Prostaglandins (PGs) produced in cerebral endothelial cells (CECs) are key signal mediators from the periphery to the brain during fever response. However, PGs are organic anions and they do not cross cell membranes by simple diffusion. We examined the expression of two principle PG carriers, PG transporter (PGT) and multidrug resistance associated protein 4 (MRP4) in cells of the blood-brain barrier and in choroid epithelial cells in vitro as well as in vivo in rat brain. We detected PGT in primary cultures of rat CECs, astrocytes, pericytes and choroid epithelial cells. LPS stimulation had no effect on the expression level of PGT in these cells; however, after LPS stimulation the polarized, dominantly luminal expression pattern of PGT significantly changed. MRP4 was expressed in CECs and its level was not influenced by LPS. In rat brain PGT was highly expressed in the supraoptic and paraventricular nuclei of the hypothalamus, in the ependymal cell layer of the 3rd ventricle and in the choroid plexus. LPS treatment increased the expression of PGT in the supraoptic and paraventricular nuclei. Our results suggest that PGT and MRP4 likely play a role in transporting PGs through the blood-brain and blood-cerebrospinal fluid barriers and may be involved in the maintenance of PG homeostasis in the brain and in the initiation of fever response.
BMS-191095, reportedly a selective mitoK(ATP) channel opener which is free from the known side effects of the prototype mitoK(ATP) channel opener diazoxide, induced acute and delayed preconditioning against glutamate excitotoxicity and delayed preconditioning against oxygen-glucose deprivation in primary cultures of rat cortical neurons. BMS-191095 dose dependently depolarized the mitochondria, increased the phosphorylation of PKC isoforms, but had no detectable effects on the activation of MAP kinases and did not influence the expressions of HSP70 and Mn-SOD. In BMS-191095-preconditioned neurons the glutamate-induced free-radical production was abolished. Our data give the first evidence that selective opening of mitoK(ATP) channels with BMS-191095 leads to remarkable neuroprotection via mechanisms that involve mitochondrial depolarization, PKC activation and attenuated free radical production during neuronal stress.
