This application proposes a novel concept for the treatment of stroke by testing the actin-sequestering protein Thymosin B4 (TB4) in a rat model of embolic stroke. T~4 improves cardiac function after myocardial infarction and promotes dermal and cornea healing. We will use a well-established embolic stroke model to optimize the dose and determine the therapeutic window of administration of TB4 by testing functional neurological outcome in both young and aged rats. Our preliminary data demonstrate that TB4 has the potential for treatment of stroke. Administration of TB4 24 hours after stroke onset improves functional neurological outcome in a rat model of embolic stroke. Our fundamental hypothesis is that treatment with TB4 promotes axonal remodeling by stimulation of oligodendrocyte progenitor cells (OPCs) in the subventricular zone (SVZ) and in the intact white matter in both young and aged rats. Oligodendrocytes (OLs) are highly vulnerable to focal cerebral ischemia and our preliminary data suggest that TB4 increases migration and differentiation of OPCs resulting in improved outcome. [In addition, our preliminary data suggests that the epidermal growth factor receptor (EGF-R) likely mediates the effect of TB4 on OPCs.] The innovation of TB4 in the treatment of stroke is that TB4 acts a neurorestorative agent, Neurorestorative agents are unique in that they act on intact parenchymal cells to stimulate neurogenesis, angiogenesis, axonal sprouting and oligodendrogenesis. Clinically, neurorestorative agents are more practical in that no significant time and therapeutic drug delivery constraints exist and that the drug targets the intact parenchymal cells, with intact cerebral blood flow. TB4 has been tested in both animal and human models with a high safety profile. This application is the first proposal to systematically test TB4 in CNS injury in both young and aged rats. Age is associated with an increased mortality rate and poor neurological outcome compared with young rats after stroke. Moreover, aged animals recover more slowly with reduced functionality when compared to younger animals. Therefore, in order to match the clinical reality of stroke, this application proposes to test TB4 in both young and aged rats. The primary specific aim of this grant application is to determine the therapeutic efficacy of TB4 for treatment of stroke in both young and aged rats.
Our specific aims are to: 1) define the optimal dose needed via a dose-response study of TB4 treatment initiated 24 hours after stroke in young and aged rats using neurological outcome as the primary endpoint, 2) determine the therapeutic window of TB4 after stroke in both young and aged rats and [3) to investigate whether epidermal growth factor receptor (EGF-R) mediates TB4 enhanced oligodendrogenesis.] Our results will provide pre-clinical evidence that TB4 is a neurorestorative agent for the treatment of stroke and will provide data for a phase I study in humans.

Public Health Relevance

This study will investigate the use of a drug, Thymosin beta4 (TB4) for treatment of ischemic stroke in a rat model. Ischemic stroke occurs when a blood clot interrupts flow in a major artery that supplies parts of the brain causing weakness and paralysis. TB4 will be given to the rat after 24 hours after stroke and every three days for four additional doses. We will measure neurological function at given times to determine if TB4 improves symptoms of the stroke. Since stroke occurs in the elderly we will also test the drug in aged rats to determine if the drug also improves symptoms in the aged.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
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Special Emphasis Panel (ZRG1-MDCN-C (56))
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Petanceska, Suzana
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Henry Ford Health System
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Morris, Daniel C; Zhang, Zheng G; Chopp, Michael (2018) Thymosin ?4 for the treatment of acute stroke: neurorestorative or neuroprotective? Expert Opin Biol Ther 18:149-158
Morris, Daniel C; Cheung, Wing Lee; Loi, Richard et al. (2017) Thymosin ?4 for the treatment of acute stroke in aged rats. Neurosci Lett 659:7-13
Santra, Manoranjan; Chopp, Michael; Santra, Sutapa et al. (2016) Thymosin beta 4 up-regulates miR-200a expression and induces differentiation and survival of rat brain progenitor cells. J Neurochem 136:118-32
Morris, D C; Cui, Y; Cheung, W L et al. (2014) A dose-response study of thymosin ?4 for the treatment of acute stroke. J Neurol Sci 345:61-7
Santra, Manoranjan; Zhang, Zheng Gang; Yang, James et al. (2014) Thymosin ?4 up-regulation of microRNA-146a promotes oligodendrocyte differentiation and suppression of the Toll-like proinflammatory pathway. J Biol Chem 289:19508-18
Wang, Lei; Chopp, Michael; Szalad, Alexandra et al. (2012) Thymosin ?4 promotes the recovery of peripheral neuropathy in type II diabetic mice. Neurobiol Dis 48:546-55
Xiong, Ye; Zhang, Yanlu; Mahmood, Asim et al. (2012) Neuroprotective and neurorestorative effects of thymosin ?4 treatment initiated 6 hours after traumatic brain injury in rats. J Neurosurg 116:1081-92
Santra, Manoranjan; Chopp, Michael; Zhang, Zheng Gang et al. (2012) Thymosin ? 4 mediates oligodendrocyte differentiation by upregulating p38 MAPK. Glia 60:1826-38
Buller, Benjamin; Chopp, Michael; Ueno, Yuji et al. (2012) Regulation of serum response factor by miRNA-200 and miRNA-9 modulates oligodendrocyte progenitor cell differentiation. Glia 60:1906-14
Morris, Daniel C; Zhang, Zheng G; Zhang, Jing et al. (2012) Treatment of neurological injury with thymosin ?4. Ann N Y Acad Sci 1269:110-6

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