The impact of muscarinic or mGlu activators on some NO-dependent biochemical pathways in MK-801 animal model

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Abstract Cognitive impairment and dementia significantly affect life quality, with conditions like Alzheimer’s, dementia, and Parkinsonian dementia posing treatment difficulties. Nitric oxide (NO﮲) is crucial for brain function, yet its imbalance contributes to neurodegeneration. Typically, NO﮲ supports synaptic activity, but under pathological conditions, oxidative stress triggers harmful peroxynitrite formation. Excessive NO﮲ disrupts protein function, aggravating CNS disorders. Recent studies investigate mGlu and muscarinic receptor modulators as potential treatments targeting NO﮲ pathways. However, clinical breakthroughs remain unattained despite ongoing research, highlighting the need for further exploration. The study examined NO֗-related biochemical pathways in reversing schizophrenia-related deficits using mGlu and muscarinic ligands. We analyzed cGMP levels, oxidative stress, and s-nitrosylation in mouse brain samples. Additionally, some aspects of MK-801 and mGlu as well as muscarinic ligands administration on oxidative burst ware analyzed in in vitro study on C8D1a and 1231N1 cells lines. MK-801, a schizophrenia model compound, disrupted NO֗ signaling, impairing neurovascular stability. The tested ligands mitigated oxidative stress and prevented harmful NO֗ derivatives. Increased SOD activity suggested prior oxidative stress, with the compounds acting as antioxidants. MK-801 altered glutamate uptake, aligning with schizophrenia’s glutamatergic theory. Findings indicate that mGlu and muscarinic receptor activators may counteract schizophrenia-related dysfunctions through NO-dependent pathways, offering potential therapeutic benefits in neurovascular regulation.

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