1,3,4 oxadiazole derivative attenuates neurotransmitter-mediated inflammatory response in EAE model of multiple sclerosis

Abstract

Multiple sclerosis (MS) has a complex pathophysiology, comprising inflammation, demyelination, and alterations in neurotransmitter levels. Dysregulation of neurotransmitters, an imbalance between GABAergic and glutamatergic activity, enhanced oxidative stress, and an inflammatory response have all been involved in the disease. These mechanisms play a crucial role in regulating neuronal plasticity and activity. This study explored the role of neurotransmitters and inflammatory mediators in experimental autoimmune encephalomyelitis (EAE)-induced MS, as well as the effect of a 1,3,4-oxadiazole derivative, i.e., 2-{[5-(3-iodophenyl)-1,3,4-oxadiazol-2-yl] sulfanyl} ethan-1-ol (abbreviated as OX-3), on reducing neurotransmitter-mediated inflammatory responses. Its activity was assessed using clinical scoring, behavioral testing, histopathological changes, molecular testing through RT-PCR, ELISA, and assessment of neurotransmitters through HPLC. Molecular docking and simulation studies were performed to analyze protein interactions. The study findings revealed that OX-3 significantly reduced the severity of the disease by improving clinical symptoms of MS. It also ameliorated the cognitive decline in MS through a significant impact on neurotransmitters. It improved the GABA/Glutamate balance and reduced the pro-inflammatory cytokine levels. The comet assay revealed a reduction in DNA damage, and antioxidant levels improved, decreasing oxidative stress. The study concludes that OX-3 exerts its neuroprotective effect by attenuating the neurotransmitter-mediated neurodegeneration.