Neuroprotective and Antioxidant Role of Oxotremorine-M, a Non-selective Muscarinic Acetylcholine Receptors Agonist, in a Cellular Model of Alzheimer Disease

Alzheimer disease (AD) is a multifactorial and age-dependent neurodegenerative disorder, whose pathogenesis, classically associated with the formation of senile plaques and neurofibrillary tangles, is also dependent on oxidative stress and neuroinflammation chronicization. Currently, the standard symptomatic therapy, based on acetylcholinesterase inhibitors, showed a limited therapeutic potential, whereas disease-modifying treatment strategies are still under extensive research. Previous studies have demonstrated that Oxotremorine-M (Oxo), a non-selective muscarinic acetylcholine receptors agonist, exerts neurotrophic functions in primary neurons, and modulates oxidative stress and neuroinflammation phenomena in rat brain. In the light of these findings, in this study, we aimed to investigate the neuroprotective effects of Oxo treatment in an in vitro model of AD, represented by differentiated SH-SY5Y neuroblastoma cells exposed to A beta(1-)(42) peptide. The results demonstrated that Oxo treatment enhances cell survival, increases neurite length, and counteracts DNA fragmentation induced by A beta(1-42) peptide. The same treatment was also able to block oxidative stress and mitochondria morphological/functional impairment associated with A beta(1-42) cell exposure. Overall, these results suggest that Oxo, by modulating cholinergic neurotransmission, survival, oxidative stress response, and mitochondria functionality, may represent a novel multi-target drug able to achieve a therapeutic synergy in AD. [GRAPHICS] .

Automated summary

Alzheimer's disease is a multifactorial and age-related neurodegenerative disorder. Its pathogenesis is associated with senile plaques, neurofibrillary tangles, oxidative stress, and neuroinflammation. Current therapies have limited effectiveness, and research on disease-modifying treatments is ongoing. Previous studies have shown that Oxo, a muscarinic acetylcholine receptor agonist, has neurotrophic effects and can modulate oxidative stress and neuroinflammation in the brain. This study investigated the neuroprotective effects of Oxo in an in vitro model of AD, and found that it enhanced cell survival, neurite length, and counteracted DNA fragmentation caused by A beta(1-42) peptide. Oxo treatment also blocked oxidative stress and mitochondrial impairment associated with A beta(1-42) exposure. These results suggest that Oxo could potentially be a novel multi-target drug for treating AD.