Pierre Sha-Ron, Lemmens Marijke A M, Figueiredo-Pereira Maria E
Department of Biological Sciences, Hunter College, City University of New York, New York, NY 10065, USA.
J Neuroinflammation. 2009 Jul 25;6:18. doi: 10.1186/1742-2094-6-18.
Chronic neuroinflammation is implicated in Parkinson's disease (PD). Inflammation involves the activation of microglia and astrocytes that release high levels of prostaglandins. There is a profound gap in our understanding of how cyclooxygenases and their prostaglandin products redirect cellular events to promote PD neurodegeneration. The major prostaglandin in the mammalian brain is prostaglandin D2, which readily undergoes spontaneous dehydration to generate the bioactive cyclopentenone prostaglandins of the J2 series. These J2 prostaglandins are highly reactive and neurotoxic products of inflammation shown in cellular models to impair the ubiquitin/proteasome pathway and cause the accumulation of ubiquitinated proteins. PD is a disorder that exhibits accumulation of ubiquitinated proteins in neuronal inclusions (Lewy bodies). The role of J2 prostaglandins in promoting PD neurodegeneration has not been investigated under in vivo conditions.
We addressed the neurodegenerative and behavioral effects of the administration of prostaglandin J2 (PGJ2) simultaneously into the substantia nigra/striatum of adult male FVB mice by subchronic microinjections. One group received unilateral injections of DMSO (vehicle, n = 6) and three groups received PGJ2 [3.4 microg or 6.7 microg (n = 6 per group) or 16.7 microg (n = 5)] per injection. Immunohistochemical and behavioral analyses were applied to assess the effects of the subchronic PGJ2 microinfusions.
Immunohistochemical analysis demonstrated a PGJ2 dose-dependent significant and selective loss of dopaminergic neurons in the substantia nigra while the GABAergic neurons were spared. PGJ2 also triggered formation of aggregates immunoreactive for ubiquitin and alpha-synuclein in the spared dopaminergic neurons. Moreover, PGJ2 infusion caused a massive microglia and astrocyte activation that could initiate a deleterious cascade leading to self-sustained progressive neurodegeneration. The PGJ2-treated mice also exhibited locomotor and posture impairment.
Our studies establish the first model of inflammation in which administration of an endogenous highly reactive product of inflammation, PGJ2, recapitulates key aspects of PD. Our novel PGJ2-induced PD model strongly supports the view that localized and chronic production of highly reactive and neurotoxic prostaglandins, such as PGJ2, in the CNS could be an integral component of inflammation triggered by insults evoked by physical, chemical or microbial stimuli and thus establishes a link between neuroinflammation and PD neurodegeneration.
慢性神经炎症与帕金森病（PD）有关。炎症涉及小胶质细胞和星形胶质细胞的激活，这些细胞会释放高水平的前列腺素。我们对环氧化酶及其前列腺素产物如何改变细胞事件以促进PD神经退行性变的理解存在重大差距。哺乳动物大脑中的主要前列腺素是前列腺素D2，它很容易自发脱水生成J2系列的生物活性环戊烯酮前列腺素。这些J2前列腺素是炎症产生的高反应性和神经毒性产物，在细胞模型中显示会损害泛素/蛋白酶体途径并导致泛素化蛋白的积累。PD是一种在神经元内含物（路易体）中表现出泛素化蛋白积累的疾病。J2前列腺素在促进PD神经退行性变中的作用尚未在体内条件下进行研究。
我们通过亚慢性微量注射将前列腺素J2（PGJ2）同时注入成年雄性FVB小鼠的黑质/纹状体，以研究其神经退行性和行为学影响。一组接受单侧注射二甲基亚砜（溶剂，n = 6），三组每注射一次接受PGJ2 [3.4微克或6.7微克（每组n = 6）或16.7微克（n = 5）]。应用免疫组织化学和行为分析来评估亚慢性PGJ2微量注射的效果。
免疫组织化学分析表明，PGJ2剂量依赖性地导致黑质中多巴胺能神经元显著且选择性地丧失，而GABA能神经元未受影响。PGJ2还在未受影响的多巴胺能神经元中引发了对泛素和α-突触核蛋白免疫反应性的聚集体形成。此外，PGJ2注射导致大量小胶质细胞和星形胶质细胞激活，这可能引发有害的级联反应，导致自我持续的进行性神经退行性变。接受PGJ2治疗的小鼠还表现出运动和姿势障碍。
我们的研究建立了第一个炎症模型，其中给予内源性高反应性炎症产物PGJ2概括了PD的关键方面。我们新的PGJ2诱导的PD模型有力地支持了这样一种观点，即中枢神经系统中局部和慢性产生的高反应性和神经毒性前列腺素，如PGJ2，可能是由物理、化学或微生物刺激引起的损伤所触发的炎症的一个组成部分，从而在神经炎症和PD神经退行性变之间建立了联系。
