Figueiredo-Pereira Maria E, Corwin Chuhyon, Babich John
Department of Biological Sciences, Hunter College and the Graduate Center, CUNY, New York, New York.
Department of Radiology, Weill Cornell Medical College, New York, New York.
Ann N Y Acad Sci. 2016 Jan;1363(1):125-37. doi: 10.1111/nyas.12987. Epub 2016 Jan 8.
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.
前列腺素（PGs）是通过环氧化酶产生的，环氧化酶是在神经炎症中起主要作用的酶。流行病学研究表明，长期使用低剂量的环氧化酶抑制剂（非甾体抗炎药（NSAIDs））可将阿尔茨海默病（AD）和帕金森病（PD）的风险降低多达50%。不幸的是，用NSAIDs抑制环氧化酶会阻断下游神经保护和神经毒性PGs的合成，从而产生不良副作用。我们关注前列腺素J2（PGJ2），因为与PGA1、D2和E2相比，它具有高度的神经毒性。与其他PGs不同，PGJ2及其代谢产物具有一个带有反应性α，β-不饱和羰基的环戊烯酮环，该环与蛋白质和谷胱甘肽（GSH）中的关键半胱氨酸形成共价迈克尔加合物。像PGJ2这样的半胱氨酸结合亲电试剂被认为在决定神经元是存活还是死亡方面起着重要作用。我们讨论了体外和体内研究，这些研究表明PGJ2会诱导与AD和PD等神经退行性疾病相关的病理过程。此外，我们还讨论了我们的工作，即使用亲脂性肽垂体腺苷酸环化酶激活肽27（PACAP27）增加细胞内环磷酸腺苷（cAMP）可抵消一些PGJ2诱导的有害影响。中和环氧化酶下游特定神经毒性PGs作用的新治疗策略可能会对慢性神经退行性疾病的治疗产生重大影响，且副作用更少。
