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.
© 2016 New York Academy of Sciences.