Neuroinflammation and J2 prostaglandins: linking impairment of the ubiquitin-proteasome pathway and mitochondria to neurodegeneration.
Neuroinflammation and J2 prostaglandins: linking impairment of the ubiquitin-proteasome pathway and mitochondria to neurodegeneration.
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DOI：
10.3389/fnmol.2014.00104
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发表时间：
2014
影响因子：
4.8
通讯作者：
Serrano P
中科院分区：
文献类型：
--
作者：
Figueiredo-Pereira ME;Rockwell P;Schmidt-Glenewinkel T;Serrano P
中枢神经系统的免疫反应是在损伤后激活的一种防御机制，以启动修复机制，而中枢神经系统的慢性过度激活(称为神经炎症)可能会加剧损伤。后者与多种神经和神经退行性疾病有关，如阿尔茨海默病和帕金森病、肌萎缩侧索硬化症、多发性硬化症、创伤性脑损伤、艾滋病毒痴呆症和普恩疾病。环氧合酶(COX-1和COX-2)是花生四烯酸转化为生物活性前列腺素的关键酶，在炎症级联反应中起核心作用。J2前列腺素是环氧合酶的内源性毒性产物，由于其水平在脑损伤时显著升高，因此它们积极参与促炎刺激引起的神经元功能障碍。在这篇综述中，我们重点介绍J2前列腺素(1)发挥作用的机制，(2)潜在地促进从急性到慢性炎症的转变和神经病理的传播，(3)干扰泛素-蛋白酶体途径和线粒体功能，以及(4)促进神经退行性疾病，如阿尔茨海默病和帕金森病，肌萎缩侧索硬化症，以及中风，创伤性脑损伤(TBI)和Krabbe病的脱髓鞘。最后，我们讨论了靶向J2前列腺素通路以预防/延缓与神经炎相关的神经变性的治疗潜力。在这种背景下，我们建议改变传统的观点，即环氧合酶是治疗神经炎症的最合适的靶点，转变为J2前列腺素通路和环氧合酶下游的其他神经毒性前列腺素，作为治疗慢性神经退行性疾病的更有效的靶点，将提供显著的益处，同时将副作用降至最低。
The immune response of the CNS is a defense mechanism activated upon injury to initiate repair mechanisms while chronic over-activation of the CNS immune system (termed neuroinflammation) may exacerbate injury. The latter is implicated in a variety of neurological and neurodegenerative disorders such as Alzheimer and Parkinson diseases, amyotrophic lateral sclerosis, multiple sclerosis, traumatic brain injury, HIV dementia, and prion diseases. Cyclooxygenases (COX-1 and COX-2), which are key enzymes in the conversion of arachidonic acid into bioactive prostanoids, play a central role in the inflammatory cascade. J2 prostaglandins are endogenous toxic products of cyclooxygenases, and because their levels are significantly increased upon brain injury, they are actively involved in neuronal dysfunction induced by pro-inflammatory stimuli. In this review, we highlight the mechanisms by which J2 prostaglandins (1) exert their actions, (2) potentially contribute to the transition from acute to chronic inflammation and to the spreading of neuropathology, (3) disturb the ubiquitin-proteasome pathway and mitochondrial function, and (4) contribute to neurodegenerative disorders such as Alzheimer and Parkinson diseases, and amyotrophic lateral sclerosis, as well as stroke, traumatic brain injury (TBI), and demyelination in Krabbe disease. We conclude by discussing the therapeutic potential of targeting the J2 prostaglandin pathway to prevent/delay neurodegeneration associated with neuroinflammation. In this context, we suggest a shift from the traditional view that cyclooxygenases are the most appropriate targets to treat neuroinflammation, to the notion that J2 prostaglandin pathways and other neurotoxic prostaglandins downstream from cyclooxygenases, would offer significant benefits as more effective therapeutic targets to treat chronic neurodegenerative diseases, while minimizing adverse side effects.
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