Neural estrogen synthesis by astrocytic aromatization, and neuroinflammation.

描述（由申请人提供）：慢性神经炎症导致神经病变，并涉及许多严重的健康状况，如中风，帕金森病和阿尔茨海默病。新出现的证据有力地支持循环雌激素(E)的抗炎作用，因为去除和替代这种类固醇分别显著地加剧和减轻了几种炎症指标。事实上，e -给药降低了几种促炎细胞因子的表达和分泌，包括IL1、IL6和TNF?。脊椎动物大脑对机械扰动或内毒素的反应是小胶质细胞中细胞因子表达和反应性星形胶质细胞中芳香化酶（E-合成酶）表达的迅速增加。重要的是，小胶质细胞因子诱导发生在星形胶质细胞芳香化酶表达之前，这表明细胞因子可能诱导反应性胶质细胞芳香化酶的表达。鉴于外周E的抗炎作用已经得到了充分的研究，我们认为神经E可能通过神经胶质芳构化，在脊椎动物大脑中作为一种快速诱导和有效的抗炎信号。更具体地说，我们假设细胞因子迅速诱导持续的胶质芳香化酶表达和随后的E合成，这反过来又导致细胞因子的减少。这种下调防止神经组织长期暴露于细胞因子分泌的有害影响。为了阐明和完善这个模型，我们将使用分子方法和行为分析来测试特定的促炎细胞因子在中枢或外周内毒素给药后诱导芳香酶转录中的作用。接下来，使用芳香化酶的药理学抑制剂，我们将测试芳香化在中枢内毒素给药后减轻细胞因子表达和疾病行为中的作用。综上所述，这些实验将探索促炎细胞因子在诱导脑、神经胶质芳构化中的令人兴奋的新作用，并进一步探索细胞因子活性被神经e供应限制的机制。这些数据对于开发靶向和预防炎症过程的治疗方法是必要的，从而降低神经退行性疾病的严重程度。

DESCRIPTION (provided by applicant): Chronic neuroinflammation contributes to neuropathy and is implicated in a number of serious health conditions such as Stroke, Parkinson's and Alzheimer's disease. Emerging evidence strongly supports an anti-inflammatory role for circulating estrogens (E) since removal and replacement of this steroid dramatically exacerbates and mitigates several indices of inflammation respectively. Indeed, E-administration decreases the expression and secretion of several pro-inflammatory cytokines including IL1, IL6 and TNF?. The vertebrate brain responds to mechanical perturbation or endotoxin with a rapid increase in cytokine expression in microglia and aromatase (E- synthase) expression in reactive astrocytes. Importantly, microglial cytokine induction occurs prior to astrocytic aromatase expression suggesting that cytokines may induce the expression of aromatase in reactive glia. Given the well-studied anti-inflammatory role of peripheral E, we propose that neural E, via glial aromatization, may serve as a rapidly induced and potent anti-inflammatory signal in the vertebrate brain. More specifically, we hypothesize that cytokines rapidly induce sustained glial aromatase expression and consequent E synthesis, which in turn, causes a decrease in cytokines. This down-regulation prevents chronic exposure of neural tissue to the deleterious effects of prolonged cytokine secretion. To elucidate and hone this model we will use a molecular approach and behavioral assays to test the role of specific pro-inflammatory cytokines in the induction of aromatase transcription following central or peripheral endotoxin administration. Next, using a pharmacological inhibitor of aromatase, we will test the role of aromatization in the mitigation of cytokine expression and sickness behavior following central endotoxin administration. Taken together these experiments will explore an exciting new role for pro-inflammatory cytokines in the induction of encephalic, glial aromatization and further, a mechanism whereby cytokine activity is curtailed by neural E-provision. These data are necessary for the development of therapies that target and prevent inflammatory processes, thereby reducing the severity of neurodegenerative disease.