Environmental enrichment cognitive neuroprotection in an experimental model of cerebral ischemia: biochemical and molecular aspects
Environmental enrichment cognitive neuroprotection in an experimental model of cerebral ischemia: biochemical and molecular aspects
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DOI：
10.1016/j.bbr.2018.04.023
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发表时间：
2018-08-01
影响因子：
2.7
通讯作者：
Martins-Silva, Cristina
中科院分区：
文献类型：
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作者：
Goncalves, Lara Vezula;Herlinger, Alice Laschuk;Martins-Silva, Cristina
中风被认为是全球发病的主要原因。目前，尚无针对中风后认知障碍的有效治疗方法。丰富环境（EE）已被提出作为在缺血事件中诱导脑耐受的预处理方法。然而，这种耐受性所涉及的基本机制尚不清楚。在此，我们的目的是在缺血性中风小鼠模型中确定 EE 预处理触发的神经保护机制，为此，在通过双侧颈动脉闭塞 (BCCAo) 或假手术造成缺血性损伤之前，将 C57B1/6 小鼠在 EE 或标准环境 (SC) 中保存五周。为了评估缺血引起的认知缺陷，对动物进行了一系列行为测试，以评估短期（STM）、长期（LTM）和工作记忆（WM）表现。尽管在 LTM 和 WM 中没有观察到 EE 的影响，但 EE 预处理能够防止缺血反应的短期缺陷。这种改善伴随着 EE 预暴露后动物梗塞体积的减少。接下来，我们旨在分析涉及胆碱能（M1 和 α 7 受体）和谷氨酸能（NMDA 亚基 GIuN1、G1uN2A、GIuN2B 和 GluN2C）神经传递、炎症介质（GFAP 和 1L-1 β 以及神经营养蛋白 BDNF）的基因表达。接受 STM 测试的动物并未出现表达变化。谷氨酸或胆碱能受体；然而，在接受 LTM 任务的动物中，EE 会导致遭受缺血性损伤的 EE 动物中 GFAP 表达增加，尽管如此，两组中均未观察到谷氨酸含量的变化。受体、炎症细胞因子 IL1-β 表达的减少和缺血动物中 GFAP 表达的增加可能有助于 EE 范式诱导的认知改善。
Stroke is considered a major cause of global morbidity. Currently, there are no effective treatments for post stroke cognitive impairment. Enriched environment (EE) has been brought forward as a preconditioning method to induce cerebral tolerance in an ischemic event. However, the subjacent mechanisms involved in this tolerance are not yet clear. Herein we aimed to identify the mechanisms of neuroprotection triggered by EE preconditioning in a murine model of ischemic stroke, In order to do so, C57B1/6 mice were kept for five weeks either in EE or in standard environment (SC) prior to ischemic injury through bilateral carotid occlusion (BCCAo) or sham surgery. To evaluate cognitive deficits resulting from ischemia, animals were subjected to a set of behavioral test to assess short-term (STM), long-term (LTM) and working memory (WM) performance. Despite no effect of EE having been observed in LTM and WM, EE preconditioning was able to prevent short-term deficits in response to ischemia. This improvement was accompanied by a reduction in the infarct volume in animals following EE pre-exposure. Next, we aimed to analyze the expression of genes involved in cholinergic (M1 and alpha 7 receptors) and glutamatergic (NMDA subunits GIuN1, G1uN2A, GIuN2B and GIuN2C) neurotransmission, inflammatory mediators (GFAP and 1L-1 beta and of the neurotrophin BDNF. Animals tested for STM did not present alterations in the expression of glutamatergic or cholinergic receptors; however, EE was shown to prevent increased expression of IL1-beta. On the other hand, in animals submitted to LTM task, EE exposure lead to increased GFAP expression in EE animals that underwent ischemic injury, affecting also the expression of NMDA subunits. In spite of that, no alterations in glutamate content were observed in either group. Altogether, this study suggests that the changes observed in the expression of glutamatergic receptors, the reduction of the inflammatory cytokine IL1-beta expression and the increased expression of GFAP in ischemic animals might contribute to the cognitive improvement induced by the EE paradigm.