Prostaglandin J2: a potential target for halting inflammation-induced neurodegeneration.
Prostaglandin J2: a potential target for halting inflammation-induced neurodegeneration.
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DOI：
10.1111/nyas.12987
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发表时间：
2016-01
影响因子：
5.2
通讯作者：
Babich J
中科院分区：
文献类型：
--
作者：
Figueiredo-Pereira ME;Corwin C;Babich J
前列腺素是通过环氧合酶产生的，环氧合酶是在神经炎症中起主要作用的酶。流行病学研究表明，长期使用低水平的环氧化酶抑制剂（NSAID）可将阿尔茨海默病（AD）和帕金森病（PD）的风险降低50%。不幸的是，用NSAID抑制环加氧酶会阻断下游神经保护和神经毒性的野牡丹素的合成，从而产生不良副作用。我们专注于前列腺素J2（PGJ 2），因为与PGA 1，D2和E2相比，它具有高度神经毒性。与其他洋地黄素不同，PGJ 2及其代谢产物具有环戊烯酮环，环戊烯酮环具有反应性α，β-不饱和羰基，与蛋白质和GSH中的关键半胱氨酸形成共价迈克尔加合物。半胱氨酸结合亲电体如PGJ 2被认为在决定神经元存活或死亡方面发挥重要作用。我们讨论了体外和体内研究表明，PGJ 2诱导相关的神经退行性疾病，如AD和PD的病理过程。此外，我们发现，增加细胞内cAMP与亲脂性肽PACAP 27抵消了一些PGJ 2诱导的有害影响。总之，新的治疗策略，中和特定的神经毒性的cyclooxygenases下游的影响，可以有一个显着的影响，慢性神经退行性疾病的治疗，不良副作用少。
Prostaglandins 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 (NSAIDs) lowers the risk for Alzheimer's (AD) and Parkinson's (PD) diseases by as much as 50%. Unfortunately, inhibiting cyclooxygenases with NSAIDs blocks the synthesis of downstream neuroprotective and neurotoxic prostaglandins, thus producing adverse side effects. We focus on prostaglandin J2 (PGJ2) because it is highly neurotoxic compared to PGA1, D2, and E2. Unlike other prostaglandins, 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. Furthermore, we found that increasing intracellular cAMP with the lipophilic peptide PACAP27 counteracts some of the PGJ2-induced detrimental effects. In conclusion, new therapeutic strategies that neutralize the effects of specific neurotoxic prostaglandins downstream from cyclooxygenases could have a significant impact on the treatment of chronic neurodegenerative disorders with fewer adverse side effects.