Memantine abrogates testicular dysfunction induced by risperidone in rats with a potential role of ERK1/2-Nrf2-caspase-3 signaling pathway

Abstract

Psychosis is usually a substantial global burden with a prevalence of 0.4-2%. On the other hand, 50 million people are suffering from dementia, with dementia-related psychosis affecting approximately 25% of them. The current experiment aimed to investigate the effect of the anti-dementia drug memantine (MEM) on testicular damage and insulin resistance induced by the chronic administration of risperidone (RIS) in rats. Six groups of Wistar albino rats were designated as follows: control, MEM-5 (rats received MEM at 5 mg/kg/day, orally, for 4 weeks), MEM-10 (rats received MEM at 10 mg/kg/day, orally, for 4 weeks), RIS (rats were administered RIS at 2.5 mg/kg/day, orally, for 4 weeks), RIS + MEM-5 (rats received MEM at 5 mg/kg/day, orally, co-administered with RIS as in the RIS group for 4 weeks), and RIS + MEM-10 (rats received MEM at 10 mg/kg/day, orally, co-administered with RIS as in the RIS group for 4 weeks). The duration of the study was 28 days. Serum testosterone, resistin, and adiponectin concentrations were determined. The homeostatic model assessment of insulin resistance (HOMA-IR) was also evaluated. Oxidative stress, inflammatory markers, and immunoblotting of ERK1/2, and Nrf2 were quantified in testicular tissue together with histopathological evaluation and a caspase-3 immunohistochemical study. MEM co-administration increased adiponectin, serum testosterone, GSH, SOD, CAT, and Nrf2 expression while decreasing HOMA-IR, resistin, MDA, NOx, ERK1/2, IL-6, TNF-α, NFĸB, and caspase-3 expression. Furthermore, MEM ameliorated all measured parameters and histopathological changes that occurred in the RIS group in a dose-dependent manner. The primary outcomes were attained by attenuating oxidative stress, inflammation, and apoptosis in the testis caused by chronic RIS administration via regulation of the ERK1/2-Nrf2 signaling pathway. Targeting the ERK1/2-Nrf2 pathway is a potential strategy for addressing testicular injury.

Keywords: Anti-dementia; Antipsychotics; Memantine; Reproductive toxicity; Risperidone.

Fig. 1

Effect of MEM on fasting glucose (A), fasting insulin (B) and HOMA-IR (C). Results represent the mean ± SEM (n = 6). Significance is at p < 0.05. ^asignificant difference relative to control group; ^bsignificance difference with respect to RIS group; ^csignificance difference against RIS + MEM-5 group.

Fig. 2

Effect of MEM on serum resistin (A) and adiponectin (B). Results represent the mean ± SEM (n = 6). Significance is at p < 0.05. ^asignificant difference relative to control group; ^bsignificance difference with respect to RIS group; ^csignificance difference against RIS + MEM-5 group.

Fig. 3

Effect of MEM on both free testosterone (A) and total testosterone (B) serum levels. Results represent the mean ± SEM (n = 6). Significance is at p < 0.05. ^asignificant difference relative to control group; ^bsignificance difference with respect to RIS group; ^csignificance difference against RIS + MEM-5 group.

Fig. 4

Representative western blot bands (A), and protein expression levels of testicular ERK1/2 (B), and Nrf2 (C). Results represent the mean ± SEM (n = 3). Significance is at p < 0.05. ^asignificant difference relative to control group; ^bsignificance difference with respect to RIS group; ^csignificance difference against RIS + MEM-5 group.

Fig. 5

Effect on histopathological picture of testicular tissue (x200) and scoring of testicular damage. (A, B, C); control, MEM-5, and MEM-10 groups respectively, showed normal seminiferous tubules, and normal germinal epithelium with normal interstitial cells of Leydig. (D): RIS group, red arrows refer to necrosis of both superficial and deep layers of the germinal epithelium lining closely packed seminiferous tubules. These tubular lumens were filled with amorphous material containing cellular debris. (E): RIS + MEM-5 group; yellow arrows refer to necrosis of superficial and deep layers of the germinal epithelium lining closely packed seminiferous tubules with the destruction of its basement membrane. These tubular lumens were filled with amorphous material containing cellular debris. (F): RIS + MEM-10 group; blue arrows refer to injury limited to superficial germinal layer in few seminiferous tubules, however, most seminiferous tubules are normal with normal germinal epithelium and Interstitial cells of Leydig are also normal. Results represent the mean ± SEM (n = 6). Significance is at p < 0.05. ^asignificant difference relative to the control group; ^bsignificance difference with respect to RIS group; ^csignificance difference against RIS + MEM-5 group.

Fig. 6

Effect of MEM on caspase-3 immunoexpression in testicular tissue (x200), and its semi-quantitative scoring. (A, B, C); control, MEM-5 and, MEM-10 groups respectively, show negative expression of caspase-3. (D, E): RIS and RIS + MEM-5 groups, respectively, show strong expression of caspase 3. (F): RIS + MEM-10 group; show weak expression of caspase-3. Results represent the mean ± SEM (n = 6). Significance is at p < 0.05. asignificant difference relative to control group; bsignificance difference with respect to RIS group; csignificance difference against RIS + MEM-5 group.

Fig. 7

Graph outlining the mechanism of RIS-evoked testicular dysfunction and the potential protective impact of MEM. One of the authors, Ehab E. Sharata, used Microsoft PowerPoint to create this graph.