Ambroxol rescues cognitive impairment by ameliorating oxidative stress and autophagic dysfunction in the streptozotocin-induced Alzheimer's disease model.

Alzheimer's disease (AD) is the most prevalent neurodegenerative disease, contributing to the majority of dementia cases worldwide. Due to its multifaceted and complex pathogenesis, drugs that completely halt the disease progression are still elusive. Several reports suggest that repurposing a clinically approved drug could be an excellent strategy to tackle this devastating disease. Ambroxol, a US-FDA and EMA-approved generic mucolytic drug, possess ameliorative action on various neurological ailments. However, its role as a disease-modifying drug targeting AD is yet to be studied. In this study, we elucidate the therapeutic potential of ambroxol in the streptozotocin (STZ)-induced AD model by assessing the behavioural, biochemical, and histological parameters. Intracerebroventricular (ICV) administration of STZ (3 mg/kg) was performed to mimic the AD pathology in rats. Ambroxol was administered (p.o.) at doses of 500 and 1000 mg/kg for three weeks. On day 21, behavioural tests, including the Y-maze test, novel object recognition test, and passive avoidance test, were performed to assess memory function. Subsequently, the animals were euthanised and the hippocampus was collected for biochemical, molecular and histological analysis. Three weeks of ambroxol treatment improved the cognitive performance in ICV-STZ-treated rats. Ambroxol treatment reduces oxidative stress by upregulating heme oxygenase-1 (HO-1) and lowering inducible nitric oxide synthase (iNOS) levels in the hippocampus of diseased rats. It also attenuates inflammatory and autophagic dysfunction, facilitating the clearance of amyloid beta (Aβ) aggregates in the hippocampus of ICV-STZ rats. The findings of this study suggest that ambroxol could be a viable repurposed drug candidate for AD treatment.