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Pharmacological investigation of oxadiazole derivatives in Alzheimer's disease: Modulation of oxidative stress, neuroinflammation, and iNOS signaling
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DOI：10.22038/ijbms.2026.89093.19230.png)
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Abstract
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Objective(s): Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by deposition of amyloid-beta (A beta) aggregates. A beta peptides alter synaptic function and produce neuroinflammation. The neurotoxic mechanisms are also related to increases in the expression of iNOS (inducible nitric oxide synthase), resulting in further neuronal degeneration and memory impairment. Materials and Methods: In the current study, we assessed the in vivo effect of the 1,3,4-oxadiazole acetamide (MA) on spatial memory and inflammatory responses induced by AlCl3 administration in animals. Results: A notable improvement in memory function was observed in the AlCl3 -induced group at 29th post-injection, following MA treatment (5, 10, and 20 mg/kg), as indicated by the behavioral analysis. This effect is correlated with decreases in inflammatory markers such as NFKB, IL-6/beta 1, IFN-gamma, TNF-alpha, and NO levels, as well as a reduction in expression of neurodegenerative markers: beta-amyloid and p-tau (*P<0.05, **P<0.01, ***P<0.001 vs disease control). The results from our study suggested that MA significantly enhances the levels of glutathione, catalase, and glutathione S-transferase while decreasing the lipid peroxidation (LPO) in comparison to the disease control group, and also improves mitochondrial dysfunction. The effects are further enhanced when MA was used in combination with aminoguanidine (AG), an iNOS inhibitor. Molecular dynamics (MD) simulations, along with protein mRNA expression and iNOS western blotting, further supported the results of in vivo experiments. Conclusion: Our study proposed that MA attenuated the cytokine release, decreased oxidative stress, and iNOS expression, leading to a decrease in neurodegeneration.
Keywords:
Alzheimer's disease
Cognitive impairment
Cytokines
Cytokines iNOS
Neuroprotection
Oxadiazole
Oxidative stress
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