Prostaglandin J2: a potential target for halting inflammation-induced neurodegeneration

Abstract

Prostaglandins (PGs) are produced via cyclooxygenases, which are enzymes that play a major role in neuroinflammation. Epidemiological studies show that chronic treatment with low levels of cyclooxygenase inhibitors (nonsteroidal anti-inflammatory drugs (NSAIDs)) lowers the risk for Alzheimer's disease (AD) and Parkinson's disease (PD) by as much as 50%. Unfortunately, inhibiting cyclooxygenases with NSAIDs blocks the synthesis of downstream neuroprotective and neurotoxic PGs, thus producing adverse side effects. We focus on prostaglandin J2 (PGJ2) because it is highly neurotoxic compared to PGA1, D2, and E2. Unlike other PGs, PGJ2 and its metabolites have a cyclopentenone ring with reactive α,β-unsaturated carbonyl groups that form covalent Michael adducts with key cysteines in proteins and GSH. Cysteine-binding electrophiles such as PGJ2 are considered to play an important role in determining whether neurons will live or die. We discuss in vitro and in vivo studies showing that PGJ2 induces pathological processes relevant to neurodegenerative disorders such as AD and PD. Further, we discuss our work showing that increasing intracellular cAMP with the lipophilic peptide PACAP27 counteracts some of the PGJ2-induced detrimental effects. New therapeutic strategies that neutralize the effects of specific neurotoxic PGs downstream from cyclooxygenases could have a significant impact on the treatment of chronic neurodegenerative disorders with fewer adverse side effects.

Keywords: Alzheimer's diseases; Michael adducts; NSAID; Parkinson's disease; chronic inflammation; cyclooxygenases; prostaglandin J2.

Figure 1

Formation of PGJ2 and its metabolites. PGJ2 is a product of spontaneous dehydration (–H₂O) of PGD2, which is the most abundant prostaglandin in the brain and the one that changes the most under pathological conditions. PGJ2 can be further metabolized into Δ12- and 15d-PGJ2 by reactions catalyzed by human serum albumin (HSA) or by dehydration (–H₂O), respectively. In rodents, the in vivo concentration of free PGJ2 in the brain upon stroke and TBI increases to neurotoxic levels. Since PGJ2 binds covalently to proteins and GSH, its cellular and intracellular concentrations in the brain are predicted to be much higher than free PGJ2. The stars indicate highly reactive a,b-unsaturated carbonyl groups.

Figure 2

Receptor-dependent and independent actions of PGJ2. Some of the PGJ2 effects are receptor mediated. The DP2 receptor, which is a G protein–coupled receptor (GPCR) for PGD2, is coupled to G_i, thus decreasing cAMP levels and increasing intracellular calcium. DP2 activation is linked to neuronal injury. We established that the peptide PACAP, which binds to its PAC1R receptor and increases cAMP, prevents some of the adverse effects of PGJ2. The nuclear receptor PPARγ is a transcription factor. PPARγ activation is associated with anti-inflammatory and neuroprotective signaling. Moreover, unlike most prostaglandins, PGJ2 and its metabolites (Δ12-PGJ2 and 15d-PGJ2) have a cyclopentenone ring with reactive α,β-unsaturated carbonyl groups (red star) that mediate their receptor-independent effects. Through S-alkylation, these groups form covalent Michael adducts with free sulfhydryls in cysteine residues in glutathione and cellular proteins. This covalent posttranslational modification by PGJ2 in the brain represents a novel pathologic change and could play a critical role in neurodegeneration in AD and PD. Pathologically activated therapeutics (PATs) are small molecules that become chemically activated at sites of tissue injury undergoing oxidative stress. These PATs are postulated to counteract the effects of electrophiles such as PGJ2, by activating the Keap1/Nrf2/ARE transcription pathway. Activation of the latter pathway induces the synthesis of endogenous antioxidant phase 2 enzymes that protect against oxidative and electrophilic stresses.

Figure 3

PGJ2 is a potential factor in the transition from acute to chronic inflammation. Besides being mediators of acute inflammation, prostaglandins also function in the transition and maintenance of chronic inflammation, thus inducing long-lasting effects. Prostaglandins, such as PGJ2, accomplish this by amplifying cytokine signaling, upregulating COX-2, inducing chemokines, and recruiting inflammatory cells such as macrophages. Thus, therapeutically targeting prostaglandins such as PGJ2 has potential to prevent/block chronic neuroinflammation relevant to neurodegeneration in AD and PD.