Neuronal oxidative damage from activated innate immunity is EP₂ receptor‐dependent

Abstract

Increase in prostaglandin (PG) E 2 levels and oxidative damage are associated with diseases of brain that involve activation of innate immunity. We tested the hypothesis that cerebral oxidative damage resulting from activation of innate immunity with intracerebroventricular (icv) lipopolysaccharide (LPS) is dependent on PGE 2 -mediated signaling. We measured two quantitative in vivo biomarkers of lipid peroxidation: F 2 -isoprostanes (IsoPs) that derive from arachidonic acid (AA) that is uniformly distributed in all cell types in brain, and F 4 -neuroprostanes (NeuroPs) that derive from docosahexaenoic acid (DHA) that is highly concentrated in neuronal membranes. LPS stimulated delayed elevations in cerebral F 2 -IsoPs and F 4 -NeuroPs that were completely suppressed by indomethacin or ibuprofen pre-treatment. LPS-induced cerebral oxidative damage was abolished by disruption of subtype 2 receptor for PGE 2 (EP 2 ). In contrast, initial oxidative damage from icv kainic acid (KA) was more rapid than with LPS also was completely suppressed by indomethacin or ibuprofen pre-treatment but was independent of EP 2 receptor activation. The protective effect of deleting the EP 2 receptor was not associated with changes in cerebral eicosaniod production, but was partially related to reduced induction of nitric oxide synthase (NOS) activity. These results suggest the EP 2 receptor as a therapeutic target to limit oxidative damage from activation of innate immunity in cerebrum. Keywords: excitotoxicityinnate immunity, isoprostanes, neuroprostanes, NSAIDs, prostaglandin E 2 . J. Neurochem. Coincident cerebral oxidative damage and elevated prostaglandin (PG) E 2 levels are characteristic of several degenerative and destructive diseases of brain including stroke, epilepsy, Alzheimer's disease, HIV-associated dementia, and Creutzfeldt-Jakob disease (Griffin et al. 1994;Pace and Leaf 1995;Montine et al. 1998Montine et al. , 1999aMontine et al. , 1999bPaoletti et al. 1998;Thornhill and Smith 1998;Minghetti et al. 2000). PGE 2 potently modulates neurodegeneration and oxidative damage in several model systems; however, some have concluded that PGE 2 is neuroprotective while others have proposed that PGE 2 promotes neuronal damage (Akaike et al. 1994;Cazevielle et al. 1994;Minghetti et al. 1997aMinghetti et al. , 1997bMinghetti et al. , 1998Bezzi et al. 1998; Kraig 1998, 1999;Levi et al. 1998;Paoletti et al. 1998;Thornhill and Smith 1998;Aloisi et al. 1999;Kelley et al. 1999;Sanzgiri et al. 1999;Drachman and Rothstein 2000;Hewett et al. 2000). Most in vivo studies suggest that PGE 2 contributes to oxidative damage and neurodegeneration, while most in vitro studies indicate that PGE 2 has neuroprotective activity. There are several possible explanations for these disparate results.Cell culture models typically are limited by use of supraphysiologic concentrations of PGE 2 , by the absence of some of the PGE 2 receptor (EP) subtypes, and by disruption of paracrine interactions between neurons and glia. In vivo studies have rel...

Pharmacologic suppression of oxidative damage and dendritic degeneration following kainic acid-induced excitotoxicity in mouse cerebrum

“…The earliest time point evaluated in KA-induced excitotoxicity was 30 min since seizures start immediately after the icv KA injection. Elevated levels of these in vivo markers of oxidative damage are in agreement with our previous findings (Montine et al, 2002;Milatovic et al, 2005;Gupta et al, 2007), as well as by others (Patel et al, 2001) and indicate that KA injection leads to profound cerebral and neuronal oxidative damage in mice.…”

“…It was also reported that NO inhibits neuronal energy production in cultured hippocampal neurons (Brorson et al, 1999), leading to rapid ATP depletion. In addition, increased production of NO in the presence of the superoxide anion radical (O 2 − ) may generate peroxynitrite radical (OONO − ) (Montine et al, 2002;Milatovic et al, 2002), a potent inducer of lipid peroxidation.…”

Divergent effects of prostaglandin receptor signaling on neuronal survival

“…The increased toxicity of LPS with addition of EP2/EP3 receptor agonists is relevant to recent in vivo studies demonstrating that in the setting of inflammation, prostaglandin receptor signaling can exhibit an opposite and toxic effect on neurons. For example, in the LPS model of innate immunity, the EP2 receptor mediates a major component of inflammatory oxidative stress and secondary synaptotoxicity [17,19]. One potential mechanism is via induction of iNOS, production of NO, and production of reactive oxygen species; alternatively, microglialderived NO may lead to presynaptic release of glutamate and excitotoxic injury.…”

“…Recent studies have demonstrated that the EP2 receptor enhances inflammatory oxidative stress and synaptotoxicity in innate immunity [17,19] and in a transgenic model of Familial AD [13]. These effects are distinct from the neuroprotective function of the EP2 receptor seen both in vitro in organotypic slices and in vivo in models of cerebral ischemia [15,16].…”

“…In models of neurodegeneration where inflammation and glial activation lead to secondary neurotoxicity, the effects of prostaglandin signaling on neuronal viability diverge. The EP2 receptor, neuroprotective in models of glutamate toxicity, enhances the inflammatory response and secondary synaptotoxicity in the lipopolysaccharide (LPS) model of innate immunity [17,19]. In a murine model of Familial Alzheimer's disease, deletion of the EP2 receptor results decreased neuronal lipid peroxidation and Aβ peptide load [13].…”