5-HT7 receptor antagonist SB269970 attenuates seizures by modulating NO/cGMP signaling pathway and neuroinflammation in a pentylenetetrazol-induced epilepsy model in rats

Epilepsy is a disease affecting the quality of life, characterized by neuronal excessive discharges resulting from the disruption of the balance between excitatory and inhibitory systems in the brain, and its pathophysiology has not been fully elucidated. In this study, we investigated the effects of serotonin 7 (5-HT7) receptor antagonist SB 269970 on seizures in a pentylenetetrazol (PTZ)-induced epilepsy model. Seventy male Wistar Albino rats (weight 230–250 g) were used in the study and the rats were randomly assigned to control and drug groups. Predetermined doses of SB 269970 (3 mg/kg), 5-HT7 agonist AS 19 (5 mg/kg), 7-NI (nNOS inhibitor, 50 mg/kg), YC-1 (guanylate cyclase activator, 10 μg/kg) were administered to the rats. PTZ (35 mg/kg) was injected intraperitoneally to induce seizures. The Racine scale was used to evaluate seizure stages. After electrocorticography (ECoG) and video recordings, the rats were sacrificed and nitric oxide (NO), cGMP, nNOS and proinflammatory cytokines (TNF-α, IL-1β and IL-6) levels in hippocampal tissue were measured by biochemical methods. The study results showed that the seizure threshold increased and the number of seizures decreased in rats administered SB 269970. In addition, the levels of proinflammatory cytokines (TNF-α, IL-6, IL-1β) and NO, cGMP and nNOS, which are increased with seizures in the hippocampal tissue, were significantly decreased by the administration of SB 269970. In contrast, the administration of 5-HT7 agonist AS-19 increased the number of seizures and caused an increase in the levels of hippocampal proinflammatory cytokines and NO, cGMP and nNOS. In conclusion, the findings of this study revealed that SB 269970 causes anticonvulsant activity by inhibiting the NO/cGMP pathway and proinflammatory cytokine (TNF-α, IL-1β and IL-6) levels in the hippocampal tissue. However, further molecular studies are needed for 5-HT7 antagonist drugs to be an option in the treatment of epilepsy.