Vardenafil increases cell proliferation in the dentate gyrus through enhancement of serotonin expression in the rat dorsal raphe

Abstract

This study was conducted to evaluate the effects of vardenafil (Levitra), a phosphodiesterase-5 (PDE-5) inhibitor, on cell proliferation in the hippocampal dentate gyrus and on 5-hyroxytryptamine (5-HT, serotonin) synthesis and tryptophan hydroxylase (TPH) expression in the rat dorsal raphe nucleus. Male Sprague-Dawley rats were divided into 6 groups (n=5 in each group): a control group, a 0.5 mg/kg-1 day vardenafil-treated group, a 1 mg/kg-1 day vardenafil-treated group, a 2 mg/kg-1 day vardenafil-treated group, a 1 mg/kg-3 day vardenafil-treated group, and a 1 mg/kg-7 day vardenafil-treated group. 5-bromo-2'-deoxyuridine (BrdU) immunohistochemistry was then performed to evaluate cell proliferation in the dentate gyrus. In addition, 5-HT and TPH immunohistochemistry was conducted to evaluate serotonin expression in the dorsal raphe. The results revealed that treatment with vardenafil increased cell proliferation in the dentate gyrus and enhanced 5-HT synthesis and TPH expression in the dorsal raphe in a dose- and duration-dependent manner. The findings demonstrate that the increasing effect of vardenafil on cell proliferation is closely associated with the enhancing effect of vardenafil on serotonin expression under normal conditions.

Keywords: Cell Proliferation; Dentate Gyrus; Serotonin; Tryptophan Hydroxylase; Vardenafil.

Fig. 1

Effect of vardenafil treatment on cell proliferation in the dentate gyrus. Above: Photomicrographs of 5-bromo-2'-deoxyuridine (BrdU)-positive cells in the dentate gyrus. 1. Control group, 2. 2 mg/kg vardenafil for 1 day-treated group. The scale bar represents 50 µm. Middle: The dose-dependent effect of vardenafil treatment for 1 day on cell proliferation in the dentate gyrus. (A) Control group, (B) 0.5 mg/kg vardenafil-treated group, (C) 1 mg/kg vardenafil-treated group, (D) 2 mg/kg vardenafil-treated group. Lower: The duration-dependent effect of 1 mg/kg vardenafil treatment on cell proliferation in the dentate gyrus. (A) Control group, (B) 1-day vardenafil-treated group, (C) 3-day vardenafil-treated group, (D) 7-day vardenafil-treated group. Values are represented as the mean±SEM.

Fig. 2

Effect of vardenafil treatment on 5-hyroxytryptamine (5-HT) expression in the dorsal raphe nucleus. Upper: Photomicrographs of 5-HT-positive cells in the dorsal raphe nucleus. 1. Control group, 2. 2 mg/kg vardenafil for 1 day-treated group. The scale bar represents 100 µm. Middle: The dose-dependent effect of 1-day vardenafil treatment on 5-HT expression in the dorsal raphe nucleus. (A) Control group, (B) 0.5 mg/kg vardenafil-treated group, (C) 1 mg/kg vardenafil-treated group, (D) 2 mg/kg vardenafil-treated group. Lower: The duration-dependent effect of 1 mg/kg vardenafil treatment on 5-HT expression in the dorsal raphe nucleus. (A) Control group, (B) 1-day vardenafil-treated group, (C) 3-day vardenafil-treated group, (D) 7-day vardenafil-treated group. Values are represented as the mean±SEM.

Fig. 3

Upper: Photomicrographs of tryptophan hydroxylase (TPH)-positive cells in the dorsal raphe nucleus. 1. Control group, 2. 2 mg/kg vardenafil for 1 day-treated group. The scale bar represents 100 mm. Middle: The dose-dependent effect of 1-day vardenafil treatment on TPH expression in the dorsal raphe nucleus. (A) Control group, (B) 0.5 mg/kg vardenafil-treated group, (C) 1 mg/kg vardenafil-treated group, (D) 2 mg/kg vardenafil-treated group. Lower: The duration-dependent effect of 1 mg/kg vardenafil treatment on TPH expression in the dorsal raphe nucleus. (A) Control group, (B) 1-day vardenafil-treated group, (C) 3-day vardenafil-treated group, (D) 7-day vardenafil-treated group. Values are represented as the mean±SEM.