Loss of dopaminergic neurons by the induction of inducible nitric oxide synthase and cyclooxygenase-2 via CD40: Relevance to Parkinson's disease
Loss of dopaminergic neurons by the induction of inducible nitric oxide synthase and cyclooxygenase-2 via CD40: Relevance to Parkinson's disease
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DOI：
10.1002/jnr.20599
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发表时间：
2005-09-15
影响因子：
4.2
通讯作者：
Sakoda, S
中科院分区：
文献类型：
--
作者：
Okuno, T;Nakatsuji, Y;Sakoda, S
一种与炎症分子上调相关的胶质反应被认为在帕金森S病(PD)的多巴胺能神经元丢失中起重要作用。在炎症分子中，诱导型一氧化氮合酶(NOS)和环氧合酶-2(COX-2)是其发病机制中的关键因素。然而，这些分子是如何在帕金森氏症大脑中被诱导的机制还不清楚。我们重点研究了CD40，它表达在神经细胞上，可能通过诱导炎性分子参与神经炎症。体外培养的小胶质细胞和星形胶质细胞在CD40刺激下，小胶质细胞和星形胶质细胞中一氧化氮合酶和环氧合酶-2的表达均上调，低剂量的干扰素-γ联合刺激可诱导中脑培养的多巴胺能神经元选择性丢失，并可被选择性的一氧化氮合酶和/或环氧合酶-2抑制剂保护。我们还发现，在CD40刺激的星形胶质细胞中，低亲和力的IgE受体CD23的增加，这是已知的诱导一氧化氮合酶表达。这些结果提示，通过CD40途径上调的NOS和COX-2可能导致多巴胺能神经元丢失，并可能参与帕金森病的神经炎症通路。(C)2005年Wiley-Liss，Inc.
A glial reaction associated with up-regulation of inflammatory molecules has been suggested to play an important role in dopaminergic neuron loss in Parkinson ' s disease (PD). Among inflammatory molecules, inducible nitric oxide synthase (NOS) and cyclooxygenase-2 (COX-2) have been focused upon as key factors in the pathogenesis. However, the mechanism of how these molecules are induced in PD brains is not clearly understood. We focused on CD40, which is expressed on neural cells and could be implicated in the neuroinflarnmation by inducing inflammatory molecules. We showed that both NOS and COX-2 were up-regulated in microglia and astrocytes by CD40 stimulation in association with a low dose of interferon-gamma (IFN-gamma) in vitro, Selective loss of dopaminergic neurons was induced by costimulation with CD40 and IFN-gamma in mesencephalic cultures, which was protected by selective inhibitors of NOS and/or COX-2. We also found in CD40-stimulated astrocytes an increase of a low-affinity IgE receptor CD23, which is known to induce NOS expression. Together these data suggest that up-regulated NOS and COX-2 via the CD40 pathway may lead to dopaminergic neuron loss and may participate in the neuroinflammaory pathway of PD. (c) 2005 Wiley-Liss, Inc.