Diphenylhydantoin Promotes Proliferation in The Subventricular Zone and Dentate Gyrus

Abstract

Problem statement: Diphenylhydantoin (phenytoin) is an antiepileptic drug that generates hyperplasia in some tissue by stimulating Epidermal Growth Factor (EGFR) and Platelet-Derived Growth Factor beta (PDGFR-β) receptors and by increasing serum levels of basic fibroblast growth factor (bFGF, FGF2 or FGF-β). Neural stem cells in the adult brain have been isolated from three regions: the Subventricular Zone (SVZ) lining the lateral wall of the lateral ventricles, the Subgranular Zone (SGZ) in the dentate gyrus at the hippocampus and the Subgranular Zone (SZC) lining between the hippocampus and the corpus callosum. Neural stem cells actively respond to bFGF, PDGFR-β or EGF by increasing their proliferation, survival and differentiation. The aim of this study was to evaluate the effect of phenytoin on proliferation and apoptosis in the three neurogenic niches in the adult brain. Approach: We orally administrated phenytoin with an oropharyngeal cannula for 30 days: 0 mg kg^-1 (controls), 1, 5, 10, 50 and 100 mg kg^-1. To label proliferative cells, three injections of 100 mg kg^-1 of BrdU was administrated every 12 h. Immunohistochemistry against BrdU or Caspase-3 active were performed to determine the number of proliferative or apoptotic cells. Results: Our results showed that phenytoin induces proliferation in the SVZ and the SGZ in a dose-dependent manner. No statistically significant effects on cell proliferation in the SCZ neither in the apoptosis rate at the SVZ, SGZ and SCZ were found. Conclusion: These data indicate that phenytoin promotes a dose-dependent proliferation in the SVZ and SGZ of the adult brain. The clinical relevance of these findings remain to be elucidated.