南京总医院神经外科庄宗等最近研究发现，氢气对蛛网膜下腔出血早期脑损伤有保护作用，该作用和核因子 - κ B 的活性存在一定联系。该研究论文最近在线发表在《神经科学研究杂志》。 氢气的生物学效应最早是通过脑缺血动物模型发现的，中风可大体上分为出血性和缺血性两类，其中脑出血可根据出血部位再分为蛛网膜下腔出血和脑实质出血两类，在各类中风患者中，脑出血的发病率相对比较低，但死亡率远远高于脑缺血。由于研究手段特别是动物模型等方面的限制，国际上研究脑出血特别是蛛网膜下腔出血的小组并不多，中国的浙江大学、南京大学和北京大学等几家单位具备相关技术，浙江大学和南京大学先后发表氢气对蛛网膜下腔出血治疗的国际论文 3 篇，浙江大学获得相关国家自然科学基金 1 项。国外从事氢气对脑出血治疗研究的机构只有美国 Loma Linda 大学，发表相关论文 6 篇，他们主要开展脑实质出血模型的研究。最新的一篇论文重点探讨了氢气对脑内肥大细胞的影响，该思路来源于日本学者关于皮肤过敏方面的研究，脑内肥大细胞在出血后 6 小时达到高峰，研究发现氢气可以对肥大细胞浸润有很明显的抑制作用，可以部分解释氢气对脑出血治疗作用的机制。 蛛网膜下腔出血早期脑损伤，以及随后导致的神经细胞凋亡是导致患者预后不良的一个重要因素。最近研究发现，氢气的神经保护效应被广泛研究，但分子机制仍难以确定。许多研究表明核因子 - κ B （ NF- κ B ）对神经元的生存发挥关键作用。本研究探讨氢气对蛛网膜下腔出血早期脑损伤的保护作用，重点关注 NF- κ B 信号通路。采用双注血蛛网膜下腔出血动物模型，腹腔注射氢气饱和生理盐水作为给氢气的途径，通过对枕叶皮质脑组织免疫荧光法测定 NF- κ B 活性、 Western 测定 Bcl-xL 和裂解的 caspase-3 含量，实时 PCR 检测 Bcl-xL 的基因表达水平， TUNEL 和尼氏染色检测枕叶皮质损伤程度。结果发现，蛛网膜下腔出血可诱导裂解的 caspase-3 显着增加，同时 TUNEL 阳性细胞明显增加（如果和 caspase-3 双标记则可区分细胞坏死和凋亡）；氢气治疗可显著增加 NF- κ B 活性和 Bcl-xL 的表达。减少神经细胞凋亡。研究结果提示，氢气可减轻动物蛛网膜下腔出血早期脑损伤，该作用和 NF- κ B/Bcl-xL 信号途径有关。 氢气对脑出血治疗研究相关文献 1. Zhuang, Zong, et al. Nuclear factor‐κB/Bcl‐XL pathway is involved in the protective effect of hydrogen‐rich saline on the brain following experimental subarachnoid hemorrhage in rabbits. Journal of Neuroscience Research (2013). 2. Manaenko A, Lekic T, Ma Q, Zhang JH, Tang J. Hydrogen inhalation ameliorated mast cell-mediated brain injury after intracerebral hemorrhage in mice. Crit Care Med. 2013 May;41(5):1266-75. 3. Hong Y, Guo S, Chen S, Sun C, Zhang J, Sun X. Beneficial effect of hydrogen-rich saline on cerebral vasospasm after experimental subarachnoid hemorrhage in rats. J Neurosci Res. 2012 Aug;90(8):1670-80. 4. Zhuang Z, Zhou ML, You WC, Zhu L, Ma CY, Sun XJ, Shi JX. Hydrogen-rich saline alleviates early brain injury via reducing oxidative stress and brain edema following experimental subarachnoid hemorrhage in rabbits. BMC Neurosci. 2012 May 15;13:47. 5. Zhan Y, Chen C, Suzuki H, Hu Q, Zhi X, Zhang JH. Hydrogen gas ameliorates oxidative stress in early brain injury after subarachnoid hemorrhage in rats. Crit Care Med. 2012 Apr;40(4):1291-6. 6. Lekic T, Manaenko A, Rolland W, Fathali N, Peterson M, Tang J, Zhang JH. Protective effect of hydrogen gas therapy after germinal matrix hemorrhage in neonatal rats. Acta Neurochir Suppl. 2011;111:237-41. 7. Manaenko A, Lekic T, Ma Q, Ostrowski RP, Zhang JH, Tang J. Hydrogen inhalation is neuroprotective and improves functional outcomes in mice after intracerebral hemorrhage. Acta Neurochir Suppl. 2011;111:179-83. 8. Chen CH, Manaenko A, Zhan Y, Liu WW, Ostrowki RP, Tang J, Zhang JH. Hydrogen gas reduced acute hyperglycemia-enhanced hemorrhagic transformation in a focal ischemia rat model. Neuroscience. 2010;169(1):402-14. rich saline on the brain following experimental subarachnoid hemorrhage in rabbits.pdf
中风有三种类型，脑血管血栓或拴塞引起的脑梗死是脑组织缺血性病变；脑组织内血管出血的脑出血性改变；脑表面血管破裂引起的蛛网膜下腔出血。在这些类型中，缺血的发病率最高，但死亡率比较低，脑出血和蛛网膜下腔出血发病率比较低，但死亡率非常高。过去学术界对脑缺血的研究比较多，现在对脑出血和蛛网膜下腔出血的研究也逐渐增多。 蛛网膜下腔出血 ( 英文： Subarachnoid hemorrhage, SAH) ，是多种病因所致脑底部或脑及脊髓表面血管破裂的急性出血性脑血管病，血液直接流入蛛网膜下腔，又称为原发性蛛网膜下腔出血。常见的病因是脑动脉畸形、动脉瘤、血液疾病等。此外，危急临床还可见因脑实质内，脑室出血，硬膜外或硬膜下血管破裂等血液穿破脑组织流入蛛网膜下腔者，称之为继发性蛛网膜下腔出血，又有外伤性蛛网膜下腔出血。蛛网膜下腔出血约占急性脑卒中的 10% ，占出血性脑卒中的 20% 。凡能引起脑出血的病因也能引起本病，但以颅内动脉瘤、动静脉畸形、高血压动脉硬化症、脑底异常血管网（ moya-moya 病）和血液病等为最常见。多在情绪激动或过度用力时发病。动脉瘤好发于脑底动脉环的大动脉分支处，以该环的前半部较多见。动静脉畸形多位于大脑半球大脑中动脉分布区。 在氢气和中风关系的研究中，对脑缺血的研究已经非常多，对脑出血的研究相对比较少，不过对蛛网膜下腔出血的研究目前已经有 3 篇文章报道。其中一篇来自美国，是呼吸氢气对早期脑损伤的效果研究，另一篇来自南京大学，是关于神经细胞凋亡的研究。这里又有一来自浙江大学附属医院神经外科的文章，是关于蛛网膜下腔出血后血管痉挛的效果观察。 脑出血特别是蛛网膜下腔出血后，血管痉挛也是临床上非常棘手的问题。其原因并不十分清楚，当血管破裂血流入脑蛛网膜下腔后，颅腔内容物增加，压力增高，并继发脑血管痉挛。一般认为，血管痉挛系因出血后血凝块和围绕血管壁的纤维索之牵引（机械因素），血管壁平滑肌细胞间形成的神经肌肉接头产生广泛缺血性损害和水肿。由于血管痉挛可以导致继发性脑组织缺血，加重病情，因此研究蛛网膜下腔出血不得不关注这个重要问题。本研究证明，氢气生理盐水注射可以减少血管痉挛的发生。 Beneficial effect of hydrogen-rich saline on cerebral vasospasm after experimental subarachnoid hemorrhage in rats Yuan Hong1,†, Songxue Guo1,†, Sheng Chen Abstract Cerebral vasospasm (CV) remains a common and devastating complication in patients with subarachnoid hemorrhage (SAH). Despite its clinical significance and extensive research, the underlying pathogenesis and therapeutic perspectives of CV remain incompletely understood. Recently, it has been suggested that molecular hydrogen (H2) can selectively reduce levels of hydroxyl radicals (·OH) and ameliorate oxidative and inflammatory injuries to organs in many models. However, whether H2 can ameliorate CV after SAH is still unknown. This study was designed to evaluate the efficacy of H2 in preventing SAH-induced CV. Experimental SAH was induced in Sprague-Dawley rats using cisterna magna blood injection. Hydrogen-rich saline (HS) was injected intraperitoneally (5 ml/kg) immediately and at 24 hr after injury. All rats were sacrificed 48 hr after the neurological examination scores had been recorded following SAH. Levels of oxidative stress and inflammation were evaluated. Basilar artery vasospasm was assessed by histological examination using light and transmission electron microscopy. HS treatment significantly improved neurological outcomes and attenuated morphological vasospasm of the basilar artery after SAH. In addition, we found that the beneficial effects of HS treatment on SAH-induced CV were associated with decreased levels of lipid peroxidation, increased activity of antioxidant enzymes, and reduced levels of proinflammatory cytokines in the basilar artery. These results indicate that H2 has the potential to be a novel therapeutic strategy for the treatment of CV after SAH, and its neuroprotective effect might be partially mediated via limitation of vascular inflammation and oxidative stress. 2012 Wiley Periodicals, Inc.
Hydrogen gas ameliorates oxidative stress in early brain injury after subarachno.pdf 蛛网膜下腔出血是脑血管病的一种，由于该疾病的模型制备相对困难，特别是病情稳定的模型，因此关于该疾病的研究比较少。从疾病的发病机制角度，该疾病和一般急性损伤存在类似的机制，例如炎症和缺血，因此氧化损伤也是重要的继发性损伤因素，采用抗氧化物质对抗蛛网膜下腔出血后脑损伤也是该领域的一个重要方向。 由于氢气的抗氧化作用有特殊的优点，本研究尝试早期呼吸氢气，并通过观察神经功能、脑水肿、血脑屏障破坏、神经细胞凋亡、不同细胞类型氧化损伤指标等，最终证明呼吸氢气对神经细胞和内皮细胞氧化损伤具有针对性保护作用，对血脑屏障破坏、神经细胞凋亡有显著改善作用。研究表明，氢气对蛛网膜下腔出血引起的脑损伤具有保护作用。并提示氢气反复使用可能对该疾病引起的慢性损伤具有可能的保护作用。该文章来自美国 LLU ，该实验室长期从事各类急性神经损伤的基础研究，在国际上有很大影响。该实验室最近几年关于氢气在神经损伤中效果的研究很有特色，已经发表相关论文 10 余篇。 这个文章仍属于典型的描述性研究，但发表的这个杂志上仍是非常不错的，至少在中风类疾病的基础研究上应该属于比较好的杂志。 蛛网膜下腔出血 ( 英文： Subarachnoid hemorrhage, SAH), 病名，是指蛛网膜下腔中出血的现象。常见的病因是脑动脉畸形，动脉瘤，血液疾病等。蛛网膜下腔出血是多种病因所致脑底部或脑及脊髓表面血管破裂的急性出血性脑血管病，血液直接这样流入蛛网膜下腔，又称为原发性蛛网膜下腔出血，此外，危急临床还可见因脑实质内，脑室出血，硬膜外或硬膜下血管破裂等血液穿破脑组织流入蛛网膜下腔者，称之为继发性蛛网膜下腔出血，又有外伤性，蛛网膜下腔出血约占急性脑卒中的 10% ，占出血性脑卒中的 20% 。 当血管破裂血流入脑蛛网膜下腔后，颅腔内容物增加，压力增高，并继发脑血管痉挛。后者系因出血后血凝块和围绕血管壁的纤维索之牵引（机械因素），血管壁平滑肌细胞间形成的神经肌肉接头产生广泛缺血性损害和水肿。另外大量积血或凝血块沉积于颅底，部分凝集的红细胞还可堵塞蛛网膜绒毛间的小沟，使脑脊液的回吸收被阻，因而可发生急性交通性脑积水，使颅内压急骤升高，进一步减少了脑血流量，加重了脑水肿，甚至导致脑疝形成。以上均可使患者病情稳定好转后，再次出现意识障碍或出现局限性神经症状。 血液进入蛛网膜下腔后、血染脑脊液可激惹对血管、脑膜和神经根等脑组织，引起 无菌性脑膜炎反应 。脑表面常有薄层凝块掩盖，其中有时可找到破裂的动脉瘤或血管。随时间推移，大量红细胞开始溶解，释放出含铁血黄素，使软脑膜呈现锈色并有不同程度的粘连。如脑沟中的红细胞溶解，蛛网膜绒毛细胞间小沟再开通，则脑脊液的回吸收可以恢复。 Hydrogen gas ameliorates oxidative stress in early brain injury after subarachnoid hemorrhage in rats. Crit Care Med. 2012 Feb 14. Zhan Y, Chen C, Suzuki H, Hu Q, Zhi X, Zhang JH. SourceDepartments of Neurosurgery, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China Departments of Neurology, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China Departments of Physiology and Pharmacology, Loma Linda University, Loma Linda, CA. Abstract OBJECTIVE: Hydrogen gas has been demonstrated to neutralize free radicals and reduce oxidative stress recently. Our objective was to determine the therapeutic effect of H2 inhalation and its antioxidative activity on early brain injury after subarachnoid hemorrhage. DESIGN: Controlled in vivo laboratory study. SETTING: Animal research laboratory. SUBJECTS: One hundred thirty-seven adult male Sprague-Dawley rats weighing 280-350 g. INTERVENTIONS: Subarachnoid hemorrhage was induced by endovascular perforation method in rats. Subarachnoid hemorrhage rats were treated with 2.9% hydrogen gas inhaled for 2 hrs after perforation. At 24 and 72 hrs, mortality, body weight, neurologic deficits, and brain water content were assessed. Blood-brain barrier permeability and apoptosis were also measured at 24 hrs. To investigate the antioxidative activity of hydrogen gas, the expression of malondialdehyde, nitrotyrosine, and 8-hydroxyguanosine, which are oxidative markers of lipid, protein, and DNA damage, respectively, were measured at 24 hrs. MEASUREMENTS AND MAIN RESULTS: Hydrogen gas significantly alleviated brain edema and blood-brain barrier disruption, reduced apoptosis, and improved neurologic function at 24 hrs but not 72 hrs after subarachnoid hemorrhage. These effects were associated with the amelioration of oxidative injury of lipid, protein, and DNA. CONCLUSIONS: Hydrogen gas could exert its neuroprotective effect against early brain injury after subarachnoid hemorrhage by its antioxidative activity.
标签: 蛛网膜
