Epilepsy refers to a clinical syndrome generated by spontaneous seizures in the central nervous system. Epilepsy triggers a complex pathological process including inflammatory response and aquaporin 4 (AQP4) increase. It has been reported that AQP4 helps to enhance the immunological function of the central nervous system in pathological conditions, but the relationship between AQP4 and inflammatory cytokines is poorly understood in chronic epilepsy processes. As an inhibitor of sulfonamide carbonic anhydrase (CA), acetazolamide (AZA) may inhibit water infiltration through AQP4. In this context, pentylenetetrazole (PTZ) is used to induce the chronic epilepsy model in rats to study the chronic epilepsy effects of AQP4 inhibition on proinflammatory cytokine expression in the hippocampus and proinflammatory cytokine quantification analysis of the plasma. Based on the assumption that AQP4 regulates proinflammatory cytokine expression, this article aims to demonstrate this effect in chronic epilepsy of rats. Rats were divided into four groups and were treated with different drugs: saline (Control), acetazolamide (AZA), pentylenetetrazole (PTZ), and pentylenetetrazole plus acetazolamide (PTZ+AZA). The data showed that seizures increased proinflammatory cytokine expression and that AZA significantly inhibited AQP4 expression. Overall, the results suggested that AQP4 inhibition could weaken excitotoxicity in epileptogenesis by reducing proinflammatory cytokines in the hippocampus. The findings provide a new insight into the involvement of cerebral edema insult and proinflammatory cytokines in the process of chronic epilepsy.