Evaluation of the Cognitive-Behavioral, Anti-Inflammatory, Antioxidant, and Neuroprotective Effects of Hydroxytyrosol on the Hippocampus in a PTZ-Induced Kindling Model

Background and objectives: Cognitive-behavioral impairments and neurological dysfunctions are commonly investigated in animal models of epilepsy. Hydroxytyrosol is a natural antioxidant in food sources with anti-inflammatory and neuroprotective properties. This study evaluated the antioxidant and anti-inflammatory effects of hydroxytyrosol on hippocampal damage in a pentylenetetrazole (PTZ)-induced seizure model in rats. Methods: Forty male Wistar rats were randomly allocated into five groups: a control group, a PTZ-induced seizure and saline-treated group (PTZ+Saline), and three PTZ-induced groups treated with intraperitoneal (i.p.) doses of HT (1 mg/kg [PTZ+HT1], 2 mg/kg [PTZ+HT2], and 4 mg/kg [PTZ+HT4]) for 5 days. Cognitive-behavioral assessments were performed using the elevated plus maze and Y-maze tests. Hippocampal catalase (CAT) activity, total antioxidant capacity (TAC), interleukin-1 beta (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α) (via ELISA), malondialdehyde (MDA) (via the thiobarbituric acid method), and apoptotic neuron density (via stereological analysis) were measured. Statistical analyses were performed using one-way ANOVA followed by Tukey's post hoc tests to assess intergroup differences. Results: Hydroxytyrosol-treated groups exhibited significantly reduced anxiety-like behaviors, hippocampal levels of pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6), and MDA compared to the PTZ+Saline group. Treatment with hydroxytyrosol significantly enhanced working memory, hippocampal CAT activity, and TAC content (p<0.05). Stereological analysis revealed significantly lower densities of dark neurons in the CA1 and CA3 hippocampal regions in hydroxytyrosol -treated rats compared to the PTZ+Saline group (p<0.05). Conclusion: Hydroxytyrosol exerts neuroprotective effects in PTZ-induced seizures through its potent anti-inflammatory and antioxidant properties, leading to improved working memory and reduced anxiety-like behaviors.