Induction of
cyclooxygenase-2 (COX-2) with production of
prostaglandins occurs in a wide spectrum of acute and chronic
neurodegenerative diseases and is associated with neuronal death. Inhibition of the COX-2 pathway and downstream production of
prostaglandins protect neurons in rodent models of
cerebral ischemia and neurodegeneration. Recent studies investigating the functions of selected
prostaglandin receptor pathways in mediating COX-2 neurotoxicity have demonstrated both toxic and paradoxically
neuroprotective effects of several receptors in models of excitotoxicity. In this study, we investigate the functions of additional
prostaglandin receptors not previously characterized in organotypic models of
glutamate excitotoxicity. We find that
PGD(2), PGI(2), and
PGF(2alpha) receptors protect motor neurons in an organotypic spinal cord model of
amyotrophic lateral sclerosis (ALS). In addition, PGI(2) and TXA(2) receptors rescue CA1 neurons in an organotypic hippocampal model of
N-methyl-d-aspartate excitotoxicity. However, in a model of
inflammation induced by
lipopolysaccharide,
prostaglandin receptors previously found to be protective in excitotoxicity now cause CA1 neuronal death. Taken together, these studies identify novel
eicosanoid receptor signaling pathways that mediate neuronal protection in excitotoxic paradigms; these data also support the emerging hypothesis that the toxic/protective effects of
eicosanoid signaling on neuronal viability diverge significantly depending on whether excitotoxicity or
inflammation predominates as the underlying toxic stimulus.