Ambroxol (ABX) is used to manage excessive production of mucus in the respiratory system. The present study sought to assess the neuroprotective potential of ambroxol by influencing the amyloidogenic, nuclear factor kappa‐light‐chain‐enhancer of activated B cells (NF‐κB), and nuclear factor erythroid 2‐related factor 2 (Nrf2) pathways in a rat model of Alzheimer's disease (AD) induced by scopolamine. The AD pathology was induced by chronic administration of scopolamine. The rats were given scopolamine at a dose of 2 mg/kg via intraperitoneal injection daily for 14 days, followed by treatment (ABX 121.5, 135, and 180 mg/kg orally and 5 mg/kg orally of donepezil) for the next 28 days while continuing to receive daily scopolamine injection. The behavior of the rats was evaluated using Modified Y‐Maze and Novel object recognition tasks. Analyses were carried out on AD pathological markers [Amyloid beta peptide 1‐40, Amyloid beta peptide 1‐42, acetylcholinesterase, beta‐secretase 1 (BACE1), total tau, and p‐tau], inflammatory markers [NF‐κB, tumor necrosis factor alpha (TNF‐α), interleukin 6 (IL‐6), and interferon γ], antioxidant markers (Nrf2 and heme Oxygenase 1 (HO‐1)], along with synaptophysin and glial fibrillary acidic protein (GFAP) immunohistochemistry and histopathological assessment of the hippocampus. Our findings indicated that ABX reduced impairment in behavior. Levels of Acetylcholinesterase, BACE1, amyloid beta 1‐40, amyloid beta 1‐42, total tau, p‐tau, NF‐κB, IFN‐γ, IL‐6, and TNF‐α decreased significantly. There was a significant increase in the levels of HO‐1 and Nrf2. It stopped the neuronal degeneration, raised synaptophysin immunoreactivity, and lowered GFAP immunoreactivity. The current research indicates that ambroxol may possess senomorphic properties by impacting the transcription factors NF‐κB and senescence‐associated secretory phenotype (SASP). Consequently, it could provide neuroprotection through alterations in the Nrf2 and NF‐κB signaling pathways in AD.
