Divergent effects of prostaglandin receptor signaling on neuronal survival

Abstract

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 protects 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 2α 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.

Function of COX-2 and Prostaglandins in Neurological Disease

“…At day in vitro 7, spinal cord slices were treated with the glutamate transport inhibitor D,L-threo-hydroxyaspartate (THA; Aldrich, Milwaukee, IL; 200 μM), a treatment which injures motor neurons with a morphology typical of excitotoxic degeneration after several weeks of treatment. The COX-2 selective inhibitor SC58236 protected motor neurons in this model, and the EP2 and EP3 agonists paradoxically also prevented motor neuron loss (Bilak et al 2004) and the DP1 receptor (Wu et al 2007). The function of the EP2, EP3, and DP1 receptors was tested pharmacologically in this paradigm (1 nM to 10 μM).…”

Misoprostol, an anti-ulcer agent and PGE2 receptor agonist, protects against cerebral ischemia

“…Deletion of the EP3 receptor had no effect on infarct volume in the present study. Previous pharmacological examinations of EP3 function have shown a neuroprotective effect of this receptor in acute NMDA toxicity in organotypic hippocampal slices [26] and in spinal cord slices subjected to chronic glutamate toxicity from blockade of astrocytic glutamate transporters; this latter EP3-mediated neuroprotection was associated with an increase in levels of the pro-survival phospho-AKT [6]. The difference observed in vivo may be due to a low abundance of EP3 receptor in brain regions supplied by the middle cerebral artery, in particular the striatum and cerebral cortex as compared to the hippocampus [11], where there are modest levels of EP3 expression in CA1-4 regions and dentate gyrus.…”

“…Misoprostol binds to the EP2-4 receptors. From previous studies demonstrating protective effects of EP2, EP3, and EP4 receptor activation in models of excitotoxicity or ischemia [1,19,20,26], we hypothesized that misoprostol, which can bind all three EP receptors, might also mediate pharmacological protection. Administration of 1 mg/kg of misoprostol at the onset of 90 min of MCAO, followed by subsequent injections at 6 and 12 h of reperfusion resulted in a significant rescue of tissue at 24 h ( Fig.…”

“…Although at least two prostaglandin signaling pathways, the PGE 2 EP1 [2,17] and the PGD 2 DP2 receptors [18] have been found to be neurotoxic, an important finding has been that a larger group of prostaglandin receptors can mediate a paradoxical and significant protective effect [6,[18][19][20]26]. EP2 and DP1-mediated neuroprotection are dependent on PKA activation [18,20], and EP3 neuroprotection is associated with increases in the pro-survival phospho-AKT [6].…”

Role of phospholipase A2s and lipid mediators in secondary damage after spinal cord injury

“…The protective effects are lost in EP2 −/− mice in transient and permanent cerebral ischemia models resulting in increases in infarct size (McCullough et al 2004;Liu et al 2005). In contrast, in models of LPS-mediated neuroinflammation, activation of the EP2 receptor results in neurotoxicity (Wu et al 2007a). These neurotoxic effects of EP2 receptor activation are seen in vitro in activated microglia and in animal models of neurodegenerative disease in which neuroinflammation is a contributing factor such as in Parkinson's disease, Alzheimer's disease, and ALS (Liang et al 2005;Jin et al 2007;Andreasson 2010).…”