Caffeic Acid Exerts Anticonvulsant Effects on Mice by Modulating Nitrite Imbalance in the Prefrontal Cortex: An Interventional Study Using Nitric Oxide Mediators

Introduction: Nitric oxide (NO) is implicated in the etiology. Caffeic acid (CA) possesses neuroprotective properties in various animal models. This study assessed the anticonvulsant properties of CA by investigating its effects on nitrergic transmission in the prefrontal cortex (PFC) during pentylenetetrazol (PTZ)-induced seizures in mice, using NO precursors and synthesis inhibitors. Methods: Sixty-four male mice were randomly divided into eight groups, including those administered intraperitoneal normal saline, CA at different doses (۱, ۴, and ۸ mg/kg), diazepam, Nomega-nitro-L-arginine methyl ester hydrochloride (L-NAME), a NO synthase inhibitor (۱۰ mg/kg), L-arginine (L-arg), a NO precursor (۱۰۰ mg/kg), effective dose of CA (۸ mg/kg) with L-arg, and sub-effective dose of CA (۱ mg/kg) + L-NAME, correspondingly. Latency to seizure and nitrite levels in the PFC were measured, and data were analyzed with the one‐way analysis of variance followed by Tukey’s post-hoc test. Results: Two doses of CA [۴ (P < ۰.۰۰۰۱) and ۸ mg/kg (P < ۰.۰۰۰۱)] and L-NAME (P < ۰.۰۰۰۱) augmented the latency to seizure while reducing nitrite levels in the PFC [doses ۱ (P < ۰.۰۰۰۱), ۴ (P < ۰.۰۰۰۱), and ۸ mg/kg (P < ۰.۰۰۰۱)], and L-NAME (P < ۰.۰۰۰۱). The co-injection of L-NAME potentiated (P < ۰.۰۰۰۱) the effect of the sub-effective dose of CA (۱ mg/kg) on latency to seizure, whereas L-NAME and L-arg potentiated (P < ۰.۰۰۰۱) and mitigated (P = ۰.۰۰۱۸) the effects of corresponding CA doses on PFC’s nitrite level, respectively. Conclusion: Our findings demonstrated a probable role for NO in the anticonvulsant properties of CA in PTZ-induced seizures. Diminished nitrergic neurotransmission partly mediated the anticonvulsant effect of CA on male mice.