Involvement of Nrf2/HO-1 antioxidant signaling and NF-κB inflammatory response in the potential protective effects of vincamine against methotrexate-induced nephrotoxicity in rats: cross talk between nephrotoxicity and neurotoxicity.

Methotrexate (MTX) is a cytotoxic chemotherapeutic agent widely used in the treatment of cancer and autoimmune diseases like rheumatoid arthritis. However, its use has been limited by its nephrotoxicity. MTX-induced renal injury results in uremia which may influence both the peripheral and central nervous systems causing cognitive and memory problems. The nephroprotective and neuroprotective activities of vincamine (10, 20 and 40 mg/kg), a natural alkaloid with known anti-oxidant, anti-apoptotic and neuroprotective properties, were investigated against MTX-induced toxicity. MTX treatment increased the markers of kidney injury and relative kidney weight, lipid peroxidation, nuclear factor-κB (NF-κB), inflammatory markers, tumor necrosis factor-α, interleukin-1β, myeloperoxidase and cyclooxygenase-2 and caspase-3 expressions, decreased catalase and superoxide dismutase activities, interleukin-10 and ATP levels and antioxidant proteins, nuclear factor erythroid 2-related factor 2 (Nrf2) and hemeoxygenase-1 (HO-1). Moreover, it disturbed rats' behavior in the locomotor activity test, Y-maze and passive avoidance task. Treatment with vincamine (40 mg/kg) effectively ameliorated MTX-induced renal injury via increasing the expression of Nrf2 and HO-1 suppressing oxidative stress, decreasing the expression of inflammatory markers, NF-κB and caspase-3 pathways and enhancing ATP levels. Additionally, it restored locomotor activity in the locomotor test and memory functions in passive avoidance and Y-maze tests.