regulation by the phosphorylation-dependent factor CREB,” Nature Reviews Molecular Cell Biology, vol. 2, no. 8, pp. 599–609, 2001.
- V. C. Foletta, D. H. Segal, and D. R. Cohen, “Transcriptional regulation in the immune system: all roads lead to AP-1,” Journal of Leukocyte Biology, vol. 63, no. 2, pp. 139–152, 1998.
- V. Budagian, E. Bulanova, L. Brovko et al., “Signaling through P2X7 receptor in human T cells involves p, MAP kinases, and transcription factors AP-1 and NF-B,” The Journal of Biological Chemistry, vol. 278, no. 3, pp. 1549–1560, 2003.
- J. J. Watters, J. A. Sommer, P. L. Fisette et al., “P2 nucleotide receptor: modulation of LPS-induced macrophage signaling and mediator production,” Drug Development Research, vol. 53, no. 2-3, pp. 91–104, 2001.
- E. Adinolfi, M. Kim, M. T. Young, F. Di Virgilio, and A. Surprenant, “Tyrosine phosphorylation of HSP90 within the P2 receptor complex negatively regulates P2 receptors,” The Journal of Biological Chemistry, vol. 278, no. 39, pp. 37344–37351, 2003.
- M. Aga, J. J. Watters, Z. A. Pfeiffer, G. J. Wiepz, J. A. Sommer, and P. J. Bertics, “Evidence for nucleotide receptor modulation of cross talk between MAP kinase and NF-B signaling pathways in murine RAW 264.7 macrophages,” American Journal of Physiology, vol. 286, no. 4, pp. C923–C930, 2004.
- Z. A. Pfeiffer, M. Aga, U. Prabhu, J. J. Watters, D. J. Hall, and P. J. Bertics, “The nucleotide receptor P2X7 mediates actin reorganization and membrane blebbing in RAW 264.7 macrophages via p38 MAP kinase and Rho,” Journal of Leukocyte Biology, vol. 75, no. 6, pp. 1173–1182, 2004.
- A. MacKenzie, H. L. Wilson, E. Kiss-Toth, S. K. Dower, R. A. North, and A. Surprenant, “Rapid secretion of interleukin-1 by microvesicle shedding,” Immunity, vol. 15, no. 5, pp. 825–835, 2001.
- S. M. Allan and N. J. Rothwell, “Cytokines and acute neurodegeneration,” Nature Reviews Neuroscience, vol. 2, no. 10, pp. 734–744, 2001.
- R. Le Feuvre, D. Brough, and N. Rothwell, “Extracellular ATP and P2X7 receptors in neurodegeneration,” European Journal of Pharmacology, vol. 447, no. 2-3, pp. 261–269, 2002.
- L. Bernardino, S. Balosso, T. Ravizza et al., “Inflammatory events in hippocampal slice cultures prime neuronal susceptibility to excitotoxic injury: a crucial role of P2 receptor-mediated IL-1 release,” Journal of Neurochemistry, vol. 106, no. 1, pp. 271–280, 2008.
- X. Wang, G. Arcuino, T. Takano et al., “P2X7 receptor inhibition improves recovery after spinal cord injury,” Nature Medicine, vol. 10, no. 8, pp. 821–827, 2004.
- S. D. Skaper, L. Facci, A. A. Culbert et al., “P2 receptors on microglial cells mediate injury to cortical neurons in vitro,” GLIA, vol. 54, no. 3, pp. 234–242, 2006.
- H. Franke, A. Günther, J. Grosche et al., “P2 receptor expression after ischemia in the cerebral cortex of rats,” Journal of Neuropathology and Experimental Neurology, vol. 63, no. 7, pp. 686–699, 2004.
- C. Volanté, S. Amadio, F. Cavaliere, N. D'Ambrosi, F. Vacca, and G. Bernardi, “Extracellular ATP and neurodegeneration,” Current Drug Targets-CNS & Neurological Disorders, vol. 2, no. 6, pp. 403–412, 2003.
- S. Honda, Y. Sasaki, K. Ohsawa et al., “Extracellular ATP or ADP induce chemotaxis of cultured microglia through -coupled P2Y receptors,” The Journal of Neuroscience, vol. 21, no. 6, pp. 1975–1982, 2001.
- C. Verderio and M. Matteoli, “ATP mediates calcium signaling between astrocytes and microglial cells: modulation by IFN-,” The Journal of Immunology, vol. 166, no. 10, pp. 6383–6391, 2001.
- G. Burnstock and J. N. Wood, “Purinergic receptors: their role in nociception and primary afferent neurotransmission,” Current Opinion in Neurobiology, vol. 6, no. 4, pp. 526–532, 1996.
- R. D. Fields and G. Burnstock, “Purinergic signalling in neuron-glia interactions,” Nature Reviews Neuroscience, vol. 7, no. 6, pp. 423–436, 2006.
- C. E. Jahr and T. M. Jessell, “ATP excites a subpopulation of rat dorsal horn neurones,” Nature, vol. 304, no. 5928, pp. 730–733, 1983.
- E. L. Werry, G. J. Liu, and M. R. Bennett, “Glutamate-stimulated ATP release from spinal cord astrocytes is potentiated by substance P,” Journal of Neurochemistry, vol. 99, no. 3, pp. 924–936, 2006.
- V. Raghavendra and J. A. DeLeo, “The role of astrocytes and microglia in persistent pain,” Advances in Molecular and Cell Biology, vol. 31, pp. 951–966, 2003.
- E. D. Milligan, S. F. Maier, and L. R. Watkins, “Review: neuronal-glial interactions in central sensitization,” Seminars in Pain Medicine, vol. 1, no. 3, pp. 171–183, 2003.
- M. Costigan and C. J. Woolf, “Pain: molecular mechanisms,” The Journal of Pain, vol. 1, no. 3, part 2, pp. 35–44, 2000.
- G. Dell'Antonio, A. Quattrini, E. Dal Cin, A. Fulgenzi, and M. E. Ferrero, “Antinociceptive effect of a new /P2X7 antagonist, oxidized ATP, in arthritic rats,” Neuroscience Letters, vol. 327, no. 2, pp. 87–90, 2002.
- O. Touzani, H. Boutin, R. Lefeuvre et al., “Interleukin-1 influences ischemic brain damage in the mouse independently of the interleukin-1 type I receptor,” The Journal of Neuroscience, vol. 22, no. 1, pp. 38–43, 2002.
- B. Safieh-Garabedian, S. Poole, A. Allchorne, J. Winter, and C. J. Woolf, “Contribution of interleukin-1 to the inflammation-induced increase in nerve growth factor levels and inflammatory hyperalgesia,” British Journal of Pharmacology, vol. 115, no. 7, pp. 1265–1275, 1995.
- C. Sommer, S. Petrausch, T. Lindenlaub, and K. V. Toyka, “Neutralizing antibodies to interleukin 1-receptor reduce pain associated behavior in mice with experimental neuropathy,” Neuroscience Letters, vol. 270, no. 1, pp. 25–28, 1999.
- G. H. Merriman, L. Ma, P. Shum et al., “Synthesis and SAR of novel 4,5-diarylimidazolines as potent receptor antagonists,” Bioorganic and Medicinal Chemistry Letters, vol. 15, no. 2, pp. 435–438, 2005.
- D. W. Nelson, R. J. Gregg, M. E. Kort et al., “Structure-activity relationship studies on a series of novel, substituted 1-benzyl-5-phenyltetrazole antagonists,” Journal of Medicinal Chemistry, vol. 49, no. 12, pp. 3659–3666, 2006.
- W. A. Carroll, D. M. Kalvin, A. Perez-Medrano et al., “Novel and potent 3-(2,3-dichlorophenyl)-4-(benzyl)-4-1,2,4-triazole antagonists,” Bioorganic & Medicinal Chemistry Letters, vol. 17, no. 14, pp. 4044–4048, 2007.
- M. Furber, L. Alcaraz, J. E. Bent et al., “Discovery of potent and selective adamantane-based small-molecule receptor antagonists/interleukin-1 inhibitors,” Journal of Medicinal Chemistry, vol. 50, no. 24, pp. 5882–5885, 2007.
- D. W. Nelson, K. Sarris, D. M. Kalvin et al., “Structure-activity relationship studies on -aryl carbohydrazide antagonists,” Journal of Medicinal Chemistry, vol. 51, no. 10, pp. 3030–3034, 2008.
- P. Honore, D. Donnelly-Roberts, M. T. Namovic et al., “A-740003 [-(1-[(cyanoimino)(5-quinolinylamino) methyl]amino-2,2- dimethylpropyl)-2-(3,4-dimethoxyphenyl)acetamide], a novel and selective receptor antagonist, dose-dependently reduces neuropathic pain in the rat,” Journal of Pharmacology and Experimental Therapeutics, vol. 319, no. 3, pp. 1376–1385, 2006.
- S. McGaraughty, K. L. Chu, M. T. Namovic et al., “-related modulation of pathological nociception in rats,” Neuroscience, vol. 146, no. 4, pp. 1817–1828, 2007.
- D. C. Broom, D. J. Matson, E. Bradshaw et al., “Characterization of -(adamantan-1-ylmethyl)-5-[(3-amino-pyrrolidin-1-yl) methyl]-2-chloro-benzamide, a antagonist in animal models of pain and inflammation,” Journal of Pharmacology and Experimental Therapeutics, vol. 327, no. 3, pp. 620–633, 2008.
- R. S. Smith, “The macrophage theory of depression,” Medical Hypotheses, vol. 35, no. 4, pp. 298–306, 1991.
- H. Anisman, Z. Merali, M. O. Poulter, and S. Hayley, “Cytokines as a precipitant of depressive illness: animal and human studies,” Current Pharmaceutical Design, vol. 11, no. 8, pp. 963–972, 2005.
- Y. Pollak and R. Yirmiya, “Cytokine-induced changes in mood and behaviour: implications for ‘depression due to a general medical condition’, immunotherapy and antidepressive treatment,” International Journal of Neuropsychopharmacology, vol. 5, no. 4, pp. 389–399, 2002.
- S. Hayley, M. O. Poulter, Z. Merali, and H. Anisman, “The pathogenesis of clinical depression: stressor- and cytokine-induced alterations of neuroplasticity,” Neuroscience, vol. 135, no. 3, pp. 659–678, 2005.
- M. R. Kraus, A. Schäfer, H. Faller, H. Csef, and M. Scheurlen, “Paroxetine for the treatment of interferon--induced depression in chronic hepatitis C,” Alimentary Pharmacology and Therapeutics, vol. 16, no. 6, pp. 1091–1099, 2002.
- J. Steiner, H. Bielau, R. Brisch et al., “Immunological aspects in the neurobiology of suicide: elevated microglial density in schizophrenia and depression is associated with suicide,” Journal of Psychiatric Research, vol. 42, no. 2, pp. 151–157, 2008.
- C. L. Raison, L. Capuron, and A. H. Miller, “Cytokines sing the blues: inflammation and the pathogenesis of depression,” Trends in Immunology, vol. 27, no. 1, pp. 24–31, 2006.
- C. Tuglu, S. H. Kara, O. Caliyurt, E. Vardar, and E. Abay, “Increased serum tumor necrosis factor-alpha levels and treatment response in major depressive disorder,” Psychopharmacology, vol. 170, no. 4, pp. 429–433, 2003.
- S. Alesci, P. E. Martinez, S. Kelkar et al., “Major depression is associated with significant diurnal elevations in plasma interleukin-6 levels, a shift of its circadian rhythm, and loss of physiological complexity in its secretion: clinical implications,” The Journal of Clinical Endocrinology & Metabolism, vol. 90, no. 5, pp. 2522–2530, 2005.
- B. B. Simen, C. H. Duman, A. A. Simen, and R. S. Duman, “TNF signaling in depression and anxiety: behavioral consequences of individual receptor targeting,” Biological Psychiatry, vol. 59, no. 9, pp. 775–785, 2006.
- N. Barden, M. Harvey, B. Gagné et al., “Analysis of single nucleotide polymorphisms in genes in the chromosome 12Q24.31 region points to P2RX7 as a susceptibility gene to bipolar affective disorder,” American Journal of Medical Genetics Part B, vol. 141, no. 4, pp. 374–382, 2006.
- S. Lucae, D. Salyakina, N. Barden et al., “P2RX7, a gene coding for a purinergic ligand-gated ion channel, is associated with major depressive disorder,” Human Molecular Genetics, vol. 15, no. 16, pp. 2438–2445, 2006.
- K. Hejjas, A. Szekely, E. Domotor et al., “Association between depression and the Gln460Arg polymorphism of P2RX7 gene: a dimensional approach,” American Journal of Medical Genetics Part B, vol. 150, no. 2, pp. 295–299, 2009.
- J. S. Wiley, L.-P. Dao-Ung, C. Li et al., “An Ile-568 to Asn polymorphism prevents normal trafficking and function of the human receptor,” The Journal of Biological Chemistry, vol. 278, no. 19, pp. 17108–17113, 2003.
- L. C. Denlinger, G. Angelini, K. Schell et al., “Detection of human nucleotide receptor polymorphisms by a novel monocyte pore assay predictive of alterations in lipopolysaccharide-induced cytokine production,” The Journal of Immunology, vol. 174, no. 7, pp. 4424–4431, 2005.
- A. M. Basso, N. A. Bratcher, R. R. Harris, M. F. Jarvis, M. W. Decker, and L. E. Rueter, “Behavioral profile of receptor knockout mice in animal models of depression and anxiety: relevance for neuropsychiatric disorders,” Behavioural Brain Research, vol. 198, no. 1, pp. 83–90, 2009.
- M. Maes, “The immunoregulatory effects of antidepressants,” Human Psychopharmacology, vol. 16, no. 1, pp. 95–103, 2001.
- Z. Xia, J. W. DePierre, and L. Nässberger, “Tricyclic antidepressants inhibit IL-6, IL-1 and TNF- release in human blood monocytes and IL-2 and interferon- in T cells,” Immunopharmacology, vol. 34, no. 1, pp. 27–37, 1996.
- D. Brustolim, R. Ribeiro-dos-Santos, R. E. Kast, E. L. Altschuler, and M. B. P. Soares, “A new chapter opens in anti-inflammatory treatments:the antidepressant bupropion lowers production of tumor necrosis factor-alpha and interferon-gamma in mice,” International Immunopharmacology, vol. 6, no. 6, pp. 903–907, 2006.
- R. Yirmiya, Y. Pollak, O. Barak et al., “Effects of antidepressant drugs on the behavioral and physiological responses to lipopolysaccharide (LPS) in rodents,” Neuropsychopharmacology, vol. 24, no. 5, pp. 531–544, 2001.
- S. Lanquillon, J.-C. Krieg, U. Bening-Abu-Shach, and H. Vedder, “Cytokine production and treatment response in major depressive disorder,” Neuropsychopharmacology, vol. 22, no. 4, pp. 370–379, 2000.
- V. Ralevic, “Purines as neurotransmitters and neuromodulators in blood vessels,” Current Vascular Pharmacology, vol. 7, no. 1, pp. 3–14, 2009.
- R. A. Olsson and J. D. Pearson, “Cardiovascular purinoceptors,” Physiological Reviews, vol. 70, no. 3, pp. 761–845, 1990.
- C. J. Lewis and R. J. Evans, “P2X receptor immunoreactivity in different arteries from the femoral, pulmonary, cerebral, coronary and renal circulations,” Journal of Vascular Research, vol. 38, no. 4, pp. 332–340, 2001.
- J. K. Phillips, A. J. McLean, and C. E. Hill, “Receptors involved in nerve-mediated vasoconstriction in small arteries of the rat hepatic mesentery,” British Journal of Pharmacology, vol. 124, no. 7, pp. 1403–1412, 1998.
- P. Valdecantos, R. Briones, P. Moya, A. Germain, and J. P. Huidobro-Toro, “Pharmacological identification of , and nucleotide receptors in the smooth muscles of human umbilical cord and chorionic blood vessels,” Placenta, vol. 24, no. 1, pp. 17–26, 2003.
- F. D. Reilly and P. T. Russell, “Neurohistochemical evidence supporting an absence of adrenergic and cholinergic innervation in the human placenta and umbilical cord,” Anatomical Record, vol. 188, no. 3, pp. 277–286, 1977.
- G. Froldi, K. Varani, A. Chinellato, E. Ragazzi, L. Caparrotta, and P. A. Borea, “P2X-purinoceptors in the heart: actions of ATP and UTP,” Life Sciences, vol. 60, no. 17, pp. 1419–1430, 1997.
- A. Chinellato, E. Ragazzi, L. Pandolfo, G. Froldi, L. Caparrotta, and G. Fassina, “Pharmacological characterization of ATP receptors mediating vasodilation on isolated rabbit aorta,” General Pharmacology, vol. 23, no. 5, pp. 861–865, 1992.
- A. Chinellato, E. Ragazzi, L. Pandolfo, G. Froldi, L. Caparrotta, and G. Fassina, “Pharmacological characterization of a new purinergic receptor site in rabbit aorta,” General Pharmacology, vol. 23, no. 6, pp. 1067–1071, 1992.
- A. Chinellato, E. Ragazzi, L. Pandolfo, G. Froldi, L. Caparrotta, and G. Fassina, “Purine- and nucleotide-mediated relaxation of rabbit thoracic aorta: common and different sites of action,” Journal of Pharmacy and Pharmacology, vol. 46, no. 5, pp. 337–341, 1994.
- W. A. Thomas, J. M. Reiner, R. A. Florentin, K. T. Lee, and W. M. Lee, “Population dynamics of arterial smooth muscle cells: V. Cell proliferation and cell death during initial 3 months in atherosclerotic lesions induced in swine by hypercholesterolemic diet and intimal trauma,” Experimental and Molecular Pathology, vol. 24, no. 3, pp. 360–374, 1976.
- Z. Mallat and A. Tedgui, “Apoptosis in the vasculature: mechanisms and functional importance,” British Journal of Pharmacology, vol. 130, no. 5, pp. 947–962, 2000.
- G. Burnstock, “Release of vasoactive substances from endothelial cells by shear stress and purinergic mechanosensory transduction,” Journal of Anatomy, vol. 194, no. 3, pp. 335–342, 1999.
- D. Kaiser, M.-A. Freyberg, and P. Friedl, “Lack of hemodynamic forces triggers apoptosis in vascular endothelial cells,” Biochemical and Biophysical Research Communications, vol. 231, no. 3, pp. 586–590, 1997.
- G. H. Gibbons, “Autocrine-paracrine factors and vascular remodeling in hypertension,” Current Opinion in Nephrology and Hypertension, vol. 2, no. 2, pp. 291–298, 1993.
- M. Baroni, C. Pizzirani, M. Pinotti et al., “Stimulation of P2 () receptors in human dendritic cells induces the release of tissue factor-bearing microparticles,” The FASEB Journal, vol. 21, no. 8, pp. 1926–1933, 2007.
- C.-W. Chiao, R. C. Tostes, and R. C. Webb, “ receptor activation amplifies lipopolysaccharide-induced vascular hyporeactivity via interleukin-1 release,” Journal of Pharmacology and Experimental Therapeutics, vol. 326, no. 3, pp. 864–870, 2008.
- J. Palomino-Doza, T. J. Rahman, P. J. Avery et al., “Ambulatory blood pressure is associated with polymorphic variation in P2X receptor genes,” Hypertension, vol. 52, no. 5, pp. 980–985, 2008.
- A. Pelleg and G. Burnstock, “Physiological importance of ATP released from nerve terminals and its degradation to adenosine in humans,” Circulation, vol. 82, no. 6, pp. 2269–2272, 1990.
- C. Cario-Toumaniantz, G. Loirand, A. Ladoux, and P. Pacaud, “ receptor activation-induced contraction and lysis in human saphenous vein smooth muscle,” Circulation Research, vol. 83, no. 2, pp. 196–203, 1998.
- C. Michiels, T. Arnould, and J. Remacle, “Hypoxia-induced activation of endothelial cells as a possible cause of venous diseases: hypothesis,” Angiology, vol. 44, no. 8, pp. 639–646, 1993.
- S. C. Robson, E. Kaczmarek, J. B. Siegel et al., “Loss of ATP diphosphohydrolase activity with endothelial cell activation,” Journal of Experimental Medicine, vol. 185, no. 1, pp. 153–163, 1997.
- J. A. Brock and T. C. Cunnane, “Effects of concentration and channel blockers on noradrenaline release and purinergic neuroeffector transmission in rat tail artery,” British Journal of Pharmacology, vol. 126, no. 1, pp. 11–18, 1999.
- D. Ramme, J. T. Regenold, K. Starke, R. Busse, and P. Illes, “Identification of the neuroeffector transmitter in jejunal branches of the rabbit mesenteric artery,” Naunyn-Schmiedeberg's Archives of Pharmacology, vol. 336, no. 3, pp. 267–273, 1987.
- N. M. Rummery, J. A. Brock, P. Pakdeechote, V. Ralevic, and W. R. Dunn, “ATP is the predominant sympathetic neurotransmitter in rat mesenteric arteries at high pressure,” The Journal of Physiology, vol. 582, no. 2, pp. 745–754, 2007.
- J. N. Wilcox and N. A. Scott, “Potential role of the adventitia in arteritis and atherosclerosis,” International Journal of Cardiology, vol. 54, pp. S21–S35, 1996.
- C. D. Buckley, D. Pilling, J. M. Lord, A. N. Akbar, D. Scheel-Toellner, and M. Salmon, “Fibroblasts regulate the switch from acute resolving to chronic persistent inflammation,” Trends in Immunology, vol. 22, no. 4, pp. 199–204, 2001.
- D. Strehlow and J. H. Korn, “Biology of the scleroderma fibroblast,” Current Opinion in Rheumatology, vol. 10, no. 6, pp. 572–578, 1998.
- E. Chiquette and R. Chilton, “Cardiovascular disease: much more aggressive in patients with type 2 diabetes,” Current Atherosclerosis Reports, vol. 4, no. 2, pp. 134–142, 2002.
- M. A. M. Loots, S. B. Kenter, F. L. Au et al., “Fibroblasts derived from chronic diabetic ulcers differ in their response to stimulation with EGF, IGF-I, bFGF and PDGF-AB compared to controls,” European Journal of Cell Biology, vol. 81, no. 3, pp. 153–160, 2002.
- F. Di Virgilio and A. Solini, “P2 receptors: new potential players in atherosclerosis,” The British Journal of Pharmacology, vol. 135, no. 4, pp. 831–842, 2002.
- A. Solini, P. Chiozzi, A. Morelli et al., “Enhanced activity in human fibroblasts from diabetic patients: a possible pathogenetic mechanism for vascular damage in diabetes,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 24, no. 7, pp. 1240–1245, 2004.
- J. L. Andersen, L. M. Rasmussen, and J. P. Ledet, “Diabetic macroangiopathy and atherosclerosis,” Diabetes, vol. 45, pp. S91–S94, 1996.
- T. Sugiyama, H. Oku, A. Komori, and T. Ikeda, “Effect of receptor activation on the retinal blood velocity of diabetic rabbits,” Archives of Ophthalmology, vol. 124, no. 8, pp. 1143–1149, 2006.
- M. Monif, C. A. Reid, K. L. Powell, M. L. Smart, and D. A. Williams, “The receptor drives microglial activation and proliferation: a trophic role for R pore,” The Journal of Neuroscience, vol. 29, no. 12, pp. 3781–3791, 2009.
- B. Sperlágh, E. S. Vizi, K. Wirkner, and P. Illes, “ receptors in the nervous system,” Progress in Neurobiology, vol. 78, no. 6, pp. 327–346, 2006.
- A. Witting, L. Chen, E. Cudaback et al., “Experimental autoimmune encephalomyelitis disrupts endocannabinoid-mediated neuroprotection,” Proceedings of the National Academy of Sciences of the United States of America, vol. 103, no. 16, pp. 6362–6367, 2006.
- D. Ferrari, C. Pizzirani, E. Adinolfi et al., “The P2 receptor: a key player in IL-1 processing and release,” The Journal of Immunology, vol. 176, no. 7, pp. 3877–3883, 2006.
- V. Ralevic and G. Burnstock, “Involvement of purinergic signaling in cardiovascular diseases,” Drug News and Perspectives, vol. 16, no. 3, pp. 133–140, 2003.
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