Cuprizone is a neurotoxin with copper-chelating ability, and it produces symptoms that are similar to those caused by multiple sclerosis lesions. Multiple sclerosis induced by cuprizone in animal models depicts oxidative stress as one of the prime factors in pathogenesis. Neurodegeneration has become an extremely serious issue on a global scale. It is preferable to use natural therapy to stop the disease’s progression and future occurrences. Cucurbita pepo is a plant with neuroprotective properties and antioxidant properties. The purpose of this study was to determine the ameliorative capability of C. pepo in cuprizone-induced behavioral parameters and histopathological alterations in Wistar rats. The study included four groups of rats: a control group (normal saline), a cuprizone-induced group, and two treatment groups receiving C. pepo at low (200 mg/kg) and high (400 mg/kg) doses for 5 weeks. We exposed the rats to a rotarod test, a forced swimming test, and an elevated plus maze test to assess their behavioral parameters, including motor coordination and anxiety level. Following the study, animals were sacrificed, and brain tissues were extracted to resolve biochemical analysis for oxidative stress along with histopathological changes to determine and compare the oxidative stress between the inducer and treated group and also to analyze the remyelination ability of C. pepo in the disease-induced rat. Results revealed that the rats treated with C. pepo demonstrated significant improvements in motor coordination (P < 0.001) and reduced anxiety-like behavior (P < 0.01) and oxidative stress markers, such as superoxide dismutase and catalase activity. Histopathological analysis showed reduced demyelination and enhanced neuronal integrity in treated groups. These findings indicate that C. pepo attenuates cuprizone-induced oxidative stress and demyelination, supporting its neuroprotective potential in multiple sclerosis models.
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