The AMPA receptor positive allosteric modulator, S18986, is neuroprotective against neonatal excitotoxic and inflammatory brain damage through BDNF synthesis
The AMPA receptor positive allosteric modulator, S18986, is neuroprotective against neonatal excitotoxic and inflammatory brain damage through BDNF synthesis
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DOI：
10.1016/j.neuropharm.2009.05.010
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发表时间：
2009-09-01
影响因子：
4.7
通讯作者：
Gressens, Pierre
中科院分区：
文献类型：
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作者：
Destot-Wong, Kim-Da;Liang, Kun;Gressens, Pierre
谷氨酸能激动剂ibotenate(作用于N-甲基-D-天冬氨酸和代谢性受体)或S-威拉地丁(作用于AMPA-海人酸受体)在新生小鼠中引起的脑损伤与脑室周围白质损伤和新生婴儿大脑皮质灰质损伤的某些方面类似，有发生脑性瘫痪的风险。IL-1β暴露可使新生小鼠大脑对兴奋性毒性损伤敏感，类似于在人类情况下观察到的情况。AMPA受体的正向调节剂作为一种潜在的神经保护剂，在成人的一些神经退行性疾病中受到越来越多的关注。然而，它们是否也能在新生儿脑损伤中起到神经保护剂的作用还有待确定。因此，本研究采用一个明确的新生儿兴奋性中毒性脑损伤的啮齿动物模型来评价AMPA受体的正性变构调节剂S18986的神经保护作用及其作用机制。在这个模型中，S18986为发育中的白质和皮质灰质提供了剂量依赖和持久的保护，使其免受兴奋性毒性侮辱以及与致敏性炎症侮辱相结合。S18986对大脑皮层灰质的神经保护作用与减少坏死性和凋亡性细胞死亡有关。S18986诱导的对NMDA受体介导的脑损伤的神经保护作用可被ERK和PI3激酶-Akt通路的抑制剂所阻断。S18986的作用可被中和的抗BDNF抗体取消，实时荧光定量聚合酶链式反应证实S18986刺激了新生儿脑内BDNF的产生。本研究为S18986作为治疗兴奋性中毒性围产期脑损伤的候选分子的作用提供了有力的实验支持，并确认BDNF是S18986介导的神经保护的关键介质。(C)2009爱思唯尔有限公司。保留所有权利。
Brain lesions induced in newborn mice by the glutamatergic agonists ibotenate (acting on NMDA and metabotropic receptors) or S-willardiine (acting on AMPA-kainate receptors) mimic some aspects of periventricular white matter lesions and neocortical grey matter damage observed in human neonates at risk for developing cerebral palsy. The neonatal mouse brain can be sensitized to excitotoxic damage by IL-1 beta exposure similar to that observed in the human situation. Positive modulators of AMPA receptors have received increasing attention as potential neuroprotective agents in a number of neurodegenerative disorders of the adult. However whether they can also act as a neuroprotectant in neonatal brain damage has yet to be defined. Therefore the present study uses a well-defined rodent model of neonatal excitotoxic brain lesions to assess the neuroprotective effects of S18986, a positive allosteric modulator of AMPA receptors, as well as its mechanisms of action. In this model, S18986 provided a dose-dependent and long-lasting protection of developing white matter and cortical grey matter against an excitotoxic insult and also when this was combined with a sensitizing inflammatory insult. Neuroprotective effects of S18986 in cortical grey matter involved decreased necrotic and apoptotic cell death. S18986-induced neuroprotection against NMDA receptor-mediated brain lesions was blocked by inhibitors of ERK and PI3 kinase-Akt pathways. S18986 effects were abolished by a neutralizing anti-BDNF antibody and real time PCR confirmed the stimulation by S18986 of BDNF production in the neonatal brain. The present study provides strong experimental support for the role of S18986 as a candidate molecule for therapy in cases of excitotoxic perinatal brain lesions and identifies BDNF as a key mediator of this S18986-mediated neuroprotection. (C) 2009 Elsevier Ltd. All rights reserved.