Metoprolol exacerbates dementia in scopolamine-induced cognitive impairment in rats: A potential role of NADPH oxidase

β-blockers have been implicated in cognitive impairment, with some studies suggesting their role in increasing the risk of vascular dementia (VD). While previous clinical and preclinical research has linked β-blockers, including metoprolol, to cognitive decline, the molecular mechanisms remain unclear. This study aims to elucidate the impact of metoprolol on scopolamine-induced cognitive impairment in rats, focusing on the role of NADPH oxidase-mediated oxidative stress. Adult male Wistar rats were administered metoprolol (30 mg/kg/day; p.o) alone or in combination with scopolamine (1 mg/kg/day; i.p). To assess the involvement of NADPH oxidase, a subset of rats also received apocynin (10 mg/kg/day; i.p), a specific NADPH oxidase inhibitor. Behavioral tests were performed to evaluate cognitive function, while biochemical analyses were conducted to measure oxidative stress markers, neuroinflammatory mediators, and mitochondrial biogenesis-related proteins. Metoprolol exacerbated scopolamine-induced cognitive decline, which was unvieled through the impaired learning and memory performance. This effect was accompanied by increased hippocampal NADPH oxidase activity, oxidative stress biomarkers, and p38 MAPK/NF-κB-mediated neuroinflammation. Subsequently, metoprolol disrupted mitochondrial biogenesis machinery through the negative regulation of the SIRT1/PGC-1α/NRF1/TFAM signaling axis, which was followed by apoptotic cell death. Co-administration of apocynin reversed most of these alterations, where attenuation of oxidative stress, neuroinflammation, and mitochondrial dysfunction were identified. In conclusion, metoprolol significantly worsens cognitive impairment, likely through oxidative stress amplification, neuroinflammation, and mitochondrial biogenesis impairment. These findings suggest that caution is needed when prescribing metoprolol to elderly patients, especially those at risk of cognitive decline. Targeting NADPH oxidase may offer a potential therapeutic approach to counteract metoprolol's adverse effects on cognitive function.