Delayed treatment with sildenafil enhances neurogenesis and improves functional recovery in aged rats after focal cerebral ischemia

Abstract

Increasing age decreases the number of new neurons in the dentate gyrus and the subventricular zone (SVZ). Sildenafil, a phosphodiesterase type 5 (PDE5) inhibitor, enhances neurogenesis in young rats. The present study tested the hypothesis that sildenafil augments neurogenesis in aged rats after focal cerebral ischemia. Nonischemic aged (18 months, n = 6) Wistar rats exhibited a significant reduction of actively proliferating and relatively quiescent cells in the SVZ measured by the number of minichromosome maintenance protein-2-positive (MCM-2+) cells, a marker of the proliferating cells, compared with nonischemic young (3-4 months, n = 8) rats. Occlusion of the middle cerebral artery did not increase the number of MCM-2+ cells in the SVZ of aged rats at 3 months after focal ischemia. However, treatment with sildenafil at a dose of 3 mg/kg (n = 8) daily for 7 consecutive days starting 7 days after focal ischemia significantly increased the number of MCM-2+ cells in the SVZ of aged rats compared with aged rats treated with saline (n = 8). Double immunostaining revealed that substantially more Ki67+ cells (a marker of proliferating cells) were doublecortin+ (a marker of migrating neuroblasts) in sildenafil-treated than in saline-treated aged animals. In addition, treatment with sildenafil significantly improved functional recovery compared with saline-treated rats. These data suggest that inhibition of PDE5 activity by sildenafil augments neurogenesis in the SVZ of aged ischemic rats, although these rats have reduced numbers of neural progenitor and stem cells in the SVZ.