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456 THE THERAPEUTIC POTENTIAL OF TRANSFORMING GROWTH FACTOR α AS A TREATMENT FOR CHRONIC STROKE.
  1. J. Su1,
  2. M. Guerra-Crespo1,
  3. J. H. Fallon1
  1. 1Department of Anatomy and Neurobiology, University of California, Irvine, CA

Abstract

Stroke is a leading cause of adult debilitation in the United States. Although current therapies preserve patients' neurologic function and prevent further brain damage after an ischemic incident, there does not yet exist a treatment that can reverse the symptoms of chronic stroke. Here we explore the potential of using transforming growth factor α (TGF-α) via different routes of administration as a possible therapy option for stroke survivors in the future. TGF-α is an important growth factor controlling the differentiation of neural precursors during development and in the adult CNS. Using fluorescent immunohistochemistry, our research shows that intracerebral infusions of TGF-α months after a transient middle cerebral artery occlusion (MCAO) can induce proliferation, migration, and differentiation (PMD response) of endogenous neural stem cells within the neurogenic subventricular zone (SVZ) toward chronically infarcted areas in the rodent brain (Guerra et al, Neuroscience abstract, 2006). A substantial increase in the immunoreactivity of proliferative cells into the ipsilateral forebrain of TGF-α-infused rats with stroke was demonstrated using the neuronal stem cell markers nestin and bromodeoxyuridine (BrdU). After 4 weeks of TGF-α infusion, a high number of cells stained positive for Neu-N, a neuronal marker, showing the integration of a portion of the migrating cells. Thus, many of the newly generated neurons acquire the properties of the neuronal input and output that have been lost in the striatum following the experimentally induced stroke. TGF-α is the only growth factor shown to induce a PMD response of endogenous neural precursors in acute (Fallon et al, 2000) and chronically damaged areas of the brain, suggesting its clinical relevance in regenerative treatment. To assess the practicality of using TGF-α as form of therapy in human stroke survivors, we also have been exploring the efficacy of TGF-α administration by intranasal, central, and peripheral routes. The objective of this study has been to intranasally infuse TGF-α for a period of 4 weeks and to determine by immunofluorescent techniques if TGF-α is able to reach the area of injury and induce the PMD response observed by the intracranial method. The ability to comfortably and safely administer therapeutic doses of TGF-α that cross the blood-brain barrier is of primary importance and has major implications in predicting patient compliance as well as identifying unforeseen neurologic and physiologic effects that may be associated with TGF-α therapy.

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