Neuroinflammation increases GABAergic tone and impairs cognitive and motor function in hyperammonemia by increasing GAT-3 membrane expression. Reversal by sulforaphane by promoting M2 polarization of microglia.
Neuroinflammation increases GABAergic tone and impairs cognitive and motor function in hyperammonemia by increasing GAT-3 membrane expression. Reversal by sulforaphane by promoting M2 polarization of microglia.
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DOI：
10.1186/s12974-016-0549-z
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发表时间：
2016-04-18
影响因子：
9.3
通讯作者：
Felipo V
中科院分区：
文献类型：
--
作者：
Hernandez-Rabaza V;Cabrera-Pastor A;Taoro-Gonzalez L;Gonzalez-Usano A;Agusti A;Balzano T;Llansola M;Felipo V
通过莱菔硫烷治疗增强内源性抗炎机制，减少神经炎症并恢复学习和运动协调。萝卜硫素减少神经炎症使细胞外GABA和谷氨酸-NO-cGMP通路正常化并确定潜在机制。确定高氨血症诱导的小胶质细胞激活损害认知和运动功能的步骤以及萝卜硫素如何恢复它们。高氨血症诱导神经炎症并增加小脑中的GABA能张力，这有助于肝性脑病（HE）的认知和运动障碍。神经炎症和GABA能紧张之间的联系仍然未知。减少神经炎症和GABA能张力的新治疗方法可以改善神经损伤。目的是，在高氨血症大鼠中，评估：我们分析了对照和高氨血症大鼠，用或不用萝卜硫素治疗，（a）Y迷宫中的学习;（B）平衡木行走中的运动协调;（c）通过微透析的谷氨酸-NO-cGMP通路和细胞外GABA;（d）小胶质细胞活化，通过免疫组织化学或蛋白质印迹标记分析促炎性（M1）（IL-1b，Iba-1）和抗炎（M2）小胶质细胞（Iba 1，IL-4，IL-10，Arg 1，YM-1）;和（e）GABA转运蛋白GAT-3的膜表达。高氨血症诱导活化的星形胶质细胞和小胶质细胞在小脑的免疫组织化学评估。高氨血症诱导的神经炎症与GABA转运蛋白GAT-3的膜表达增加有关，主要是在活化的星形胶质细胞中。这也与小脑中细胞外GABA的增加以及Y迷宫中的运动不协调和学习能力受损有关。萝卜硫素促进小胶质细胞从M1表型向M2表型的极化，减少IL-1b并增加小脑中的IL-4、IL-10、Arg 1和YM-1。这与星形胶质细胞失活和GAT-3膜表达、细胞外GABA、谷氨酸-一氧化氮-cGMP通路以及学习和运动协调的正常化有关。神经炎症通过增加GAT-3膜表达增加小脑中的GABA能张力。这会损害Y迷宫中的运动协调和学习。萝卜硫素可能是一种新的治疗方法，通过促进小胶质细胞从M1分化为M2来改善高氨血症、肝性脑病和其他与神经炎症相关的病理的认知和运动功能。
Enhancing endogenous anti-inflammatory mechanisms by sulforaphane treatment reduces neuroinflammation and restores learning and motor coordination. Reduction of neuroinflammation by sulforaphane normalizes extracellular GABA and glutamate-NO-cGMP pathway and identify underlying mechanisms. Identify steps by which hyperammonemia-induced microglial activation impairs cognitive and motor function and how sulforaphane restores them. Hyperammonemia induces neuroinflammation and increases GABAergic tone in the cerebellum which contributes to cognitive and motor impairment in hepatic encephalopathy (HE). The link between neuroinflammation and GABAergic tone remains unknown. New treatments reducing neuroinflammation and GABAergic tone could improve neurological impairment. The aims were, in hyperammonemic rats, to assess whether: We analyzed in control and hyperammonemic rats, treated or not with sulforaphane, (a) learning in the Y maze; (b) motor coordination in the beam walking; (c) glutamate-NO-cGMP pathway and extracellular GABA by microdialysis; (d) microglial activation, by analyzing by immunohistochemistry or Western blot markers of pro-inflammatory (M1) (IL-1b, Iba-1) and anti-inflammatory (M2) microglia (Iba1, IL-4, IL-10, Arg1, YM-1); and (e) membrane expression of the GABA transporter GAT-3. Hyperammonemia induces activation of astrocytes and microglia in the cerebellum as assessed by immunohistochemistry. Hyperammonemia-induced neuroinflammation is associated with increased membrane expression of the GABA transporter GAT-3, mainly in activated astrocytes. This is also associated with increased extracellular GABA in the cerebellum and with motor in-coordination and impaired learning ability in the Y maze. Sulforaphane promotes polarization of microglia from the M1 to the M2 phenotype, reducing IL-1b and increasing IL-4, IL-10, Arg1, and YM-1 in the cerebellum. This is associated with astrocytes deactivation and normalization of GAT-3 membrane expression, extracellular GABA, glutamate-nitric oxide-cGMP pathway, and learning and motor coordination. Neuroinflammation increases GABAergic tone in the cerebellum by increasing GAT-3 membrane expression. This impairs motor coordination and learning in the Y maze. Sulforaphane could be a new therapeutic approach to improve cognitive and motor function in hyperammonemia, hepatic encephalopathy, and other pathologies associated with neuroinflammation by promoting microglia differentiation from M1 to M2.