EFFECTS OF PROSTAGLANDIN E2 ON CELLS CULTURED FROM THE RAT ORGANUM VASCULOSUM LAMINAE TERMINALIS AND MEDIAN PREOPTIC NUCLEUS

The time course of the induction of enzymes responsible for the formation of prostaglandin E-2 (PGE2) after an inflammatory insult, in relation to the concomitant febrile response, suggests that peripherally generated PGE(2) is involved in the induction of the early phase of fever, while centrally produced PGE(2) exerts pyrogenic capacities during the later stages of fever within the hypothalamic median preoptic nucleus (MnPO). The actions of peripherally derived PGE(2) on the brain might occur at the level of the organum vasculosum laminae terminalis (OVLT), which lacks a tight blood-brain barrier and is implicated in fever, while the effects of PGE(2) within the MnPO might interfere with glutamatergic neurotransmission within a recently characterized central efferent pathway for the activation of cold-defence reactions. Using the fura-2 ratio imaging technique we, therefore, measured changes of the intracellular Ca2+-concentration in primary neuroglial microcultures of rat OVLT and MnPO stimulated with PGE(2) and/or glutamate. In cultures from the OVLT, as opposed to those derived from the MnPO, substantial numbers of neurons (8% of 385), astrocytes (19% of 645) and microglial cells (28% of 43) directly responded to PGE(2) with a transient increase of intracellular Ca2+. The most pronounced effect of PGE2 on cells from MnPO microcultures was its modulatory influence on the strength of glutamate-induced Ca2+-signals. In 72 out of 512 neurons and in 105 out of 715 astrocytes PGE(2) significantly augmented glutamate-induced Ca2+-signals. About 30% of these neurons were GABAergic. These observations are in agreement with putative roles of peripheral PGE(2) as a directly acting circulating agent at the level of the OVLT, and of central MnPO-intrinsic PGE(2) as an enhancer of glutamatergic neurotransmission, which causes disinhibition of thermogenic heat production, a crucial component for the manifestation of fever. In microcultures from both brain sites investigated incubation with PGE(2) significantly reduced the lipopolysaccharide-induced release of cytokines (tumor necrosis factor-alpha and interleukin-6) into the supernatant. PGE(2), thus, seems to be involved in a negative feed-back loop to limit the strength of the brain inflammatory process and to play a dual role with pro-as well as anti-inflammatory properties. (C) 2015 IBRO. Published by Elsevier Ltd. All rights reserved.