Pharmacological significance of prostaglandin E₂ and D₂ transport at the brain barriers

Prostaglandin (PG) E₂ and PGD₂, which are biosynthesized from arachidonic acid generated by enzymatic cleavage of membrane phospholipid in response to various stimuli, play key roles in multiple brain pathophysiological processes, including modulation of synaptic plasticity, neuroinflammation, and sleep promotion. Concentrations of PGE₂ and PGD₂ in brain interstitial fluid (ISF) and cerebrospinal fluid (CSF) are maintained at appropriate levels for normal brain function by regulatory systems. The blood-brain barrier (BBB) and the blood-CSF barrier (BCSFB) possess ISF/CSF-to-blood efflux transport systems that are the primary cerebral clearance pathways for PGE₂ and PGD₂. However, regulatory dysfunction at the brain barriers may seriously affect brain function. In a mouse inflammation model, significant reduction of PGE₂ efflux transport at the BBB has been observed. Several kinds of cephalosporin antibiotics and nonsteroidal anti-inflammatory drugs inhibit the BBB- and BCSFB-mediated efflux transport of PGE₂ and PGD₂. Especially, drugs that inhibit multidrug resistance-associated protein 4 (MRP4)-mediated PGE₂ transport are capable of reducing PGE₂ efflux at the BBB. Thus, it might be important in the treatment of inflammatory and infectious diseases to use drugs that do not inhibit clearance of PGE₂ at the brain barriers, in order to avoid unexpected adverse CNS effects. Further, considering that PGD₂ in CSF is a natural sleep-promoting factor, changes in the activity of the PGD₂ efflux transport system at the BCSFB may modify the PGD₂ level in CSF, thus affecting physiological sleep. These findings indicate that the efflux transport systems at the brain barriers play key roles in the pathophysiology and pharmacology of PGE₂ and PGD₂.