This study aimed to assess the preventive potential of apremilast (APRE) against methotrexate (MTX)-induced renal damage in rats through modulation of nuclear factor erythroid 2-related factor 2/heme oxygenase-1 (Nrf2/HO-1) signaling and toll-like receptor 4/nuclear factor-kappa B/p38 mitogen-activated protein kinase/caspase-3 (TLR4/NF-κB/p38 MAPK/Caspase-3) signaling pathways. Four groups of male Wistar albino rats were assigned: control, APRE, MTX, MTX + APRE. Histopathological investigation and biochemical analysis of the serum renal damage indicators (urea and creatinine) were used to evaluate the renal toxicity of MTX. Testing for renal malondialdehyde (MDA) and reduced glutathione (GSH) was conducted. The levels of renal tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), Nrf2, HO-1, and cleaved caspase-3 were measured using the ELISA method. Using an immunohistochemistry method, the expression of NF-κB p65 in the kidney was investigated. Western blotting was used to examine the expression of TLR4 and p38 MAPK proteins. MTX administration resulted in significant renal injury, as evidenced by elevated serum urea and creatinine levels. The kidneys were significantly affected as evidenced by histopathological alterations and increased levels of renal MDA, TNF-α, IL-6, Bcl-2-associated x (Bax), and cleaved caspase-3, alongside decreased levels of GSH and B-cell lymphoma 2 (Bcl-2) expression. These outcomes were linked to inhibition of Nrf2/HO-1 signaling and activation of the TLR4/NF-κB/p38 MAPK/Caspase-3 pathway. Co-treatment with APRE at 20 mg/kg/day for 21 days markedly improved all biochemical and pathological alterations evoked by MTX, demonstrating significant nephroprotective effects. Apremilast inhibits methotrexate’s harmful effects on the kidneys by activating signaling cascades that include Nrf2/HO-1, while simultaneously downregulating TLR4/NF-κB/p38 MAPK/Caspase-3.

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.