Astrocytes synthesize primary and cyclopentenone prostaglandins that are negative regulators of their proliferation

Recently, the modulation of cellular inflammatory responses via endogenous regulators became a major focus of medically relevant investigations. Prostaglandins (PGs) are attractive regulatory molecules, but their synthesis and mechanisms of action in brain cells are still unclear. Astrocytes are involved in manifestation of neuropathology and their proliferation is an important part of astrogliosis, a cellular neuroinflammatory response. The aims of our study were to measure synthesis of PGs by astrocytes, and evaluate their influence on proliferation in combination with addition of inflammatory pathway inhibitors. With UPLC-MS/MS analysis we detected primary PGs (1410 +/- 36 pg/mg PGE(2), 344 +/- 24 PGD(2)) and cyclopentenone PGs (cyPGs) (87 +/- 17 15d-PGJ(2), 308 +/- 23 PGA(2)) in the extracellular medium after 24-h lipopolysaccharide (LPS) stimulation of astrocytes. PGs reduced astrocytic proliferation with the following order of potencies (measured as inhibition at 20 mu M): most potent 15d-PGJ(2) (90%) and PGA(2) (80%), > PGD(2) (40%) > 15d-PGA(2) (20%) > PGE(2) (5%), the least potent. However, PGF(2 alpha) and 2-cyclopenten-1-one, and ciglitazone and rosiglitazone (synthetic agonists of PPAR gamma) had no effect. Combinations of cyPGs with SC-560 or NS-398 (specific anti-inflammatory inhibitors of cyclooxygenase-1 and -2, respectively) were not effective; while GW9662 (PPAR gamma antagonist) or MK-741 (inhibitor of multidrug resistance protein-1, MRP1, and CysLT1 receptors) amplified the inhibitory effect of PGA(2) and 15d-PGJ(2). Although concentrations of individual PGs and cyPGs are low, all of them, as well as primary PGs suppress proliferation. Thus, the effects are potentially additive, and activated PGs synthesis suppresses proliferation in astrocytes. (C) 2018 Elsevier Inc. All rights reserved.