Neural Plasticity

Neural Plasticity / 2020 / Article

Review Article | Open Access

Volume 2020 |Article ID 1969482 |

Wei Liu, Xiaohui Wang, Margaret O’Connor, Guan Wang, Fang Han, "Brain-Derived Neurotrophic Factor and Its Potential Therapeutic Role in Stroke Comorbidities", Neural Plasticity, vol. 2020, Article ID 1969482, 13 pages, 2020.

Brain-Derived Neurotrophic Factor and Its Potential Therapeutic Role in Stroke Comorbidities

Academic Editor: Francesca Foti
Received01 Aug 2019
Revised14 Oct 2019
Accepted08 Nov 2019
Published27 Jan 2020


With the rise in the aging global population, stroke comorbidities have become a serious health threat and a tremendous economic burden on human society. Current therapeutic strategies mainly focus on protecting neurons from cytotoxic damage at the acute phase upon stroke onset, which not only is a difficult way to ameliorate stroke symptoms but also presents a challenge for the patients to receive effective treatment in time. The brain-derived neurotrophic factor (BDNF) is the most abundant neurotrophin in the adult brain, which possesses a remarkable capability to repair brain damage. Recent promising preclinical outcomes have made BDNF a popular late-stage target in the development of novel stroke treatments. In this review, we aim to summarize the latest progress in the understanding of the cellular/molecular mechanisms underlying stroke pathogenesis, current strategies and difficulties in drug development, the mechanism of BDNF action in poststroke neurorehabilitation and neuroplasticity, and recent updates in novel therapeutic methods.

1. Introduction

Stroke is a destructive cerebrovascular disease that occurs when a blood vessel carrying oxygen and nutrients to the brain either bursts or is blocked by a clot. As the second leading cause of human death and the third leading cause of disability, stroke claims around 6.5 million lives and 44 million disability-adjusted life-years (DALYs) globally every year. Thus, this disease has become an enormous threat to human health and a huge burden to the healthcare system worldwide [14]. So far, the only FDA-approved medication for ischemic stroke is the tissue plasminogen activator (tPA) when applied within 3 hours of an acute ischemic stroke attack, which therefore benefits only a small portion of the patients (2-5%) [57]. A great deal of effort has been made toward developing neuroprotectants, which mostly aim to block individual cytotoxic pathways in the early stages of stroke pathogenesis. However, clinical trials for these neuroprotective drugs have had little success, possibly due to the involvement of complex mechanisms in the cytotoxic and neuronal death processes during stroke [8, 9]. This failure demanded a change in strategy for the development of stroke therapeutics.

In recent years, neurorehabilitation and recovery have become new popular directions in the scientific research and drug development of stroke. As a result, neurotrophins have become a rising star in this field. Of particular interest is BDNF, due to its high cerebral abundance and ability to attenuate neuronal injury and repair brain damage. Preclinical studies using BDNF, or its mimetics, have generated promising results in the treatment of acute brain injuries and are on track for use in clinical trials in the near future [1012]. In this review, we aim to summarize recent progress in the research and development of stroke therapeutics, including the challenges and potential of BDNF and its downstream signaling pathways as new targets.

2. Stroke Pathogenesis: The Molecular Mechanisms

By continuing to expand our knowledge of the molecular mechanisms underlying the pathogenesis of stroke, we stand a better chance in the fight against this devastating disease. Thanks to decades of joint effort across human society, we now understand more about what occurs at the molecular level in a poststroke brain, which has conversely helped scientists to study this disease in more detail as well as to aid them in developing new therapeutic plans for treatment.

Although stroke is classified as ischemic or hemorrhagic depending on the pathophysiology (ischemia or hemorrhage), the clinical presentation of stroke in patients is largely the same independent of the cause [13]. In the case of ischemia, clotting within the brain cuts off the core supply of oxygen and glucose causing a drastic reduction in the peri-infarct area. Influenced cells in the ischemic area experience energy depletion or reduction, leading to failures in ATP-dependent pumps and ionic imbalance. This subsequently results in cell membrane depolarization and increased permeability, accompanied with the release of excitotoxic neurotransmitters and activation of glutamate receptors. Through the opened glutamate receptor ion channels, Ca2+ and Na+ influxes cause an overload in cytoplasmic ions, which subsequently activate lipid peroxidases, proteases, and phospholipases. High levels of Ca2+, Na+, and ADP result in the production of oxygen radicals and the opening of mitochondrial permeability transition pores, which eventually triggers apoptosis cascades. Thereafter, immune responses follow with microglia activation, proinflammatory cytokine release, and immune cell infiltration through the compromised blood-brain barrier (BBB) (Figure 1) [14].

In the case of intracerebral hemorrhage, in addition to the pathological processes triggered by the loss of oxygen and glucose supply, burst blood vessels add complexity to the disease by introducing even more components that are deleterious to the brain. These components include nucleic acids, proteins, and lipids as well as components of the complement system, immunoglobulin, and cells that release toxic prooxidative and proinflammation substances. Moreover, continuous secondary damage is caused by hemoglobin released by lysed red blood cells. It degrades into heme and iron, which further generate free radicals that damage macromolecules in healthy cells [15]. In this kind of stroke, the clean-up of the hematoma is important for long-term recovery after hemorrhagic stroke.

3. Current Barriers and Strategies to Treat Stroke

Due to the different physiological conditions of stroke-insulted brains, along with the variety of possible causes and subsequent pathological events, there are enormous complexities and barriers to the effective treatment of stroke. To date, the only FDA-approved drug for ischemic stroke is the tPA that breaks down blood clots in the brain. However, as shown in clinical studies, treatment with tPA is only effective if administered within 4.5 hours postischemia. Although it was recently reported that the timeframe for effective thrombolysis treatment extends up to 9 hours after the onset of a stroke, this time window remains narrow [57], not to mention the side effects of tPA, which include enhanced risk of brain hemorrhage. In fact, the number of patients actually benefiting from tPA is very limited (2-5%) [16].

Thus far, strategies to treat stroke have mainly focused on intervention in its pathological process. N-Methyl-D-aspartic acid receptor (NMDAR) antagonists, free radical scavengers, and molecules reducing immune cell infiltration have already shown promising results in animal models [8, 1720]; however, all of these treatments have unfortunately failed in clinical trials [8, 9]. In general, the failures could be attributed to several challenges. Firstly, there is the narrow time window for treatment. Upon stroke, excitotoxic neurotransmitters, Ca2+, and free radicals start to accumulate rapidly and disturb normal cellular functions immediately. These therapies are not very practical for the timely treatment of patients before irreversible damage occurs. Second, complex underlying mechanisms make it difficult to target a single molecule or pathway to efficiently attenuate all deleterious effects. Third, the pathological mechanisms of stroke remain largely unclear. Fourth, current animal models cannot represent the full scope of stroke as seen in human patients, especially the disease’s unpredictable location and severity.

Nevertheless, these previous failures provide us with valuable knowledge and experience to reconsider our current therapeutic strategies and to begin focusing on other potential plans. New strategies include targeting cell death amelioration (neuroprotection) and repairing and regeneration (neurorehabilitation and recovery) in longer therapeutic windows which may eventually meet our needs [14, 21, 22]. Although in recent years there have been many reports of beneficial effects from off-label rehabilitative drug prescriptions that claim to alleviate symptoms of stroke patients, there remains no available neuroprotective medication to mitigate brain damage in acute or later phases poststroke. It is vital that future efforts change their focus and strategy in order to develop effective drugs for the treatment of stroke.

4. Neurotrophins: Potential New Candidates for Stroke Rehabilitation

Neurotrophins are a class of secreted proteins essential for the growth, differentiation, development, survival, and recovery of the nervous system [23]. Comprised of the nerve growth factor (NGF), BDNF, neurotrophin-3 (NT-3), and neurotrophin-4/5 (NT-4/5), neurotrophins bind to their high-affinity tyrosine kinase receptors (Trks), TrkA, TrkB, and TrkC, as well as their low-affinity receptor, p75NTR (details are shown in Figure 2). Upon binding by neurotrophins, the Trks form homodimers and their intracellular receptor tyrosine kinase domains autophosphorylate each other to initiate downstream cascades of signaling transduction which lead to protein regulation and functional changes in the cell. Among the neurotrophins, BDNF is the most abundant in the adult brain, and extensive studies have reported on its neuroprotective effects in various neurological disorders, including both neurodegenerative diseases and acute brain injuries. This made BDNF a good candidate for the new direction of therapeutic strategies to treat stroke.

BDNF was the second neurotrophic factor to be identified when it was discovered by Barde et al. in 1982 [24], following the characterization of NGF by Nobel Laureates Levi-Montalcini and Cohen in 1956 [25, 26]. After three decades of extensive research and use in translational medicine, we now possess a wealth of knowledge regarding the biological properties and physiological functions of this protein.

BDNF plays a significant role in the development and functioning of the central nervous system. It is broadly involved in synapse maturation, synaptic plasticity, neurite outgrowth and arborization, and maintenance of normal cognitive function, while dysfunction of BDNF may contribute to the progression of multiple neurological diseases and psychiatric disorders [2732]. The beneficial effects of BDNF in chronic neurological diseases and psychiatric disorders have been extensively reviewed in recent years [27, 3335]. The prosurvival and neuroprotective functions of BDNF are mainly drawn from two signaling pathways activated by TrkB: the phosphatidylinositol 3-kinase (PI3K)/Akt and the mitogen-activated protein kinase/extracellular-signal-regulated kinase (MAPK/ERK) pathways. They both play significant roles in the cell cycle, division, and survival, by regulating the level and activity of certain transcription factors [35]. Therefore, BDNF appears to be a prime candidate for use as a stroke treatment.

5. Role of BDNF in Stroke and Poststroke Rehabilitation

BDNF plays a significant role in the prognosis, pathogenesis, and rehabilitation of stroke. It is well established that low levels of circulating BDNF are associated with a high risk of stroke and poor recovery, while BDNF expression in the brain is acutely stimulated by a stroke [3640]. Clinically, positive outcomes have been demonstrated by using several stroke treatments that manipulate BDNF levels, including administration of hormones and neurotransmitter-targeting compounds, transplantation of stem cells, and regulation of other related genes [4146]. We will now summarize the major, recent findings regarding stroke treatment and try to delineate the potential therapeutic capabilities of BDNF by focusing on different aspects of a stroke’s cellular and molecular mechanisms.

5.1. BDNF Attenuates Stroke-Induced Cell Death

As mentioned previously, through the activation of its downstream PI3K/Akt and MAPK/ERK pathways, BDNF is capable of protecting neurons from apoptosis, a critical event that directly leads to neuronal cell death and brain damage during stroke (Figure 3) [4750]. The neuroprotective effects of both sex hormones and antioxidants to stroke may be exerted via these two pathways. In the rat model of middle cerebral artery occlusion (MCAO), poststroke administration of progesterone increased BDNF expression, attenuated apoptosis, and reduced neuronal injury via the PI3K/Akt pathway [51], while combinatorial treatment of progesterone and vitamin D protected neuronal cells from ischemia/reperfusion- (I/R-) induced apoptosis by increasing B-cell leukemia/lymphoma 2 (BCL-2) expression and suppressing caspase-3 cleavage via the BDNF-TrkB-ERK pathway (Figure 3) [52]. Antioxidants from natural products and from endogenous sources were also found to be capable of protecting neurons from I/R-induced apoptosis. A key enzyme catalyzing heme oxidative degradation and maintaining redox homeostasis in the cell, heme oxygenase-1 (HO-1), was upregulated by progesterone and vitamin D hormone during treatment of ischemic strokes [52]. Moreover, overexpression of HO-1 in the CA1 region of the hippocampus, prior to ischemia, significantly protected the brain from I/R injury. This led to increased relative ratio of BCL-2/BAX (BCL-2-associated X protein) and decreased cleaved-caspase-3 protein levels and, thus, less apoptosis. Similarly, when a natural isoflavonoid extracted from the root of Pueraria, puerarin, was administered 1 hour after I/R, there was a stimulation of BDNF expression in astrocytes and further suppression of apoptosis due to the promotion of BCL-2 and reduction in BAX expression [44].

In addition to apoptosis, a few novel types of cell death that play significant roles in the pathologic process of stroke have been identified, such as autophagy [53], necroptosis [10, 54], ferroptosis [55], parthanatos [56], and pyroptosis [57]. Although the role of BDNF in most of these cell deaths remains largely elusive, the latest evidence suggests that BDNF-TrkB signaling may protect neurons under ischemic insult from ferroptosis and necroptosis. Ishii et al. recently proposed that BDNF protects neurons from ferroptosis-like cell death via circadian activation of nuclear factor-E2-related factor 2 (Nrf2) in astrocytes [58]. Meanwhile, suppression of both neuronal cell apoptosis and necroptosis was observed by a new high-affinity TrkB agonistic antibody which thus reduced the infarct size and facilitated functional recovery in the rat MCAO model [10]. Experimental evidence from other disease models suggests this antinecroptotic effect may be mediated by the MAPK/ERK and PI3K/Akt pathways [59, 60]. Although more investigations are needed, these newly discovered neuronal cell death types may serve as novel targets for stroke treatment in the future (extensively reviewed by Fricker et al. [61]).

5.2. BDNF Promotes Neurite Outgrowth and Neurogenesis in Poststroke Rehabilitation

Neurite outgrowth and neurogenesis are hallmarks of the regenerative capability of the brain after injury, and the BDNF-TrkB signaling pathway plays a pivotal role in these processes [6264]. In a cortical cell culture derived from endothelial nitric oxide synthase (eNOS) knockout mice, the reduced neurite outgrowth is shown to be caused by a BDNF-TrkB reduction [45]. Niacin, one of the most effective medications currently in clinical use for increasing high-density lipoprotein cholesterol, was tested in the rat MCAO model and found to promote neurite outgrowth and to increase synaptophysin expression, via activation of the BDNF-TrkB pathway [65].

Testosterone also exerts beneficial effects in stroke treatment by promoting neurogenesis and neurite outgrowth, which may be due to activation of the BDNF-TrkB pathway. Although testosterone was initially found to be deleterious in the acute phase of stroke, it was later suggested that testosterone treatment after ischemia could significantly enhance functional recovery in rats by increasing BDNF levels in both serum and the brain of experimental rats compared to untreated controls or those treated with testosterone and flutamide (an antiandrogen) [66].

Cilostazol is another clinically used medication found to have preventive effects on stroke [43, 67]. Cilostazol is a type 3 phosphodiesterase (PDE3) inhibitor that activates cAMP-responsive element binding protein (CREB) signaling and is commonly used to improve the symptoms of a certain blood flow problem in the legs (intermittent claudication). Post-I/R treatment with cilostazol was found to reduce infarct size, attenuate brain injury, and promote neurogenesis in a mouse MCAO model. These rehabilitative effects of cilostazol were most likely mediated by the activation of the BDNF-TrkB pathway, given that the number of BDNF-positive astrocytes in both the ipsilateral subventricular zone (SVZ) and the peri-infarct area was found to be significantly increased after treatment [43].

5.3. BDNF Facilitates Functional Recovery in Poststroke Rehabilitation

Functional recovery, the final outcome of poststroke rehabilitation, is a key endpoint for stroke patients in clinical trials, as well as for the experimental animals used in preclinical/scientific research. In recent years, novel therapeutic plans (e.g., gene/cell therapy) have greatly facilitated poststroke functional recovery. In an intracerebral hemorrhage mouse model, intracranial implantation of BDNF-overexpressing 3T3 fibroblasts significantly promoted poststroke neurogenesis and functional recovery [68]. In another study, intracerebral transplantation of genetically modified, BDNF-overexpressing human mesenchymal stem cells (MSCs) was achieved, resulting in significantly improved functional recovery in the rat MCAO model [69].

Erythropoietin (EPO) is a hematopoietic cytokine that shows neuroprotective effects in stroke by enhancing angiogenesis and neurogenesis and by upregulating synaptic plasticity-related genes, including BDNF [70]. Postischemia treatment with recombinant human EPO (rhEPO) in the rat MCAO model significantly increased the density of cerebral microvessels and the levels of the vascular endothelial growth factor (VEGF) and BDNF in the brain. Intriguingly, rhEPO was not able to induce BDNF expression in neurospheres from the SVZ, which implies the contribution of paracrine BDNF from endothelial cells in the neurogenesis and subsequent functional improvement [71].

In addition to administration of therapeutic agents and manipulation of gene expression, physical exercise was also capable of promoting BDNF expression and improving the neurological outcome after experimental stroke (reviewed by Alcantara et al. [72]). Ke et al. claimed that voluntary exercise is correlated with an increase in hippocampal BDNF levels and functional recovery [73]. In line with this, treadmill exercise increased only mature BDNF but not proBDNF in the cortex of rats that had experienced cortical ischemic stroke [74]. It was further reported that compared to those who were sedentary or who performed high-intensity exercise, MCAO rats who performed low-intensity exercise exhibited the greatest recovery in spatial memory and had a significant increase in PSD-95 and BDNF expression [75].

5.4. BDNF Induces Neuroplasticity in Poststroke Rehabilitation

The significant role that BDNF plays in the regulation and maintenance of synaptic plasticity has been extensively investigated and well described in recent decades. BDNF is well known for its involvement in Hebbian-type long-term potentiation (LTP) and long-term depression (LTD) and, more recently, in homeostatic synaptic plasticity (HSP) [30, 76]. However, unlike the synaptic plasticity that is crucial for normal cognitive function, the neuroplasticity discussed in poststroke rehabilitation mainly refers to the brain’s capability to recover from damage in order to restore its normal structure and function.

The crucial role of BDNF in neuroplasticity was primarily revealed by studies that focused on the poststroke treatment of aphasia and lost motor function, which are largely mediated by the process of neuroplasticity [77, 78]. In previous studies using rat ischemia models, it was found that when BDNF synthesis was blocked, the beneficial effects on the recovery of skilled reaching were mostly negated [79], while intravenous administration of BDNF significantly enhanced the functional motor recovery of the treated rats, compared to the untreated controls [80, 81]. Behavioral and physical therapies, such as aerobic/physical exercise, transcranial direct current stimulation (tDCS), and extremely low-frequency electromagnetic field therapy (ELF-EMF), were all found to increase the blood and/or brain levels of BDNF [72, 77, 8285]. In addition, BDNF-mediated learning memory may also be partially involved in the poststroke rehabilitation of motor function and language relearning [8688].

6. BDNF as a Therapeutic Agent in the Treatment of Stroke

The use of BDNF as a direct therapeutic agent for the treatment of stroke has been extensively investigated in rodent models (Figure 4). In the rat MCAO model of ischemia, pretreatment with intraventricular or intravenous BDNF drastically reduced the infarct size and the extent of neuronal cell death. It also stimulated neurogenesis, promoted sensorimotor recovery, and induced neural plasticity [62, 80, 8991]. Grafting of BDNF-overexpressing fibroblast cells into the medial part of the somatosensory cortex lowered the number of DNA breakages and upregulated the level of full-length TrkB in the penumbra [90]. Conversely, blockade of BDNF expression by antisense oligonucleotides largely abolished the postischemia recovery of motor function and skilled reaching [79].

At the cellular level, neurogenesis and migration have been commonly used as parameters to evaluate the therapeutic effects of BDNF on stroke recovery. In a photothrombotic ischemia model, Schäbitz et al. found that intravenous injection of BDNF significantly increased the number of doublecortin-positive cells in the dentate gyrus (DG) of the hippocampus and promoted the migration of neural progenitor cells (NPCs) towards the striatum [62]. In another study using the mouse MCAO model, vasculature-dependent generation and migration of neuronal precursor cells were observed from the SVZ to the ischemic striatum, which benefitted from the sustained expression of BDNF by the endothelial cells. Also, although astrocytes did not actively express BDNF themselves, they seemed to trap a large amount of BDNF which was also able to contribute to poststroke migration of neuronal precursor cells [92].

In the exploration of immuno-/cell therapies for stroke, once again, BDNF seems to be a clear target. Intravenous transplantation of an immortal human microglial cell line into rat brains 48 hours following MCAO resulted in the upregulation of several neurotrophic factors, including BDNF, and anti-inflammatory cytokines, which helped with the functional recovery from ischemia [93]. Hydroxysafflor yellow A (HSYA) is a natural product and the active ingredient found in the Chinese herbal medicine Flos Carthami Tinctorii, which was recently shown to exert neuroprotective effects in cerebral ischemia by enhancing BDNF expression in microglia [94, 95]. In another study, intranasal delivery of BDNF was shown to increase the number of activated and phagocytotic microglia, as well as the level of cytokines and transcription factors, in order to protect brain tissue from ischemic insult and reduce neuronal injury (Figure 4) [96].

7. Improvement of BDNF Delivery and the Development of New TrkB Agonists

Despite all the advantages of using BDNF to fix neurological impairments, there are drawbacks to this biomacromolecule that have to be taken into consideration when viewing it as a potential product from the drug development pipeline.

First of all, although it binds less than proBDNF, BDNF still exhibits low affinity to p75NTR, a proapoptotic receptor that can elicit the neuronal cell death process [30]. Second, there is the matter of specificity. TrkB expresses universally in different organs of the human body and has other important physiological roles, such as the regulation of metabolism and energy homeostasis [97, 98]. Specifically, TrkB is also a therapeutic target for obesity, possibly due to its involvement in the leptin-melanocortin pathway that controls appetite. Therefore, the delivery of BDNF needs to be more specific to reduce the side effect of weight loss. Third, BDNF has a low transport rate across the intact BBB and a short serum half-life (less than 10 min), which together indicate a narrow treatment window that demands a large amount of BDNF to maintain an effective therapeutic dose. Fourth, intracranially administrated BDNF cannot diffuse into the parenchyma of targeted tissues given its tendency to be physically “sticky” () [99]. Finally, manufacturing of BDNF remains largely limited by current technology, and consequently, the cost is correspondingly high.

To cope with these drawbacks and maximize the therapeutic efficacy of the BDNF-TrkB pathway in stroke treatment, improved BDNF delivery methods and alternative TrkB agonists have been developed in recent years. We will summarize the progress as follows (Figure 4).

7.1. Improvement of BDNF Delivery

In 1999, Wu and Pardridge first improved the plasma pharmacokinetics of BDNF by incorporating polyethylene glycol (PEG) moieties at the surface of its carboxyl residues. This modified BDNF was then linked to OX26mAb to facilitate capillary endothelial transferrin receptor-mediated transport through the BBB. Peripheral administration of PEG-BDNF-OX26mAb, but not BDNF alone, was able to restore the neuronal cell density in the CA1 region and significantly reduce the infarct size after transient ischemic insult in rats [100, 101].

Genetic modification may be another fast and effective method to achieve long-term and specific delivery of BDNF. For instance, when fused to a rabies virus glycoprotein-derived peptide, BDNF was able to enter nerve cells via intravenous administration and exhibited neuroprotective effects in a mouse model of stroke [102]. Fibrin is a protein abundantly found in hematoma surrounding the damage sites after intracerebral hemorrhage. BDNF was therefore fused with a fibrin-binding domain (FBD) to make FBD-BDNF, which could be specifically concentrated and retained at the lesion sites for a longer time than BDNF alone [103]. Similarly, fusing BDNF with a collagen-binding domain successfully retained BDNF for a longer time from degradation and promoted neurogenesis in the SVZ in an intracerebral hemorrhage model [104].

Utilizing novel drug-delivery methods, BDNF can also penetrate the BBB with higher efficacy. Harris et al. performed intravenous administration of a nanoparticle polyion complex formulation of BDNF which demonstrated better brain uptake, significantly reduced tissue loss, and increased expression of myelin basic protein [105]. With an ultrasound and microbubble system, Rodríguez-Frutos et al. delivered BDNF to the brain with higher efficiency and achieved better poststroke recovery of injured white matter, as measured by increased oligodendrocyte number and remyelination markers [106].

7.2. Development of New TrkB Agonists

Another solution to circumvent the disadvantages of using BDNF directly as a medication is to develop new TrkB agonists. One of the most extensively studied compounds that imitates the function of BDNF is 7,8-dihydroxyflavone (7,8-DHF), a small molecule TrkB agonist that protects neurons from kainic acid-induced toxicity and experimental ischemia [107]. 7,8-DHF efficiently induces TrkB autophosphorylation and downstream activation of various signaling pathways, including the Akt and ERK pathways. Pretreatment with 7,8-DHF in vitro and in vivo reduced the death of immature neurons in the hippocampus in a controlled cortical impact (CCI) model [108]. Postinjury treatment with 7,8-DHF within 10 min was also effective for reducing brain edema and cell death via Akt activation [11]. In another related study using the fluid percussion injury (FPI) model, treatment with 7,8-DHF successfully restored TrkB signaling and memory function in the Barnes maze test [109]. 7,8-DHF also exhibited beneficial effects in the treatment of neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), and amyotrophic lateral sclerosis (ALS) [110114]. Recently, a derivative of 7,8-DHF, namely, BrAD-R13, was approved by the FDA for use in clinical trials for the treatment of mild to moderate AD.

A pharmacophore proven to be critical in activating TrkB signaling is the BDNF mimetic LM22A4, which activates the Akt and ERK signaling pathways comparably to BDNF. Massa et al. performed intranasal administration of LM22A4, in in vitro neurodegenerative disease models to promote cell survival, and in a rat parietal CCI model to reduce neuronal cell death [115]. Based on the sequence of BDNF loop 4 and loop 1 β-turn, Gudasheva and colleagues have recently created two dimeric dipeptides, which mimic full-length BDNF. They exhibited varied abilities to activate the Akt and ERK pathways and exhibited therapeutic effects in the rat MCAO model [116].

As the strategy of immunotherapy has prevailed in recent years, several specific TrkB agonistic antibodies have been developed which exhibited promising preclinical effects in the treatment of acute and chronic neurological diseases. Recent studies suggest that TrkB agonistic antibodies bind to the receptor with high specificity and affinity to activate its downstream signaling cascades; thus, they exhibit protective effects in ischemic stroke [10, 117], HD [118], and glaucoma [119] and regulate energy metabolism [120]. Using a human short-chain variable fragment antibody library, Merkouris et al. screened new TrkB agonistic antibodies and characterized their function at the cellular level. These antibodies induced TrkB phosphorylation, downstream signaling pathway activation, and gene expression to comparable levels as BDNF [121]. Together, these studies made great strides toward BDNF-based therapeutics for neurological diseases.

8. To Avoid Preclinical Research Pitfalls

While novel therapeutic targets have emerged from preclinical studies, none has yet been proven to be as effective in clinical trials. The Stroke Therapy Academic Industry Roundtable has reported recommendations on preclinical drug discovery for ischemia that may shed light on the development of therapeutic plans, which would lower the risk of wasted effort on, and money in, failing clinical trials [122].

First of all, a good preclinical study generally starts with the right animal models. Rodents are usually considered at the first place, as the scientific community has a wealth of experience in using them to model brain diseases. Second, the candidate drugs should be monitored closely based on their mechanisms of actions, functional and pathological outcomes, and physiological properties. For the neuroprotective drugs that exhibit efficacy at the time of damage, it is important to plot dose-response and administration time-response curves in order to learn the effective range of concentrations and functional time windows in the acute phase of disease onset; while for the neurorestorative drugs, long-term monitoring of functional outcomes is more important. Last but not the least, to avoid bias and increase the reproducibility of the data, the experiments should be carried out in at least two laboratories independently in a blinded, randomized fashion with both rodents and upper-level species, preferably with nonhuman primates [122].

9. Conclusions

To date, the role of the BDNF-TrkB pathway in mediating functional rehabilitation and recovery from stroke has been extensively investigated. A great number of studies suggest that BDNF exerts favorable effects in poststroke recovery due to its attenuation of cell death, promotion of neurogenesis/-migration, and remyelination of axons, as well as its ability to interfere with neuroinflammatory factors and cells. Nevertheless, more detailed mechanisms of the BDNF-TrkB pathway’s effect on stroke recovery, or that of other brain insults, remain elusive and will require further in-depth investigation. Moreover, due to the unfavorable physical and biochemical properties of BDNF as a treatment agent, the prospect of its clinical use has been greatly hampered. Therefore, the use of new technologies to manufacture BDNF, innovative strategies to control its targeted delivery, and production of BDNF mimetics in comprehensive preclinical studies may pave the way for future clinical application of the BDNF-TrkB signaling pathway in stroke treatment.

Conflicts of Interest

The authors declare no conflicts of financial interests.

Authors’ Contributions

Wei Liu and Xiaohui Wang contributed equally to this work.


We thank Dr. Bai Lu (Tsinghua University) for inspiring this work and his helpful discussion on the manuscript. This work is supported by the Fund for Incubating Program of Capital Medical University (No. PYZ2018058) (X.H.W.).


  1. D. Mukherjee and C. G. Patil, “Epidemiology and the global burden of stroke,” World Neurosurgery, vol. 76, Supplement 6, pp. S85–S90, 2011. View at: Publisher Site | Google Scholar
  2. B. Deresse and D. Shaweno, “Epidemiology and in-hospital outcome of stroke in South Ethiopia,” Journal of the Neurological Sciences, vol. 355, no. 1-2, pp. 138–142, 2015. View at: Publisher Site | Google Scholar
  3. V. L. Feigin, R. V. Krishnamurthi, P. Parmar et al., “Update on the global burden of ischemic and hemorrhagic stroke in 1990-2013: the GBD 2013 study,” Neuroepidemiology, vol. 45, no. 3, pp. 161–176, 2015. View at: Publisher Site | Google Scholar
  4. K. Strong, C. Mathers, and R. Bonita, “Preventing stroke: saving lives around the world,” Lancet Neurology, vol. 6, no. 2, pp. 182–187, 2007. View at: Publisher Site | Google Scholar
  5. M. McDermott, L. E. Skolarus, and J. F. Burke, “A systematic review and meta-analysis of interventions to increase stroke thrombolysis,” BMC Neurology, vol. 19, no. 1, p. 86, 2019. View at: Publisher Site | Google Scholar
  6. H. Ma, B. C. V. Campbell, M. W. Parsons et al., “Thrombolysis guided by perfusion imaging up to 9 hours after onset of stroke,” New England Journal of Medicine, vol. 380, no. 19, pp. 1795–1803, 2019. View at: Publisher Site | Google Scholar
  7. B. C. V. Campbell, H. Ma, P. A. Ringleb et al., “Extending thrombolysis to 4·5–9 h and wake-up stroke using perfusion imaging: a systematic review and meta-analysis of individual patient data,” Lancet, vol. 394, no. 10193, pp. 139–147, 2019. View at: Publisher Site | Google Scholar
  8. G. Z. Feuerstein and J. Chavez, “Translational medicine for stroke drug discovery: the pharmaceutical industry perspective,” Stroke, vol. 40, 3, Supplement 1, pp. S121–S125, 2009. View at: Publisher Site | Google Scholar
  9. K. Kikuchi, E. Tanaka, Y. Murai, and S. Tancharoen, “Clinical trials in acute ischemic stroke,” CNS Drugs, vol. 28, no. 10, pp. 929–938, 2014. View at: Publisher Site | Google Scholar
  10. F. Han, X. Guan, W. Guo, and B. Lu, “Therapeutic potential of a TrkB agonistic antibody for ischemic brain injury,” Neurobiology of Disease, vol. 127, pp. 570–581, 2019. View at: Publisher Site | Google Scholar
  11. C.-H. Wu, T.-H. Hung, C.-C. Chen et al., “Post-injury treatment with 7,8-dihydroxyflavone, a TrkB receptor agonist, protects against experimental traumatic brain injury via PI3K/Akt signaling,” PLoS ONE, vol. 9, no. 11, p. e113397, 2014. View at: Publisher Site | Google Scholar
  12. D. J. Cook, C. Nguyen, H. N. Chun et al., “Hydrogel-delivered brain-derived neurotrophic factor promotes tissue repair and recovery after stroke,” Journal of Cerebral Blood Flow and Metabolism, vol. 37, no. 3, pp. 1030–1045, 2017. View at: Publisher Site | Google Scholar
  13. E. J. Benjamin, M. J. Blaha, S. E. Chiuve et al., “Heart disease and stroke statistics-2017 update: a report from the American Heart Association,” Circulation, vol. 135, no. 10, pp. e146–e603, 2017. View at: Publisher Site | Google Scholar
  14. B. A. Sutherland, J. Minnerup, J. S. Balami, F. Arba, A. M. Buchan, and C. Kleinschnitz, “Neuroprotection for ischaemic stroke: translation from the bench to the bedside,” International Journal of Stroke, vol. 7, no. 5, pp. 407–418, 2012. View at: Publisher Site | Google Scholar
  15. H. Zheng, C. Chen, J. Zhang, and Z. Hu, “Mechanism and therapy of brain edema after intracerebral hemorrhage,” Cerebrovascular Diseases, vol. 42, no. 3-4, pp. 155–169, 2016. View at: Publisher Site | Google Scholar
  16. D. J. Miller, J. R. Simpson, and B. Silver, “Safety of thrombolysis in acute ischemic stroke: a review of complications, risk factors, and newer technologies,” The Neurohospitalist, vol. 1, no. 3, pp. 138–147, 2011. View at: Publisher Site | Google Scholar
  17. S. F. Traynelis, L. P. Wollmuth, C. J. McBain et al., “Glutamate receptor ion channels: structure, regulation, and function,” Pharmacological Reviews, vol. 62, no. 3, pp. 405–496, 2010. View at: Publisher Site | Google Scholar
  18. J. Yuan, “Neuroprotective strategies targeting apoptotic and necrotic cell death for stroke,” Apoptosis, vol. 14, no. 4, pp. 469–477, 2009. View at: Publisher Site | Google Scholar
  19. C. Y. Yu, G. Ng, and P. Liao, “Therapeutic antibodies in stroke,” Translational Stroke Research, vol. 4, no. 5, pp. 477–483, 2013. View at: Publisher Site | Google Scholar
  20. C. Iadecola and J. Anrather, “The immunology of stroke: from mechanisms to translation,” Nature Medicine, vol. 17, no. 7, pp. 796–808, 2011. View at: Publisher Site | Google Scholar
  21. E. H. Lo, “A new penumbra: transitioning from injury into repair after stroke,” Nature Medicine, vol. 14, no. 5, pp. 497–500, 2008. View at: Publisher Site | Google Scholar
  22. M. D. Ginsberg, “Neuroprotection for ischemic stroke: past, present and future,” Neuropharmacology, vol. 55, no. 3, pp. 363–389, 2008. View at: Publisher Site | Google Scholar
  23. D. R. Kaplan and F. D. Miller, “Neurotrophin signal transduction in the nervous system,” Current Opinion in Neurobiology, vol. 10, no. 3, pp. 381–391, 2000. View at: Publisher Site | Google Scholar
  24. Y. A. Barde, D. Edgar, and H. Thoenen, “Purification of a new neurotrophic factor from mammalian brain,” The EMBO Journal, vol. 1, no. 5, pp. 549–553, 1982. View at: Google Scholar
  25. S. Cohen and R. Levi-Montalcini, “A nerve growth-stimulating factor isolated from snake venom,” Proceedings of the National Academy of Sciences of the United States of America, vol. 42, no. 9, pp. 571–574, 1956. View at: Publisher Site | Google Scholar
  26. R. Levi-Montalcini and S. Cohen, “In vitro and in vivo effects of a nerve growth-stimulating agent isolated from snake venom,” Proceedings of the National Academy of Sciences of the United States of America, vol. 42, no. 9, pp. 695–699, 1956. View at: Publisher Site | Google Scholar
  27. B. Lima Giacobbo, J. Doorduin, H. C. Klein, R. A. J. O. Dierckx, E. Bromberg, and E. F. J. de Vries, “Brain-derived neurotrophic factor in brain disorders: focus on neuroinflammation,” Molecular Neurobiology, vol. 56, no. 5, pp. 3295–3312, 2019. View at: Publisher Site | Google Scholar
  28. Y. Dwivedi, “Involvement of brain-derived neurotrophic factor in late-life depression,” The American Journal of Geriatric Psychiatry, vol. 21, no. 5, pp. 433–449, 2013. View at: Publisher Site | Google Scholar
  29. Y. Dwivedi, “Brain-derived neurotrophic factor: role in depression and suicide,” Neuropsychiatric Disease and Treatment, vol. 5, no. 1, pp. 433–449, 2009. View at: Publisher Site | Google Scholar
  30. B. Lu, P. T. Pang, and N. H. Woo, “The yin and yang of neurotrophin action,” Nature Reviews Neuroscience, vol. 6, no. 8, pp. 603–614, 2005. View at: Publisher Site | Google Scholar
  31. M. F. Egan, M. Kojima, J. H. Callicott et al., “The BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function,” Cell, vol. 112, no. 2, pp. 257–269, 2003. View at: Publisher Site | Google Scholar
  32. V. Begni, M. A. Riva, and A. Cattaneo, “Cellular and molecular mechanisms of the brain-derived neurotrophic factor in physiological and pathological conditions,” Clinical Science (London, England), vol. 131, no. 2, pp. 123–138, 2017. View at: Publisher Site | Google Scholar
  33. A. H. Nagahara and M. H. Tuszynski, “Potential therapeutic uses of BDNF in neurological and psychiatric disorders,” Nature Reviews Drug Discovery, vol. 10, no. 3, pp. 209–219, 2011. View at: Publisher Site | Google Scholar
  34. J. Cai, F. Hua, L. Yuan et al., “Potential therapeutic effects of neurotrophins for acute and chronic neurological diseases,” BioMed Research International, vol. 2014, 12 pages, 2014. View at: Publisher Site | Google Scholar
  35. H. Zhao, A. Alam, C. Y. San et al., “Molecular mechanisms of brain-derived neurotrophic factor in neuro-protection: recent developments,” Brain Research, vol. 1665, pp. 1–21, 2017. View at: Publisher Site | Google Scholar
  36. A. Pikula, A. S. Beiser, T. C. Chen et al., “Serum brain-derived neurotrophic factor and vascular endothelial growth factor levels are associated with risk of stroke and vascular brain Injury,” Stroke, vol. 44, no. 10, pp. 2768–2775, 2013. View at: Publisher Site | Google Scholar
  37. T. M. Stanne, N. D. Aberg, S. Nilsson et al., “Low circulating acute brain-derived neurotrophic factor levels are associated with poor long-term functional outcome after ischemic stroke,” Stroke, vol. 47, no. 7, pp. 1943–1945, 2016. View at: Publisher Site | Google Scholar
  38. Y. Béjot, C. Mossiat, M. Giroud, A. Prigent-Tessier, and C. Marie, “Circulating and brain BDNF levels in stroke rats. Relevance to clinical studies,” PLoS ONE, vol. 6, no. 12, 2011. View at: Publisher Site | Google Scholar
  39. Y. Béjot, A. Prigent-Tessier, C. Cachia et al., “Time-dependent contribution of non neuronal cells to BDNF production after ischemic stroke in rats,” Neurochemistry International, vol. 58, no. 1, pp. 102–111, 2011. View at: Publisher Site | Google Scholar
  40. M. Pedard, C. Breniere, N. Pernet, C. Vergely, Y. Bejot, and C. Marie, “Brain-derived neurotrophic factor in peripheral blood mononuclear cells and stroke outcome,” Experimental Biology and Medicine, vol. 243, no. 15-16, pp. 1207–1211, 2018. View at: Publisher Site | Google Scholar
  41. T. Genovese, D. Impellizzeri, A. Ahmad et al., “Post-ischaemic thyroid hormone treatment in a rat model of acute stroke,” Brain Research, vol. 1513, pp. 92–102, 2013. View at: Publisher Site | Google Scholar
  42. M. J. Van Kanegan, D. N. He, D. E. Dunn et al., “BDNF mediates neuroprotection against oxygen-glucose deprivation by the cardiac glycoside oleandrin,” Journal of Neuroscience, vol. 34, no. 3, pp. 963–968, 2014. View at: Publisher Site | Google Scholar
  43. Y. Tanaka, R. Tanaka, M. Liu, N. Hattori, and T. Urabe, “Cilostazol attenuates ischemic brain injury and enhances neurogenesis in the subventricular zone of adult mice after transient focal cerebral ischemia,” Neuroscience, vol. 171, no. 4, pp. 1367–1376, 2010. View at: Publisher Site | Google Scholar
  44. N. Wang, Y. Zhang, L. Wu et al., “Puerarin protected the brain from cerebral ischemia injury via astrocyte apoptosis inhibition,” Neuropharmacology, vol. 79, pp. 282–289, 2014. View at: Publisher Site | Google Scholar
  45. X. Cui, M. Chopp, A. Zacharek et al., “Endothelial nitric oxide synthase regulates white matter changes via the BDNF/TrkB pathway after stroke in mice,” PLoS ONE, vol. 8, no. 11, p. e80358, 2013. View at: Publisher Site | Google Scholar
  46. D. Qi, C. Ouyang, Y. Wang et al., “HO-1 attenuates hippocampal neurons injury via the activation of BDNF-TrkB- PI3K/Akt signaling pathway in stroke,” Brain Research, vol. 1577, pp. 69–76, 2014. View at: Publisher Site | Google Scholar
  47. B. Cheng and M. P. Mattson, “NT-3 and BDNF protect CNS neurons against metabolic/excitotoxic insults,” Brain Research, vol. 640, no. 1-2, pp. 56–67, 1994. View at: Publisher Site | Google Scholar
  48. T. Kubo, T. Nonomura, Y. Enokido, and H. Hatanaka, “Brain-derived neurotrophic factor (BDNF) can prevent apoptosis of rat cerebellar granule neurons in culture,” Developmental Brain Research, vol. 85, no. 2, pp. 249–258, 1995. View at: Publisher Site | Google Scholar
  49. O. G. Vidaurre, S. Gascon, R. Deogracias et al., “Imbalance of neurotrophin receptor isoforms TrkB-FL/TrkB-T1 induces neuronal death in excitotoxicity,” Cell Death & Disease, vol. 3, no. 1, p. e256, 2012. View at: Publisher Site | Google Scholar
  50. J. R. Gomes, J. T. Costa, C. V. Melo et al., “Excitotoxicity downregulates TrkB.FL signaling and upregulates the neuroprotective truncated TrkB receptors in cultured hippocampal and striatal neurons,” Journal of Neuroscience, vol. 32, no. 13, pp. 4610–4622, 2012. View at: Publisher Site | Google Scholar
  51. T. Ishrat, I. Sayeed, F. Atif, F. Hua, and D. G. Stein, “Progesterone is neuroprotective against ischemic brain injury through its effects on the phosphoinositide 3-kinase/protein kinase B signaling pathway,” Neuroscience, vol. 210, pp. 442–450, 2012. View at: Publisher Site | Google Scholar
  52. F. Atif, S. Yousuf, I. Sayeed, T. Ishrat, F. Hua, and D. G. Stein, “Combination treatment with progesterone and vitamin D hormone is more effective than monotherapy in ischemic stroke: the role of BDNF/TrkB/Erk1/2 signaling in neuroprotection,” Neuropharmacology, vol. 67, pp. 78–87, 2013. View at: Publisher Site | Google Scholar
  53. F. Adhami, G. Liao, Y. M. Morozov et al., “Cerebral ischemia-hypoxia induces intravascular coagulation and autophagy,” The American Journal of Pathology, vol. 169, no. 2, pp. 566–583, 2006. View at: Publisher Site | Google Scholar
  54. A. Degterev, Z. Huang, M. Boyce et al., “Chemical inhibitor of nonapoptotic cell death with therapeutic potential for ischemic brain injury,” Nature Chemical Biology, vol. 1, no. 2, pp. 112–119, 2005. View at: Publisher Site | Google Scholar
  55. Q.-z. Tuo, P. Lei, K. A. Jackman et al., “Tau-mediated iron export prevents ferroptotic damage after ischemic stroke,” Molecular Psychiatry, vol. 22, no. 11, pp. 1520–1530, 2017. View at: Publisher Site | Google Scholar
  56. S. A. Andrabi, H. C. Kang, J. F. Haince et al., “Iduna protects the brain from glutamate excitotoxicity and stroke by interfering with poly(ADP-ribose) polymer-induced cell death,” Nature Medicine, vol. 17, no. 6, pp. 692–699, 2011. View at: Publisher Site | Google Scholar
  57. J. Barrington, E. Lemarchand, and S. M. Allan, “A brain in flame; do inflammasomes and pyroptosis influence stroke pathology?” Brain Pathology, vol. 27, no. 2, pp. 205–212, 2017. View at: Publisher Site | Google Scholar
  58. T. Ishii, E. Warabi, and G. E. Mann, “Circadian control of BDNF-mediated Nrf2 activation in astrocytes protects dopaminergic neurons from ferroptosis,” Free Radical Biology & Medicine, vol. 133, pp. 169–178, 2019. View at: Publisher Site | Google Scholar
  59. S. L. Locatelli, G. Careddu, G. G. Stirparo, L. Castagna, A. Santoro, and C. Carlo-Stella, “Dual PI3K/ERK inhibition induces necroptotic cell death of Hodgkin lymphoma cells through IER3 downregulation,” Scientific Reports, vol. 6, no. 1, 2016. View at: Publisher Site | Google Scholar
  60. D. Bollino, I. Balan, and L. Aurelian, “Valproic acid induces neuronal cell death through a novel calpain-dependent necroptosis pathway,” Journal of Neurochemistry, vol. 133, no. 2, pp. 174–186, 2015. View at: Publisher Site | Google Scholar
  61. M. Fricker, A. M. Tolkovsky, V. Borutaite, M. Coleman, and G. C. Brown, “Neuronal cell death,” Physiological Reviews, vol. 98, no. 2, pp. 813–880, 2018. View at: Publisher Site | Google Scholar
  62. W. R. Schabitz, T. Steigleder, C. M. Cooper-Kuhn et al., “Intravenous brain-derived neurotrophic factor enhances poststroke sensorimotor recovery and stimulates neurogenesis,” Stroke, vol. 38, no. 7, pp. 2165–2172, 2007. View at: Publisher Site | Google Scholar
  63. C. Labelle and N. Leclerc, “Exogenous BDNF, NT-3 and NT-4 differentially regulate neurite outgrowth in cultured hippocampal neurons,” Brain Research. Developmental Brain Research, vol. 123, no. 1, pp. 1–11, 2000. View at: Publisher Site | Google Scholar
  64. T. Numakawa, S. Suzuki, E. Kumamaru, N. Adachi, M. Richards, and H. Kunugi, “BDNF function and intracellular signaling in neurons,” Histology and Histopathology, vol. 25, no. 2, pp. 237–258, 2010. View at: Publisher Site | Google Scholar
  65. X. Cui, M. Chopp, A. Zacharek et al., “Niacin treatment of stroke increases synaptic plasticity and axon growth in rats,” Stroke, vol. 41, no. 9, pp. 2044–2049, 2010. View at: Publisher Site | Google Scholar
  66. H. Fanaei, S. M. Karimian, H. R. Sadeghipour et al., “Testosterone enhances functional recovery after stroke through promotion of antioxidant defenses, BDNF levels and neurogenesis in male rats,” Brain Research, vol. 1558, pp. 74–83, 2014. View at: Publisher Site | Google Scholar
  67. T. Takagi and H. Hara, “Protective effects of cilostazol against hemorrhagic stroke: current and future perspectives,” Journal of Pharmacological Sciences, vol. 131, no. 3, pp. 155–161, 2016. View at: Publisher Site | Google Scholar
  68. S. J. Chen, J. C. Tsai, C. Y. Lin, C. K. Chang, T. H. Tseng, and C. L. Chien, “Brain-derived neurotrophic factor-transfected and nontransfected 3T3 fibroblasts enhance migratory neuroblasts and functional restoration in mice with intracerebral hemorrhage,” Journal of Neuropathology and Experimental Neurology, vol. 71, no. 12, pp. 1123–1136, 2012. View at: Publisher Site | Google Scholar
  69. K. Kurozumi, K. Nakamura, T. Tamiya et al., “BDNF gene-modified mesenchymal stem cells promote functional recovery and reduce infarct size in the rat middle cerebral artery occlusion model,” Molecular Therapy, vol. 9, no. 2, pp. 189–197, 2004. View at: Publisher Site | Google Scholar
  70. M. Mengozzi, I. Cervellini, P. Villa et al., “Erythropoietin-induced changes in brain gene expression reveal induction of synaptic plasticity genes in experimental stroke,” Proceedings of the National Academy of Sciences of the United States of America, vol. 109, no. 24, pp. 9617–9622, 2012. View at: Publisher Site | Google Scholar
  71. L. Wang, Z. Zhang, Y. Wang, R. Zhang, and M. Chopp, “Treatment of stroke with erythropoietin enhances neurogenesis and angiogenesis and improves neurological function in rats,” Stroke, vol. 35, no. 7, pp. 1732–1737, 2004. View at: Publisher Site | Google Scholar
  72. C. C. Alcantara, L. F. Garcia-Salazar, M. A. Silva-Couto, G. L. Santos, D. S. Reisman, and T. L. Russo, “Post-stroke BDNF concentration changes following physical exercise: a systematic review,” Frontiers in Neurology, vol. 9, p. 637, 2018. View at: Publisher Site | Google Scholar
  73. Z. Ke, S. P. Yip, L. Li, X. X. Zheng, and K. Y. Tong, “The effects of voluntary, involuntary, and forced exercises on brain-derived neurotrophic factor and motor function recovery: a rat brain ischemia model,” PLoS ONE, vol. 6, no. 2, p. e16643, 2011. View at: Publisher Site | Google Scholar
  74. A. Quirié, M. Hervieu, P. Garnier et al., “Comparative effect of treadmill exercise on mature BDNF production in control versus stroke rats,” PLoS ONE, vol. 7, no. 9, p. e44218, 2012. View at: Publisher Site | Google Scholar
  75. P. C. Shih, Y. R. Yang, and R. Y. Wang, “Effects of exercise intensity on spatial memory performance and hippocampal synaptic plasticity in transient brain ischemic rats,” PLoS ONE, vol. 8, no. 10, p. e78163, 2013. View at: Publisher Site | Google Scholar
  76. G. Wang, J. Gilbert, and H. Y. Man, “AMPA receptor trafficking in homeostatic synaptic plasticity: functional molecules and signaling cascades,” Neural Plasticity, vol. 2012, Article ID 825364, 12 pages, 2012. View at: Publisher Site | Google Scholar
  77. C. S. Mang, K. L. Campbell, C. J. Ross, and L. A. Boyd, “Promoting neuroplasticity for motor rehabilitation after stroke: considering the effects of aerobic exercise and genetic variation on brain-derived neurotrophic factor,” Physical Therapy, vol. 93, no. 12, pp. 1707–1716, 2013. View at: Publisher Site | Google Scholar
  78. N. Cichon, M. Bijak, P. Czarny et al., “Increase in blood levels of growth factors involved in the neuroplasticity process by using an extremely low frequency electromagnetic field in post-stroke patients,” Frontiers in Aging Neuroscience, vol. 10, p. 294, 2018. View at: Publisher Site | Google Scholar
  79. M. Ploughman, V. Windle, C. L. MacLellan, N. White, J. J. Doré, and D. Corbett, “Brain-derived neurotrophic factor contributes to recovery of skilled reaching after focal ischemia in rats,” Stroke, vol. 40, no. 4, pp. 1490–1495, 2009. View at: Publisher Site | Google Scholar
  80. W. R. Schäbitz, C. Berger, R. Kollmar et al., “Effect of brain-derived neurotrophic factor treatment and forced arm use on functional motor recovery after small cortical ischemia,” Stroke, vol. 35, no. 4, pp. 992–997, 2004. View at: Publisher Site | Google Scholar
  81. Y. Zhang and W. M. Pardridge, “Blood-brain barrier targeting of BDNF improves motor function in rats with middle cerebral artery occlusion,” Brain Research, vol. 1111, no. 1, pp. 227–229, 2006. View at: Publisher Site | Google Scholar
  82. S. M. Harnish, A. D. Rodriguez, D. S. Blackett et al., “Aerobic exercise as an adjuvant to aphasia therapy: theory, preliminary findings, and future directions,” Clinical Therapeutics, vol. 40, no. 1, pp. 35–48.e6, 2018. View at: Publisher Site | Google Scholar
  83. J. Fridriksson, J. Elm, B. C. Stark et al., “BDNF genotype and tDCS interaction in aphasia treatment,” Brain Stimulation, vol. 11, no. 6, pp. 1276–1281, 2018. View at: Publisher Site | Google Scholar
  84. R. G. A. de Boer, K. Spielmann, M. H. Heijenbrok-Kal, R. van der Vliet, G. M. Ribbers, and W. M. E. van de Sandt-Koenderman, “The role of the BDNF Val66Met polymorphism in recovery of aphasia after stroke,” Neurorehabilitation and Neural Repair, vol. 31, no. 9, pp. 851–857, 2017. View at: Publisher Site | Google Scholar
  85. V. N. Shishkova, L. I. Zotova, N. G. Maljukova et al., “An assessment of cerebrolysin effect on BDNF level in patients with post stroke aphasia depending on carbohydrate metabolism disorders,” Zhurnal Nevrologii i Psikhiatrii Imeni S.S. Korsakova, vol. 115, no. 5, pp. 57–63, 2015. View at: Publisher Site | Google Scholar
  86. M. Mizuno, K. Yamada, A. Olariu, H. Nawa, and T. Nabeshima, “Involvement of brain-derived neurotrophic factor in spatial memory formation and maintenance in a radial arm maze test in rats,” The Journal of Neuroscience, vol. 20, no. 18, pp. 7116–7121, 2000. View at: Google Scholar
  87. J. Hall, K. L. Thomas, and B. J. Everitt, “Rapid and selective induction of BDNF expression in the hippocampus during contextual learning,” Nature Neuroscience, vol. 3, no. 6, pp. 533–535, 2000. View at: Publisher Site | Google Scholar
  88. Y. L. Ma, H. L. Wang, H. C. Wu, C. L. Wei, and E. H. Y. Lee, “Brain-derived neurotrophic factor antisense oligonucleotide impairs memory retention and inhibits long-term potentiation in rats,” Neuroscience, vol. 82, no. 4, pp. 957–967, 1997. View at: Publisher Site | Google Scholar
  89. W. R. Schabitz, C. Sommer, W. Zoder, M. Kiessling, M. Schwaninger, and S. Schwab, “Intravenous brain-derived neurotrophic factor reduces infarct size and counterregulates Bax and Bcl-2 expression after temporary focal cerebral ischemia,” Stroke, vol. 31, no. 9, pp. 2212–2217, 2000. View at: Publisher Site | Google Scholar
  90. I. Ferrer, J. Krupinski, E. Goutan, E. Martí, S. Ambrosio, and E. Arenas, “Brain-derived neurotrophic factor reduces cortical cell death by ischemia after middle cerebral artery occlusion in the rat,” Acta Neuropathologica, vol. 101, no. 3, pp. 229–238, 2001. View at: Publisher Site | Google Scholar
  91. W. R. Schabitz, S. Schwab, M. Spranger, and W. Hacke, “Intraventricular brain-derived neurotrophic factor reduces infarct size after focal cerebral ischemia in rats,” Journal of Cerebral Blood Flow and Metabolism, vol. 17, no. 5, pp. 500–506, 1997. View at: Publisher Site | Google Scholar
  92. S. Grade, Y. C. Weng, M. Snapyan, J. Kriz, J. O. Malva, and A. Saghatelyan, “Brain-derived neurotrophic factor promotes vasculature-associated migration of neuronal precursors toward the ischemic striatum,” PLoS ONE, vol. 8, no. 1, p. e55039, 2013. View at: Publisher Site | Google Scholar
  93. D. Narantuya, A. Nagai, A. M. Sheikh et al., “Human microglia transplanted in rat focal ischemia brain induce neuroprotection and behavioral improvement,” PLoS ONE, vol. 5, no. 7, p. e11746, 2010. View at: Publisher Site | Google Scholar
  94. Y. Lv, Y. Qian, A. Ou-yang, and L. Fu, “Hydroxysafflor yellow a attenuates neuron damage by suppressing the lipopolysaccharide-induced TLR4 pathway in activated microglial cells,” Cellular and Molecular Neurobiology, vol. 36, no. 8, pp. 1241–1256, 2016. View at: Publisher Site | Google Scholar
  95. Y. Lv, Y. Qian, L. Fu, X. Chen, H. Zhong, and X. Wei, “Hydroxysafflor yellow A exerts neuroprotective effects in cerebral ischemia reperfusion-injured mice by suppressing the innate immune TLR4-inducing pathway,” European Journal of Pharmacology, vol. 769, pp. 324–332, 2015. View at: Publisher Site | Google Scholar
  96. Y. Jiang, N. Wei, T. Lu, J. Zhu, G. Xu, and X. Liu, “Intranasal brain-derived neurotrophic factor protects brain from ischemic insult via modulating local inflammation in rats,” Neuroscience, vol. 172, pp. 398–405, 2011. View at: Publisher Site | Google Scholar
  97. G. Y. Liao, C. E. Kinney, J. J. An, and B. Xu, “TrkB-expressing neurons in the dorsomedial hypothalamus are necessary and sufficient to suppress homeostatic feeding,” Proceedings of the National Academy of Sciences of the United States of America, vol. 116, no. 8, pp. 3256–3261, 2019. View at: Publisher Site | Google Scholar
  98. T. J. Unger, G. A. Calderon, L. C. Bradley, M. Sena-Esteves, and M. Rios, “Selective deletion of Bdnf in the ventromedial and dorsomedial hypothalamus of adult mice results in hyperphagic behavior and obesity,” The Journal of Neuroscience, vol. 27, no. 52, pp. 14265–14274, 2007. View at: Publisher Site | Google Scholar
  99. S. D. Croll, C. R. Chesnutt, J. S. Rudge et al., “Co-infusion with a TrkB-Fc receptor body carrier enhances BDNF distribution in the adult rat brain,” Experimental Neurology, vol. 152, no. 1, pp. 20–33, 1998. View at: Publisher Site | Google Scholar
  100. D. Wu and W. M. Pardridge, “Neuroprotection with noninvasive neurotrophin delivery to the brain,” Proceedings of the National Academy of Sciences of the United States of America, vol. 96, no. 1, pp. 254–259, 1999. View at: Publisher Site | Google Scholar
  101. Y. Zhang and W. M. Pardridge, “Neuroprotection in transient focal brain ischemia after delayed intravenous administration of brain-derived neurotrophic factor conjugated to a blood-brain barrier drug targeting system,” Stroke, vol. 32, no. 6, pp. 1378–1384, 2001. View at: Publisher Site | Google Scholar
  102. A. Fu, Y. Wang, L. Zhan, and R. Zhou, “Targeted delivery of proteins into the central nervous system mediated by rabies virus glycoprotein-derived peptide,” Pharmaceutical Research, vol. 29, no. 6, pp. 1562–1569, 2012. View at: Publisher Site | Google Scholar
  103. Q. Q. Han, W. Jin, Z. F. Xiao et al., “The promotion of neurological recovery in an intracerebral hemorrhage model using fibrin-binding brain derived neurotrophic factor,” Biomaterials, vol. 32, no. 12, pp. 3244–3252, 2011. View at: Publisher Site | Google Scholar
  104. J. Guan, B. Zhang, J. Zhang et al., “Nerve regeneration and functional recovery by collagen-binding brain-derived neurotrophic factor in an intracerebral hemorrhage model,” Tissue Engineering Part A, vol. 21, no. 1-2, pp. 62–74, 2015. View at: Publisher Site | Google Scholar
  105. N. M. Harris, R. Ritzel, N. S. Mancini et al., “Nano-particle delivery of brain derived neurotrophic factor after focal cerebral ischemia reduces tissue injury and enhances behavioral recovery,” Pharmacology Biochemistry and Behavior, vol. 150-151, pp. 48–56, 2016. View at: Publisher Site | Google Scholar
  106. B. Rodríguez-Frutos, L. Otero-Ortega, J. Ramos-Cejudo et al., “Enhanced brain-derived neurotrophic factor delivery by ultrasound and microbubbles promotes white matter repair after stroke,” Biomaterials, vol. 100, pp. 41–52, 2016. View at: Publisher Site | Google Scholar
  107. S. W. Jang, X. Liu, M. Yepes et al., “A selective TrkB agonist with potent neurotrophic activities by 7,8-dihydroxyflavone,” Proceedings of the National Academy of Sciences of the United States of America, vol. 107, no. 6, pp. 2687–2692, 2010. View at: Publisher Site | Google Scholar
  108. L. Chen, X. Gao, S. Zhao, W. Hu, and J. Chen, “The small-molecule TrkB agonist 7, 8-dihydroxyflavone decreases hippocampal newborn neuron death after traumatic brain injury,” Journal of Neuropathology and Experimental Neurology, vol. 74, no. 6, pp. 557–567, 2015. View at: Publisher Site | Google Scholar
  109. R. Agrawal, E. Noble, E. Tyagi, Y. Zhuang, Z. Ying, and F. Gomez-Pinilla, “Flavonoid derivative 7,8-DHF attenuates TBI pathology via TrkB activation,” Biochimica et Biophysica Acta - Molecular Basis of Disease, vol. 1852, no. 5, pp. 862–872, 2015. View at: Publisher Site | Google Scholar
  110. N. Aytan, J. K. Choi, I. Carreras et al., “Protective effects of 7,8-dihydroxyflavone on neuropathological and neurochemical changes in a mouse model of Alzheimer’s disease,” European Journal of Pharmacology, vol. 828, pp. 9–17, 2018. View at: Publisher Site | Google Scholar
  111. G. García-Díaz Barriga, A. Giralt, M. Anglada-Huguet et al., “7,8-dihydroxyflavone ameliorates cognitive and motor deficits in a Huntington’s disease mouse model through specific activation of the PLCγ1 pathway,” Human Molecular Genetics, vol. 26, no. 16, pp. 3144–3160, 2017. View at: Publisher Site | Google Scholar
  112. X. H. Li, C. F. Dai, L. Chen, W. T. Zhou, H. L. Han, and Z. F. Dong, “7,8-Dihydroxyflavone ameliorates motor deficits via suppressing α-synuclein expression and oxidative stress in the MPTP-induced mouse model of Parkinson’s disease,” CNS Neuroscience & Therapeutics, vol. 22, no. 7, pp. 617–624, 2016. View at: Publisher Site | Google Scholar
  113. O. T. Korkmaz, N. Aytan, I. Carreras et al., “7,8-Dihydroxyflavone improves motor performance and enhances lower motor neuronal survival in a mouse model of amyotrophic lateral sclerosis,” Neuroscience Letters, vol. 566, pp. 286–291, 2014. View at: Publisher Site | Google Scholar
  114. M. Jiang, Q. Peng, X. Liu et al., “Small-molecule TrkB receptor agonists improve motor function and extend survival in a mouse model of Huntington’s disease,” Human Molecular Genetics, vol. 22, no. 12, pp. 2462–2470, 2013. View at: Publisher Site | Google Scholar
  115. S. M. Massa, T. Yang, Y. Xie et al., “Small molecule BDNF mimetics activate TrkB signaling and prevent neuronal degeneration in rodents,” Journal of Clinical Investigation, vol. 120, no. 5, pp. 1774–1785, 2010. View at: Publisher Site | Google Scholar
  116. T. A. Gudasheva, P. Povarnina, I. O. Logvinov, T. A. Antipova, and S. B. Seredenin, “Mimetics of brain-derived neurotrophic factor loops 1 and 4 are active in a model of ischemic stroke in rats,” Drug Design, Development and Therapy, vol. 10, pp. 3545–3553, 2016. View at: Publisher Site | Google Scholar
  117. G. S. Kim, S. Cho, J. W. Nelson, G. J. Zipfel, and B. H. Han, “TrkB agonist antibody pretreatment enhances neuronal survival and long-term sensory motor function following hypoxic ischemic injury in neonatal rats,” PLoS ONE, vol. 9, no. 2, p. e88962, 2014. View at: Publisher Site | Google Scholar
  118. D. Todd, I. Gowers, S. J. Dowler et al., “A monoclonal antibody TrkB receptor agonist as a potential therapeutic for Huntington’s disease,” PLoS ONE, vol. 9, no. 2, p. e87923, 2014. View at: Publisher Site | Google Scholar
  119. Y. Bai, J. Xu, F. Brahimi, Y. Zhuo, M. V. Sarunic, and H. U. Saragovi, “An agonistic TrKb mAb causes sustained TrkB activation, delays RGC death, and protects the retinal structure in optic nerve axotomy and in glaucoma,” Investigative Ophthalmology and Visual Science, vol. 51, no. 9, pp. 4722–4731, 2010. View at: Publisher Site | Google Scholar
  120. M. Perreault, G. Feng, S. Will et al., “Activation of TrkB with TAM-163 results in opposite effects on body weight in rodents and non-human primates,” PLoS ONE, vol. 8, no. 5, 2013. View at: Publisher Site | Google Scholar
  121. S. Merkouris, Y. A. Barde, K. E. Binley et al., “Fully human agonist antibodies to TrkB using autocrine cell-based selection from a combinatorial antibody library,” Proceedings of the National Academy of Sciences of the United States of America, vol. 115, no. 30, pp. E7023–E7032, 2018. View at: Publisher Site | Google Scholar
  122. M. Fisher, G. Feuerstein, D. W. Howells et al., “Update of the stroke therapy academic industry roundtable preclinical recommendations,” Stroke, vol. 40, no. 6, pp. 2244–2250, 2009. View at: Publisher Site | Google Scholar

Copyright © 2020 Wei Liu 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.

More related articles

 PDF Download Citation Citation
 Download other formatsMore
 Order printed copiesOrder

Related articles

Article of the Year Award: Outstanding research contributions of 2020, as selected by our Chief Editors. Read the winning articles.