Sesamol Attenuates Meta-Chlorophenyl Piperazine Induced Obsessive Compulsive Disorder in Mice: Integration of Behavioural, Neurochemical, and Histopathological Metrics

Abstract

Background: As we know, the Obsessive Compulsive Disorder (OCD) is a debilitating neuropsychiatric condition characterized by persistent obsessions and repetitive compulsions. Current frontline pharmacotherapies, such as Selective Serotonin Reuptake Inhibitors (SSRIs), exhibit suboptimal efficacy, leaving approximately 40 to 60 percent of patients treatment-resistant. The serotonergic agonist meta-chlorophenylpiperazine (m-CPP) is widely utilized to model compulsive-like states in rodents, which are heavily aggravated by secondary neurochemical disruption and central oxido-nitrosative stress. Sesamol, a natural phenolic lignan isolated from sesame oil (Sesamumindicum L.), exhibits potent blood-brain barrier permeability alongside established antioxidant and neuroprotective activities. Objective: The present study investigates the therapeutic potential and neuroprotective architecture of sesamol against a stable, progressive obsessive-compulsive-like phenotype chronically induced by m-CPP in Swiss albino mice. Methods: For the study, thirty-six male Swiss albino mice were randomly assigned to six experimental cohorts (n = 6 per group) over a consecutive 21-day timeline. The disease state was induced via daily administration of m CPP (0.1 mg/kg, i.p.). Treatment groups received daily oral doses of sesamol (2, 4, and 8 mg/kg, p.o.), while fluoxetine (15 mg/kg, i.p.) served as the standard reference drug. On day 21, compulsive phenotypes and psychomotor scores were indexed via the marble burying test and an actophotometer. On day 22, whole-brain homogenates were isolated to quantify alterations in central neurotransmitters (serotonin, gamma-aminobutyric acid [GABA]), membrane lipid peroxidation (malondialdehyde [MDA]), and endogenous antioxidant defenses (reduced glutathione [GSH], catalase). Results: Chronic challenge with meta-chlorophenyl piperazine precipitated robust obsessive-compulsive-like phenotypes, as demonstrated by a significant surge in buried marbles and a severe depletion in exploratory motor activity compared to the healthy control group. This behavioral disruption was directly mirrored by a deep exhaustion of central serotonin, gamma-aminobutyric acid, reduced glutathione, and catalase pools alongside a massive accumulation of toxic lipid peroxidation signatures. Qualitative histopathological analysis verified these findings, revealing that m-CPP induced notable vacuolar degeneration and nuclear pyknosis within a substantial subset of resident striatal neurons. Daily oral pre-treatment with sesamol brought about a highly significant, dose dependent reversal of these deficits. Notably, the highest dose of sesamol showcased optimal anti-compulsive efficacy by reducing buried marbles below the standard drug baseline, completely renormalizing psychomotor activity indices, restoring neurochemical availability, suppressing membrane lipid peroxidation close to baseline physiological dimensions, and exceptionally preserving striatal neuronal morphology against neurodegenerative injury. Conclusion: These collective findings demonstrate that sesamol attenuates chronically induced obsessive compulsive-like phenotypes in mice. This therapeutic performance is mediated by its combined capacity to restabilize monoaminergic and inhibitory neurotransmitter pathways while simultaneously preserving striatal cellular integrity against central oxido-nitrosative damage, highlighting it as a promising bioactive candidate for advanced psychiatric drug discovery.