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.