Sharma Aruna, Muresanu Dafin F, Sahib Seaab, Tian Z Ryan, Castellani Rudy J, Nozari Ala, Lafuente José Vicente, Buzoianu Anca D, Bryukhovetskiy Igor, Manzhulo Igor, Patnaik Ranjana, Wiklund Lars, Sharma Hari Shanker
International Experimental Central Nervous System Injury & Repair (IECNSIR), Department of Surgical Sciences, Anesthesiology & Intensive Care Medicine, Uppsala University Hospital, Uppsala University, Uppsala, Sweden.
Department of Clinical Neurosciences, University of Medicine & Pharmacy, Cluj-Napoca, Romania; "RoNeuro" Institute for Neurological Research and Diagnostic, Cluj-Napoca, Romania.
Prog Brain Res. 2020;258:1-77. doi: 10.1016/bs.pbr.2020.09.003. Epub 2020 Nov 2.
Sleep deprivation (SD) is common in military personnel engaged in combat operations leading to brain dysfunction. Military personnel during acute or chronic SD often prone to traumatic brain injury (TBI) indicating the possibility of further exacerbating brain pathology. Several lines of evidence suggest that in both TBI and SD alpha-melanocyte-stimulating hormone (α-MSH) and brain-derived neurotrophic factor (BDNF) levels decreases in plasma and brain. Thus, a possibility exists that exogenous supplement of α-MSH and/or BDNF induces neuroprotection in SD compounded with TBI. In addition, mesenchymal stem cells (MSCs) are very portent in inducing neuroprotection in TBI. We examined the effects of concussive head injury (CHI) in SD on brain pathology. Furthermore, possible neuroprotective effects of α-MSH, MSCs and neurotrophic factors treatment were explored in a rat model of SD and CHI. Rats subjected to 48h SD with CHI exhibited higher leakage of BBB to Evans blue and radioiodine compared to identical SD or CHI alone. Brain pathology was also exacerbated in SD with CHI group as compared to SD or CHI alone together with a significant reduction in α-MSH and BDNF levels in plasma and brain and enhanced level of tumor necrosis factor-alpha (TNF-α). Exogenous administration of α-MSH (250μg/kg) together with MSCs (1×10) and cerebrolysin (a balanced composition of several neurotrophic factors and active peptide fragments) (5mL/kg) significantly induced neuroprotection in SD with CHI. Interestingly, TiO nanowired delivery of α-MSH (100μg), MSCs, and cerebrolysin (2.5mL/kg) induced enhanced neuroprotection with higher levels of α-MSH and BDNF and decreased the TNF-α in SD with CHI. These observations are the first to show that TiO nanowired administration of α-MSH, MSCs and cerebrolysin induces superior neuroprotection following SD in CHI, not reported earlier. The clinical significance of our findings in light of the current literature is discussed.
睡眠剥夺（SD）在参与战斗行动的军事人员中很常见，会导致脑功能障碍。急性或慢性睡眠剥夺期间的军事人员往往容易发生创伤性脑损伤（TBI），这表明脑病理状况可能会进一步恶化。多项证据表明，在TBI和SD中，血浆和大脑中的α-黑素细胞刺激素（α-MSH）和脑源性神经营养因子（BDNF）水平都会降低。因此，外源性补充α-MSH和/或BDNF有可能在合并TBI的SD中诱导神经保护作用。此外，间充质干细胞（MSCs）在TBI中诱导神经保护方面非常重要。我们研究了SD中的震荡性脑损伤（CHI）对脑病理的影响。此外，还在SD和CHI大鼠模型中探索了α-MSH、MSCs和神经营养因子治疗可能的神经保护作用。与单独的相同SD或CHI相比，遭受48小时SD并伴有CHI的大鼠血脑屏障对伊文思蓝和放射性碘的渗漏更高。与单独的SD或CHI相比，SD合并CHI组的脑病理也更加严重，同时血浆和大脑中的α-MSH和BDNF水平显著降低，肿瘤坏死因子-α（TNF-α）水平升高。外源性给予α-MSH（250μg/kg）、MSCs（1×10）和脑蛋白水解物（几种神经营养因子和活性肽片段的平衡组合物）（5mL/kg）可在SD合并CHI中显著诱导神经保护作用。有趣的是，通过TiO纳米线递送α-MSH（100μg）、MSCs和脑蛋白水解物（2.5mL/kg）可增强神经保护作用，使α-MSH和BDNF水平更高，并降低SD合并CHI中的TNF-α。这些观察结果首次表明，通过TiO纳米线给予α-MSH、MSCs和脑蛋白水解物可在CHI的SD后诱导卓越的神经保护作用，这在之前尚未见报道。我们根据当前文献讨论了研究结果的临床意义。
