Melatonin and zinc supplements with physical and mental activities subside neurodegeneration and hepatorenal injury induced by aluminum chloride in rats: Inclusion of GSK-3β-Wnt/β-catenin signaling pathway

Alzheimer's disease (AD) is an irreversible, progressive cognitive dysfunction. Inflammaging is the greatest common factor between AD and hepatorenal malfunction. This study aimed to use melatonin (MEL) and zinc sulfate (Zn) in addition to physical and mental activities (PMA) to ameliorate AlCl3-induced AD as well as investigate their impact on the associated hepatorenal impairment. Methods: Seven groups of rats each received: saline (control group), AlCl3 (70 mg/kg, i.p.), PMA, either alone or with a combination of Mel (10 mg/kg, p.o) and/or Zn (16 mg/kg, p.o). Neurological deterioration was assessed after 5 weeks using behavioral tests, histopathological examination, and measurements of acetylcholinesterase (ACHE), brain monoamines, oxidative stress, and inflammatory markers, Amyloid precursor protein (APP), amyloid-beta (A beta), tau levels, and brain derived neurotrophic factor (BDNF). Moreover, the GSK-3 beta-Wnt/beta-catenin signaling pathway was assessed. Additionally, oxidative stress and inflammatory markers were determined in liver and kidney tissues with concurrent evaluation of hepatic and renal functions. Results: The histopathological examination revealed a cerebral cortex and hippocampus deterioration in the AD group with a decline in spatial learning and memory, besides a significant increase in AD markers in the brain and disturbance in GSK-3 beta-Wnt/beta-catenin signaling. The AD group showed hepatorenal injuries supported by elevated oxidative stress and inflammatory markers. However, adding Mel and Zn to PMA significantly attenuated the neurodegeneration and enhanced hepatic and renal functions by ameliorating oxidant and inflammatory markers. Conclusions: Combining Mel and Zn supplements with PMA defends against AlCl3-induced AD by modulating GSK-3 beta-Wnt/beta-catenin signaling and palliates the associated hepatorenal dysfunction.