Mechanisms of microglia-mediated neurotoxicity in a new model of the stroke penumbra
Mechanisms of microglia-mediated neurotoxicity in a new model of the stroke penumbra
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DOI：
10.1523/jneurosci.5643-07.2008
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发表时间：
2008-02-27
影响因子：
5.3
通讯作者：
Schlichter, Lyanne C.
中科院分区：
文献类型：
--
作者：
Kaushal, Vikas;Schlichter, Lyanne C.
缺血性中风后，核心区的神经元迅速死亡，而在缓慢发展的半影区的神经元死亡更容易接受治疗干预。小胶质细胞激活有助于延迟炎症，但由于半影区的神经毒性机制还没有很好地理解，我们开发了一个体外模型的小胶质细胞激活和传播的神经元杀伤。为了概括核心中的炎症触发因素，将小胶质细胞暴露于氧葡萄糖剥夺的神经元和星形胶质细胞。为了模拟发育中的半影区，洗涤小胶质细胞并使其与健康的幼稚神经元和星形胶质细胞相互作用。我们发现，氧-葡萄糖剥夺（OGD）应激神经元释放谷氨酸，通过其II组代谢型谷氨酸受体（mGluRs）激活小胶质细胞。小胶质细胞活化涉及核因子κ B（NF-κ B），一种促进其促炎功能的转录因子。活化的小胶质细胞变得神经毒性，通过肿瘤坏死因子-α（TNF-α）介导的凋亡机制杀死幼稚神经元，并涉及caspase-8和caspase-3的活化。与一些早期模型（例如，小胶质细胞被脂多糖激活），神经毒性不被诱导型一氧化氮合酶（iNOS）抑制剂（S-甲基异硫脲）或过氧亚硝酸根清除剂[5，10，15，20-四（N-甲基-4 ′-吡啶基）卟啉合铁（III）氯化物]降低，并且不需要p38促分裂原激活蛋白激酶（MAPK）激活。在不暴露于OGD应激神经元的情况下，通过用（2S，2 ' R，3 ' R）-2-（2 ' 3 '-二羧基环丙基）甘氨酸或谷氨酸盐直接激活小胶质细胞II组mGluR诱发相同的小胶质细胞神经毒性行为，所述（2S，2 ' R，3 ' R）-2-（2 ' 3 '-二羧基环丙基）甘氨酸或谷氨酸盐刺激TNF-α（而非一氧化氮）的产生并通过NF-κ B（而非p38 MAPK）的激活介导TNF-α依赖性神经毒性。总之，这些结果支持靶向小胶质细胞II组mGluRs、TNF α过度产生和NF-κ B活化以减少缺血半暗带中神经元死亡的潜在治疗策略。
After an ischemic stroke, neurons in the core are rapidly committed to die, whereas neuron death in the slowly developing penumbra is more amenable to therapeutic intervention. Microglia activation contributes to delayed inflammation, but because neurotoxic mechanisms in the penumbra are not well understood, we developed an in vitro model of microglia activation and propagated neuron killing. To recapitulate inflammatory triggers in the core, microglia were exposed to oxygen glucose-deprived neurons and astrocytes. To model the developing penumbra, the microglia were washed and allowed to interact with healthy naive neurons and astrocytes. We found that oxygen-glucose deprivation ( OGD)-stressed neurons released glutamate, which activated microglia through their group II metabotropic glutamate receptors ( mGluRs). Microglia activation involved nuclear factor kappa B ( NF-kappa B), a transcription factor that promotes their proinflammatory functions. The activated microglia became neurotoxic, killing naive neurons through an apoptotic mechanism that was mediated by tumor necrosis factor-alpha ( TNF-alpha), and involved activation of both caspase-8 and caspase-3. In contrast to some earlier models ( e.g., microglia activation by lipopolysaccharide), neurotoxicity was not decreased by an inducible nitric oxide synthase ( iNOS) inhibitor ( S-methylisothiourea) or a peroxynitrite scavenger [ 5,10,15,20-tetrakis( N-methyl-4 '-pyridyl) porphinato iron ( III) chloride], and did not require p38 mitogen-activated protein kinase ( MAPK) activation. The same microglia neurotoxic behavior was evoked without exposure to OGD-stressed neurons, by directly activating microglial group II mGluRs with ( 2S, 2 ' R, 3 ' R)-2-( 2 ' 3 '-dicarboxycyclopropyl) glycine or glutamate, which stimulated production of TNF-alpha ( not nitric oxide) and mediated TNF-alpha-dependent neurotoxicity through activation of NF-kappa B ( not p38 MAPK). Together, these results support potential therapeutic strategies that target microglial group II mGluRs, TNF alpha overproduction, and NF-kappa B activation to reduce neuron death in the ischemic penumbra.