Inhibition of NMDA Receptors Downregulates Astrocytic AQP4 to Suppress Seizures

Aquaporin 4 (AQP4), a water-specific channel protein locating on the astrocyte membrane, has been found to be antagonist, agonist and undergone closely related to epilepsy. Our previous study showed that inhibition of an N-methyl-d-aspartate receptor (NMDAR) subunit NR2A can suppress epileptic seizures, suggesting that AQP4 is potentially involved in NR2A-mediated epilepsy treatment. In this study, we aimed to explore the relevance of AQP4 in NR2A-mediated seizures treatment in pentylenetetrazol (PTZ)-induced rat models. We performed electroencephalogram (EEG) recording and examined AQP4 expression at mRNA and protein levels, and the downstream molecules of AQP4 as well. It showed that AQP4 expression was increased after the induction of seizures. Lateral ventricle pretreatment of NR2A inhibitor could mitigate the PTZ-induced seizures severity and counterbalance the increase of AQP4 expression. In contrast, NR2A activator that resulted in seizures aggravation could further augment the seizure-related elevations of AQP4 expression. Pharmacological inhibition of AQP4 alone could also suppress the PTZ-induced seizure activities, with decreased expressions of NF-kappa B p65, interleukin (IL)-1, IL-6, and tumor necrosis factor (TNF)-alpha in the brain. The results indicated that increased expression of AQP4 might be an important mechanism involved in NR2A of NMDAR-mediated treatment for epileptic seizures, enlightening a potentially new target for seizures treatment.