氢水对大鼠脑震荡后认知障碍及抑郁样行为的治疗作用及其机制研究

The cognitive disorders and depression after concussion possess a high incidence and wide influence; however, there is still a lack of safe and effective comprehensive treatment now. Our previous studies have confirmed that hydrogen rich water can improve the cognitive impairment and play a neuroprotective role after moderate and severe traumatic brain injury in rats through its anti-oxidative stress and anti-inflammatory mechanisms. In addition, we have also observed the trend that hydrogen rich water might have the ability to improve cognitive impairment and depression-like behavior after concussion in rats. Whether there is a definite therapeutic effect of hydrogen rich water on post-concussion cognitive impairment and depression-like behavior and what is the potential mechanism have not yet been reported. Therefore, we intend to construct a rat brain concussion model with hydrogen rich water pre-conditioning and/or post-injury intervention, and then observe the therapeutic effects of hydrogen rich water on post-concussions through neurobehavioral tests and depressive-like behavior assessments at different time points, after that, we will measure the oxidation products, inflammatory factors, and abnormal discharges in the hippocampus, prefrontal cortex, and lateral habenular nucleus, analyze theirs’ correlation ship with cognitive impairment and depression-like behavior symptoms, in order to analyze the potential mechanism of hydrogen rich water in improving cognition impairment and depression-like behaviors after cerebral concussion in rats from the aspects of anti-oxidative stress, anti-inflammatory and inhibition of burst discharge of lateral habenular nucleus. Our research could provide new ideas and strategies for the prevention and treatment of cognitive disorders and depression-like behaviors after concussion.

脑震荡后认知障碍及抑郁状态发病率高，影响范围广，目前尚缺乏安全有效的综合治疗手段。我们前期的研究已证实氢水可通过抗氧化应激及抗炎性反应机制改善大鼠中重度颅脑损伤后的认知障碍，并起到神经保护作用，且观察到氢水还有改善大鼠脑震荡后出现的认知障碍及抑郁样行为的趋势；关于氢水对脑震荡后认知障碍及抑郁样行为是否确有治疗作用及其潜在机制，目前尚无研究报道。因此，本项目拟构建大鼠脑震荡模型，给予大鼠氢水预适应和伤后干预，通过不同时间点的神经行为学检查和抑郁样行为评测等手段观察氢水干预对脑震荡后认知障碍及抑郁样行为的治疗效果，同时通过测定海马体、前额叶皮层及外侧缰核等相关脑区氧化产物、炎性因子及异常放电等指标，分析其与认知抑郁症状的相关性，从抗氧化应激、抗炎性反应及抑制外侧缰核簇状放电等角度探讨氢水改善大鼠脑震荡后认知障碍及抑郁样行为的潜在机制，为脑震荡后认知障碍及抑郁样行为的防治研究提供新思路和新策略。

颅脑损伤患者中超过80%为轻型颅脑损伤，其临床病患一般无需接受手术治疗，整体预后明显优于其他中重型颅脑损伤，但伤后常可见患者认知障碍，抑郁、躁动表现，尤其在反复性轻型颅脑损伤的患者中，上述功能障碍更加常见，并且伴有认知记忆失调，阻碍患者回归社会和工作。近些年来氢水治疗成为各类慢性疾病的热点，从2007年起首次报道动物呼吸2%的氢气治疗脑缺血再灌注损伤，我们证明了在氢水、氢气治疗颅脑外伤类疾病的机制，主要通过氢分子的抗氧化和抗炎作用改善整体脑内环境，最终缓解相应症状，改善整体预后。.本项目采用C57/BL6n小鼠，创新使用悬重闭合型颅脑打击模型，配合可坠落平台，良好的模拟了反复性轻型颅脑损伤的自然受伤机制。对于动物模型，预适应氢水喂养至伤后30日，一方面通过形态学和行为学检测观察氢水对于rmTBI小鼠的焦虑抑郁样行为改善效果以及认知功能障碍改善；通过免疫组化分析检测脑内多个时间点炎症反应标志物水平，提供应用氢分子治疗rmTBI损伤的抗炎性证据，另一方面，通过多模态多时间点影像数据检测，对实验动物脑组织进行实时动态研究，影像数据包括T2像、DTI、MRS及神经纤维重建等数据分析，进一步探讨氢分子对脑内宏观表现的治疗效果，为之后的临床患者治疗和影像学表现分析奠定基础。我们的研究显示，小鼠反复性轻型颅脑损伤后30日左右认知能力，短期记忆能力明显下降，表现为Morris水迷宫实验定位航行实验寻找隐蔽站台时间显著长于对照组，同时间点取脑组织显示海马结构中NLRP-3炎症小体染色阳性，，而对于伤后持续氢水喂养组的小鼠，其海马组织中NLRP-3表达含量明显低于打击组小鼠，考虑这一区别主要是氢分子发挥了抗炎，抗氧化应激的作用。另一方面，伤后早期核磁共振显示颅内存在微出血点和弥漫性轴索损伤的征象，对应位置中晚期可以观察到瘢痕化和软化灶形成，1H-MRS结果也提示存在脑内脱髓鞘改变及其代谢产物的增加，这一现象主要集中在伤后7-14日这一时间段，提示炎性反应和氧化应激的高峰时期早于伤后7天，这一推测能够解释伤后7-14日焦虑抑郁样行为异常以及伤后晚期回归正常的现象。氢水干预后小鼠1H-MRS检测上述代谢产物的含量与对照组无显著差异，且后续炎症反应标志物含量下降，验证了氢水对rmTBI小鼠的保护作用，展示了氢水治疗轻型脑损伤的临床应用前景。

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