Phenytoin enhances the phosphorylation of epidermal growth factor receptor and fibroblast growth factor receptor in the subventricular zone and promotes the proliferation of neural precursor cells and oligodendrocyte differentiation

Abstract

Phenytoin is a widely used antiepileptic drug that induces cell proliferation in several tissues, such as heart, bone, skin, oral mucosa and neural precursors. Some of these effects are mediated via fibroblast growth factor receptor (FGFR) and epidermal growth factor receptor (EGFR). These receptors are strongly expressed in the adult ventricular-subventricular zone (V-SVZ), the main neurogenic niche in the adult brain. The aim of this study was to determine the cell lineage and cell fate of V-SVZ neural progenitors expanded by phenytoin, as well as the effects of this drug on EGFR/FGFR phosphorylation. Male BALB/C mice received 10 mg/kg phenytoin by oral cannula for 30 days. We analysed the proliferation of V-SVZ neural progenitors by immunohistochemistry and western blot. Our findings indicate that phenytoin enhanced twofold the phosphorylation of EGFR and FGFR in the V-SVZ, increased the number of bromodeoxyuridine (BrdU)+/Sox2+ and BrdU+/doublecortin+ cells in the V-SVZ, and expanded the population of Olig2-expressing cells around the lateral ventricles. After phenytoin removal, a large number of BrdU+/Receptor interacting protein (RIP)+ cells were observed in the olfactory bulb. In conclusion, phenytoin enhanced the phosphorylation of FGFR and EGFR, and promoted the expression of neural precursor markers in the V-SVZ. In parallel, the number of oligodendrocytes increased significantly after phenytoin removal.

The EGFR signaling pathway controls gut progenitor differentiation during planarian regeneration and homeostasis

“…This role in stem cell differentiation appears to be widespread among bilaterian animals (Freeman et al, 1992;Galvez-Contreras et al, 2015;Yoo et al, 2004). Moreover, studies performed in Drosophila and mouse have demonstrated the role of the EGFR pathway in the maintenance of the intestine (Jiang et al, 2011;Wong et al, 2012), as demonstrated here in planarians.…”

Rapid Eye Movement Sleep Deprivation Produces Long-Term Detrimental Effects in Spatial Memory and Modifies the Cellular Composition of the Subgranular Zone

“…In the present study, we found a reduction in the expression of phosphorylated-IGF-1R in the animals that were sacrificed immediately after SD. These changes could be attributed to fluctuation in glucocorticoid levels that has been reported in SD animals ( Galvez-Contreras et al, 2016 ). IGF-1 has a rapid mechanism of action and a short biological half-life ( Rabinovsky et al, 2003 ).…”

“…Four animals per group were decapitated and hippocampi were treated with protease tablets (complete mini EDTA-free, Roche, 04693159001) plus lysis buffer (Base Tris pH = 7.5, NaCl, NaF, Na 3 VO 4 , NP40) as described previously ( Krishack et al, 2015 ; Shiwa et al, 2015 ; Galvez-Contreras et al, 2016 ). Briefly, the homogenate was centrifuged for 30 min at 14,000 rpm/4°C, and the supernatant was recovered and processed for Lowry protein assay ( Lowry et al, 1951 ).…”

Differential effects of antiseizure medications on neurogenesis: Evidence from cells to animals

“…It also expanded the number of Olig2 + cells around the lateral ventricles. Although PHT significantly decreased the proportion of mature neurons (NG2 + glia and NeuN + cells) but promoted the percent of mature oligodendrocyte RIP + cells in the OB [ 54 ]. The same investigators also showed that PHT (10 mg/kg, 30 days) dose-dependently promoted the proliferation of NSC in the SVZ and SGZ areas of the adult mice brain [ 55 ].…”