• Users Online: 63
  • Home
  • Print this page
  • Email this page
Home About us Editorial board Ahead of print Current issue Search Archives Submit article Instructions Subscribe Contacts Login 

   Table of Contents      
Year : 2017  |  Volume : 3  |  Issue : 3  |  Page : 152-155

Drug treatments that optimize endogenous neurogenesis as a therapeutic option for stroke

1 Center of Excellence for Aging and Brain Repair, University of South Florida, Tampa, FL, USA
2 Center for Neuropsychiatric Research, National Health Research Institutes, Taiwan

Date of Submission05-Aug-2017
Date of Decision03-Sep-2017
Date of Acceptance05-Sep-2017
Date of Web Publication12-Oct-2017

Correspondence Address:
Seongjin Yu
Center for Neuropsychiatric Research, National Health Research Institutes
Login to access the Email id

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/bc.bc_20_17

Rights and Permissions

Cell death and neurogenesis have been examined after stroke in the subventricular zone of the adult mammalian brain. New research focuses on the use of drugs to improve the viability of neural progenitor cells in rats after stroke. The aim of the drugs is to lengthen the timeframe for stroke therapy by targeting the endogenous repair mechanism that follows injury. In this paper, we look at the broad state of stroke therapy to assess the effectiveness of endogenous neurogenesis-enhancing drugs on stroke. This paper is a review article. Referred literature in this paper has been listed in the reference section. The data sets supporting the conclusions of this article are available online by searching various databases, including PubMed. Some original points in this article come from the laboratory practice in our research center and the authors' experiences.

Keywords: Central nervous system disorders, endogenous neural progenitor cells, neurogenesis, neurogenesis-enhancing drugs, regenerative medicine, stroke

How to cite this article:
Dewan SN, Wang Y, Yu S. Drug treatments that optimize endogenous neurogenesis as a therapeutic option for stroke. Brain Circ 2017;3:152-5

How to cite this URL:
Dewan SN, Wang Y, Yu S. Drug treatments that optimize endogenous neurogenesis as a therapeutic option for stroke. Brain Circ [serial online] 2017 [cited 2023 Jun 6];3:152-5. Available from: http://www.braincirculation.org/text.asp?2017/3/3/152/216588

  Introductions Top

At the occurrence of an ischemic brain injury, bodily responses include apoptosis, leakage of the blood–brain barrier, inflammation cell death, excitotoxicity, as well as endogenous neural repair (see the study by Brouns and De Deyn1 for further details).[1] Many of these reactions occur following stroke lasting anywhere from hours to 2 days. An occurrence of these responses includes the apoptosis at the ischemic site.[2] It has been demonstrated that the p53 messenger RNA (mRNA) or protein is upregulated following stroke in a rodent distal middle cerebral artery occlusion (MCAo) model, leading to p53-dependent apoptosis in the penumbra.[3],[4] Furthermore, the density of the terminal deoxynucleotidyl transferase 20-deoxyuridine 50-triphosphate dUTP nick end labeling (TUNEL) located within the ischemic cortex peaks 2 days following MCAo and stabilizes within 6 days.[5] It was also demonstrated that animals have reduced brain infarction when given a p53 inhibitor treatment preceding or directly following MCAo.[6],[7] No beneficial effects on neuronal loss[7] or locomotor behaviors were recorded when the p53 inhibitor treatment was administered 3 h or later following MCAo.[5] Clinical applications for these drugs have been limited by the limited therapeutic window caused by the short length of apoptosis/necrosis in the ischemic region. Because of the narrow therapeutic window treatments aiming at suppressing apoptosis in the ischemic region, treatments must occur soon after MCAo.

In a study of the adult mammalian brain, cerebral ischemia was found to induce novel neurogenesis within the subventricular zone (SVZ) several days following stroke, representing a late bodily repair mechanism.[8] Utilizing bromodeoxyuridine (BrdU) labeling to measure to proliferation of neural progenitor cells (NPCs), a rise in BrdU immunoreactivity was recorded as soon as 2 days post-MCAo within the SVZ postischemia.[5] Immunoreactivity remained constant through day 4, then wanted from day 6 to day 8 returning to baseline around day 10. This trend demonstrates a divergence between cell death in the ischemic-lesioned area and cell propagation in the SVZ. A longer treatment window may be achieved by focusing on the viability of endogenous NPCs within the SVZ following stroke.[5],[9]

  Endogenous Neurogenesis-Enhancing Drugs Top

Several drugs in development directed toward the endogenous repair mechanisms that follow stroke control the differentiation, migration, or procreation of NPCs in the SVZ. Several of these drugs which may have the potential to create a longer timeframe for stroke therapy are described below.


While stroke can induce the propagation of NPCs in the SVZ, a majority of the cells die following injury.[10] NPC cells within the SVZ express high levels of p53 protein.[11] Amplified TUNEL activity was discovered within the SVZ of stroke rats[5] demonstrating that apoptosis is a factor in the death of NPCs. Because initiation of NPC propagation in SVZ ensues at a later stage,[12] beginning at 6-day post-MCAo, 12 treatments of pifithrin-a and p53 inhibitor were found to enhance motor function in stroke rats[5] while also improving viability of endogenous NPCs in the SVZ. These results suggest that p53 inhibition may attenuate the survival of endogenous NPCs and change biological outcomes several days following stroke.

Trophic factors

Specific trophic factors have been revealed to improve neural reparative activity after stroke. Some of the trophic factors that have received much attention from stroke researchers are discussed below.

Bone morphogenetic protein 7

Bone morphogenetic protein 7 (BMP7) is a trophic protein in the transforming growth factor-b superfamily that can promote DNA synthesis. DNA synthesis was examined by BrdU incorporation in mesencephalic-cultured neurons.[13] Treatment with BMP7 following MCAo improved sensorimotor function,[14],[15] lowered body asymmetry, and increased locomotor activity from 7-day postinjury to 14-day postinjury.[16] BMP7 simultaneously increased BrdU immunoreactivity in the corpus callosum, lesioned cortex, and SVZ. BrdU-positive cells are colabled with NeuN and nestin.[17] These results back the idea that BMP7 ameliorates functional recovery through the propagation of neuronal precursors in the stroke brain.

Brain-derived neurotrophic factor

In stroke animals, systemic administration of brain-derived neurotrophic factor (BDNF) improved the movement of NPCs into the lesioned site,[18] while in nonstroke animals, BDNF has been shown to increase movement of NPCs from the SVZ to the olfactory bulbs.[19],[20],[21] Atorvastatin (a BDNF-activating chemical) increased movement of SVZ cells.[9],[22] Furthermore, gene therapy through adeno-associated virus infection induces an overexpression of BDNF enabling improved functional recovery and NPC movement from the SVZ.[23] The results suggest that treatment with BDNF or increasing endogenous BDNF expression improved the movement of NPCs from the SVZ and enabled behavioral recovery in stroke animals.

Other trophic factors

Multiple other trophic factors have been shown to enhance neurorepair in stroke animals.

One such trophic factor is GDNF which is overexpressed through the transplantation of human umbilical cord CD34þ or neural stem cells leading to enhanced neurogenesis.[24],[25] Increased GDNF concentration amplified cell propagation in the SVZ[26] and the recruitment of novel neuroblasts into the striatum following MCAo.[27] Additional trophic factors, such as basic fibroblast growth factor, epidermal growth factor, and hepatocyte growth factor, have been determined to raise the number of BrdU-positive cells in the SVZ and advance endogenous neurogenesis in the stroke brain.[26],[28],[29],[30]

Cocaine- and amphetamine-regulated transcript

Cocaine- and amphetamine-regulated transcript (CART) is a peptide found in the brain. The expression of CART can be increased by electroconvulsive shock or focal cerebral ischemia in vivo[31] and oxygen–glucose deprivation in culture.[32] Recent experimentation has exemplified that CART treatment administered intranasally 3 days following MCAo improved neuronal repair[32],[33] by facilitating NPC propagation and movement from the SVZ. The movement and propagation of NPCs enhanced reinnervation in lesioned cortex and improved the functional recovery of stroke animals and also reduced cerebral infarction.[9],[34] Within the SVZ, CART improved the proliferating cell nuclear antigen, NPC marker Musashi-1, immunolabeling of BrdU, while upregulated BDNF mRNA. CART treatment increased neurosphere formation in an SVZ culture while anti-BDNF-blocking antibodies provoked CART-mediated cell movement from the SVZ. Increased expression of Fluoro-Ruby fluorescence and GAP43 in the injured cortex was triggered by CART. CART treatment was also found to increase N-acetylaspartate levels in the injured cortex using 1H-magnetic resonance spectroscopy. These results show that neuroregeneration in the stroke brain can be improved through intranasal CART treatment.[9],[34]

  Naturally Occurring Compounds as Agents for Enhancing Endogenous Neurogenesis in Stroke Top

During the prestrike period, dietary supplementation has been shown to exhibit neuroprotective properties by reducing inflammation and increasing neurogenesis. By stimulating endogenous brain restoration, dietary supplementation can prevent the brain from undergoing further insult and injury.[35],[36] Certain foods high in antioxidants such as polyphenols from blueberries, green tea, and amino acids such as carnosine exhibit anti-inflammatory properties and could, therefore, lessen the harmful effects of reactive oxygen species in the blood, brain, and other body tissues.[35],[36] Further research should consider the effectiveness of a poststroke dietary treatment in dampening the secondary cell death cascade that follows stroke. It may also be clinically relevant to examine the use of dietary supplement as an additional treatment for prevention and chronic disease treatment in stroke and other diseases. We see the future of dietary supplements as an assisting treatment for treating stroke acutely, subacutely, and chronically.

  An Overview of Recent Advances in Stroke Therapeutics Top

At present, tissue plasminogen activator (tPA) is the standard for treating ischemic stroke. The use case of tPA is narrowed by its 4.5-hour poststroke therapeutic window, and hemorrhagic transformation (HT) affects if administered outside of the therapeutic window. An effective stroke treatment is possible if the risk of HT and other drawbacks associated with delayed tPA is reduced. Drugs that maintain the patency of the cerebrovasculature to prevent delayed tPA-induced HT have promise as a treatment for ischemic stroke and have been the focus of much pharmaceutically oriented preclinical research. Drugs examined for HT ameliorating and endogenous neurogenerative properties include those discussed above as well as brain vasculature enhancing and blood brain barrier preserving drugs.[9],[19],[20],[21],[23],[25],[34] Hurdles regarding optimization of the drug regimen exist before clinical application can be reached. Uncertainties regarding the dose, timing, and route of the drug must be resolved for these drugs to be presented as effective treatment options.

  Conclusion Top

At present, the narrow therapeutic window for stroke limits the scope of drugs usable for treatment. Multiple peptides, chemicals, and trophic factors that target the endogenous repair originating in the NPCs in the SVZ have been shown to improve behavioral performance poststroke.[35],[36],[37] The experimental method discussed proposes a possible treatment strategy for increasing the treatment window for stroke. Stroke is often difficult to treat directly following injury; therefore, this approach could increase further treatment opportunity.

Financial support and sponsorship

National Health Research Institutes, Taiwan.

Conflicts of interest

There are no conflicts of interest.

  References Top

Brouns R, De Deyn PP. The complexity of neurobiological processes in acute ischemic stroke. Clin Neurol Neurosurg 2009;111:483-95.  Back to cited text no. 1
Luo Y, Kuo CC, Shen H, Chou J, Greig NH, Hoffer BJ, et al. Delayed treatment with a p53 inhibitor enhances recovery in stroke brain. Ann Neurol 2009;65:520-30.  Back to cited text no. 2
Culmsee C, Zhu X, Yu QS, Chan SL, Camandola S, Guo Z, et al. A synthetic inhibitor of p53 protects neurons against death induced by ischemic and excitotoxic insults, and amyloid beta-peptide. J Neurochem 2001;77:220-8.  Back to cited text no. 3
Li Y, Chopp M, Zhang ZG, Zaloga C, Niewenhuis L, Gautam S, et al. P53-immunoreactive protein and p53 mRNA expression after transient middle cerebral artery occlusion in rats. Stroke 1994;25:849-55.  Back to cited text no. 4
Li Y, Chopp M, Powers C, Jiang N. Apoptosis and protein expression after focal cerebral ischemia in rat. Brain Res 1997;765:301-12.  Back to cited text no. 5
Leker RR, Aharonowiz M, Greig NH, Ovadia H. The role of p53-induced apoptosis in cerebral ischemia: Effects of the p53 inhibitor pifithrin alpha. Exp Neurol 2004;187:478-86.  Back to cited text no. 6
Abrahams JM, Gokhan S, Flamm ES, Mehler MF. De novo neurogenesis and acute stroke: Are exogenous stem cells really necessary? Neurosurgery 2004;54:150-5.  Back to cited text no. 7
Luo Y, Shen H, Liu HS, Yu SJ, Reiner DJ, Harvey BK, et al. CART peptide induces neuroregeneration in stroke rats. J Cereb Blood Flow Metab 2013;33:300-10.  Back to cited text no. 8
Meletis K, Wirta V, Hede SM, Nistér M, Lundeberg J, Frisén J, et al. P53 suppresses the self-renewal of adult neural stem cells. Development 2006;133:363-9.  Back to cited text no. 9
Felling RJ, Levison SW. Enhanced neurogenesis following stroke. J Neurosci Res 2003;73:277-83.  Back to cited text no. 10
Jordan J, Böttner M, Schluesener HJ, Unsicker K, Krieglstein K. Bone morphogenetic proteins: Neurotrophic roles for midbrain dopaminergic neurons and implications of astroglial cells. Eur J Neurosci 1997;9:1699-709.  Back to cited text no. 11
Schallert T, Fleming SM, Leasure JL, Tillerson JL, Bland ST. CNS plasticity and assessment of forelimb sensorimotor outcome in unilateral rat models of stroke, cortical ablation, parkinsonism and spinal cord injury. Neuropharmacology 2000;39:777-87.  Back to cited text no. 12
Kawamata T, Ren J, Chan TC, Charette M, Finklestein SP. Intracisternal osteogenic protein-1 enhances functional recovery following focal stroke. Neuroreport 1998;9:1441-5.  Back to cited text no. 13
Chou J, Harvey BK, Chang CF, Shen H, Morales M, Wang Y, et al. Neuroregenerative effects of BMP7 after stroke in rats. J Neurol Sci 2006;240:21-9.  Back to cited text no. 14
Chang CF, Lin SZ, Chiang YH, Morales M, Chou J, Lein P, et al. Intravenous administration of bone morphogenetic protein-7 after ischemia improves motor function in stroke rats. Stroke 2003;34:558-64.  Back to cited text no. 15
Bath KG, Akins MR, Lee FS. BDNF control of adult SVZ neurogenesis. Dev Psychobiol 2012;54:578-89.  Back to cited text no. 16
Bagley JA, Belluscio L. Dynamic imaging reveals that brain-derived neurotrophic factor can independently regulate motility and direction of neuroblasts within the rostral migratory stream. Neuroscience 2010;169:1449-61.  Back to cited text no. 17
Yu SJ, Tseng KY, Shen H, Harvey BK, Airavaara M, Wang Y, et al. Local administration of AAV-BDNF to subventricular zone induces functional recovery in stroke rats. PLoS One 2013;8:e81750.  Back to cited text no. 18
Chiaramello S, Dalmasso G, Bezin L, Marcel D, Jourdan F, Peretto P, et al. BDNF/TrkB interaction regulates migration of SVZ precursor cells via PI3-K and MAP-K signalling pathways. Eur J Neurosci 2007;26:1780-90.  Back to cited text no. 19
Schäbitz WR, Steigleder T, Cooper-Kuhn CM, Schwab S, Sommer C, Schneider A, et al. Intravenous brain-derived neurotrophic factor enhances poststroke sensorimotor recovery and stimulates neurogenesis. Stroke 2007;38:2165-72.  Back to cited text no. 20
Chen J, Zhang C, Jiang H, Li Y, Zhang L, Robin A, et al. Atorvastatin induction of VEGF and BDNF promotes brain plasticity after stroke in mice. J Cereb Blood Flow Metab 2005;25:281-90.  Back to cited text no. 21
Yuan M, Wen SJ, Yang CX, Pang YG, Gao XQ, Liu XQ, et al. Transplantation of neural stem cells overexpressing glial cell line-derived neurotrophic factor enhances Akt and Erk1/2 signaling and neurogenesis in rats after stroke. Chin Med J (Engl) 2013;126:1302-9.  Back to cited text no. 22
Ou Y, Yu S, Kaneko Y, Tajiri N, Bae EC, Chheda SH, et al. Intravenous infusion of GDNF gene-modified human umbilical cord blood CD34+ cells protects against cerebral ischemic injury in spontaneously hypertensive rats. Brain Res 2010;1366:217-25.  Back to cited text no. 23
Shang J, Deguchi K, Ohta Y, Liu N, Zhang X, Tian F, et al. Strong neurogenesis, angiogenesis, synaptogenesis, and antifibrosis of hepatocyte growth factor in rats brain after transient middle cerebral artery occlusion. J Neurosci Res 2011;89:86-95.  Back to cited text no. 24
Kobayashi T, Ahlenius H, Thored P, Kobayashi R, Kokaia Z, Lindvall O, et al. Intracerebral infusion of glial cell line-derived neurotrophic factor promotes striatal neurogenesis after stroke in adult rats. Stroke 2006;37:2361-7.  Back to cited text no. 25
Nakaguchi K, Jinnou H, Kaneko N, Sawada M, Hikita T, Saitoh S, et al. Growth factors released from gelatin hydrogel microspheres increase new neurons in the adult mouse brain. Stem Cells Int 2012;2012:915160.  Back to cited text no. 26
Won SJ, Xie L, Kim SH, Tang H, Wang Y, Mao X, et al. Influence of age on the response to fibroblast growth factor-2 treatment in a rat model of stroke. Brain Res 2006;1123:237-44.  Back to cited text no. 27
Roh MS, Cui FJ, Ahn YM, Kang UG. Up-regulation of cocaine- and amphetamine-regulated transcript (CART) in the rat nucleus accumbens after repeated electroconvulsive shock. Neurosci Res 2009;65:210-3.  Back to cited text no. 28
Xu Y, Zhang W, Klaus J, Young J, Koerner I, Sheldahl LC, et al. Role of cocaine- and amphetamine-regulated transcript in estradiol-mediated neuroprotection. Proc Natl Acad Sci U S A 2006;103:14489-94.  Back to cited text no. 29
Baldauf K, Reymann KG. Influence of EGF/bFGF treatment on proliferation, early neurogenesis and infarct volume after transient focal ischemia. Brain Res 2005;1056:158-67.  Back to cited text no. 30
Liu HS, Shen H, Luo Y, Hoffer BJ, Wang Y, Yang Y, et al. Post-treatment with cocaine- and amphetamine-regulated transcript enhances infarct resolution, reinnervation, and angiogenesis in stroke rats – An MRI study. NMR Biomed 2016;29:361-70.  Back to cited text no. 31
Jia J, Chen X, Zhu W, Luo Y, Hua Z, Xu Y, et al. CART protects brain from damage through ERK activation in ischemic stroke. Neuropeptides 2008;42:653-61.  Back to cited text no. 32
Kaneko Y, Cortes L, Sanberg C, Acosta S, Bickford PC, Borlongan CV, et al. Dietary supplementations as neuroprotective therapies: Focus on NT-020 diet benefits in a rat model of stroke. Int J Mol Sci 2012;13:7424-44.  Back to cited text no. 33
Yasuhara T, Hara K, Maki M, Masuda T, Sanberg CD, Sanberg PR, et al. Dietary supplementation exerts neuroprotective effects in ischemic stroke model. Rejuvenation Res 2008;11:201-14.  Back to cited text no. 34
Mao P, Ardeshiri A, Jacks R, Yang S, Hurn PD, Alkayed NJ, et al. Mitochondrial mechanism of neuroprotection by CART. Eur J Neurosci 2007;26:624-32.  Back to cited text no. 35
Wu B, Hu S, Yang M, Pan H, Zhu S. CART peptide promotes the survival of hippocampal neurons by upregulating brain-derived neurotrophic factor. Biochem Biophys Res Commun 2006;347:656-61.  Back to cited text no. 36
Douglass J, McKinzie AA, Couceyro P. PCR differential display identifies a rat brain mRNA that is transcriptionally regulated by cocaine and amphetamine. J Neurosci 1995;15:2471-81.  Back to cited text no. 37


    Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
    Access Statistics
    Email Alert *
    Add to My List *
* Registration required (free)  

  In this article
Endogenous Neuro...
Naturally Occurr...
An Overview of R...

 Article Access Statistics
    PDF Downloaded275    
    Comments [Add]    

Recommend this journal