The central nervous system (CNS) is segregated from the circulating blood and peripheral tissues by endothelial and epithelial barriers. To overcome refractory CNS diseases, it is important to understand the membrane transport systems of drugs and the endogenous compounds that relate to the pathogenesis of CNS diseases at these barriers. The endothelial barrier in the brain is the blood-brain barrier (BBB). Our studies clariˆed the eOEux transport of prostaglandin E 2 (PGE 2), a modulator of neural excitation and in‰ammatory responses, across the BBB via plasma membrane transporters such as organic anion transporter 3 (Oat3) and multidrug resistance-associated protein 4 (Mrp4). This eOEux transport was attenuated by peripheral in‰ammation or cerebral treatment with neuroexcitatory L-glutamate, suggesting that BBB-mediated PGE 2 elimination was altered under several pathological conditions. We also examined excitatory amino acid transporter (EAAT) 1 and 3 as L-glutamate eOEux transporters of the inner blood-retinal barrier (BRB) and blood-cerebrospinal barrier. It was considered that these eOEux membrane transporters participated in the homeostasis of neuroexcitatory and neuroin‰ammatory responses in the brain and retina. Moreover, we identiˆed connexin 43 (Cx43) hemichannels as a new membrane transport system that is activated under pathological conditions and recognizes several monocarboxylate drugs, such as valproate. As it is expected that the action of these membrane transporters across the CNS barriers is of great importance in understanding the pathology of various neuroexcitatory diseases, our studies should contribute to the establishment of therapeutic strategies for refractory CNS diseases.