Extracellular concentrations of glutamate increase during epileptic seizures. Glutamate signaling can occur via endothelial NMDA receptors to activate an intracellular cascade that upregulates P-glycoprotein [60
influx via the NMDA receptor is known to activate phospholipase A2, which can release arachidonic acid from the cell membrane. Therefore, Ca2+
might represent the link that drives the activation of arachidonic acid signaling. The inflammatory enzyme cyclooxygenase-2 was clearly demonstrated to be a key downstream effector that processes arachidonic acid [60
]. Prostaglandin E2, as the main end product of cyclooxygenase-2, was shown to act via the endothelial EP1 receptor [62
]. The events downstream of EP1 receptors must still be identified; these events then drive the transcriptional activation of the P-glycoprotein-encoding gene.