Hydrogen Sulfide Ameliorates Homocysteine-Induced Alzheimer's Disease-Like Pathology, Blood-Brain Barrier Disruption, and Synaptic Disorder.
Hydrogen Sulfide Ameliorates Homocysteine-Induced Alzheimer's Disease-Like Pathology, Blood-Brain Barrier Disruption, and Synaptic Disorder.
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硫化氢可以改善同型半胱氨酸诱导的阿尔茨海默氏病，类似于血脑屏障，血脑屏障破坏和突触障碍。
DOI：
10.1007/s12035-015-9212-4
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发表时间：
2016-05
影响因子：
5.1
通讯作者：
Tyagi N
中科院分区：
文献类型：
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作者：
Kamat PK;Kyles P;Kalani A;Tyagi N
血浆总同型半胱氨酸（Hcy）水平升高与阿尔茨海默病（AD）风险增加有关。在转硫途径中，Hcy被代谢成硫化氢（H2S），硫化氢是一种突触调节剂，也是一种神经保护剂。然而，硫化氢和NMDAR激活在高同型半胱氨酸血症（HHcy）诱导的血脑屏障（BBB）破坏和突触功能障碍中导致AD病理的作用尚不清楚。因此，我们假设H2S和MK801对神经元NMDA-R的抑制作用；减轻hcy诱导的血脑屏障破坏和突触功能障碍，部分通过减少神经元基质降解。Hcy脑内（IC）治疗显著损害脑血流量（CBF）、脑循环和记忆功能。Hcy治疗还降低了脑内CBS和CSE的表达，同时增加了NMDA-R （NR1）和突触体Ca2+的表达，表明兴奋性毒性。此外，我们发现Hcy治疗增加了脑内ICAM-1、MMP-2和MMP-9的蛋白和mRNA表达，也增加了脑内MMP-2、-9的活性。ICAM-1、GFAP表达升高，VE-Cadherin、Claudin-5表达降低，提示血脑屏障破坏和血管炎症。此外，我们还发现海马中MAP-2、PSD-95、SAP-97、SNAP-25、synaptophysin和BDNF的表达下降，显示突触功能障碍。此外，NaHS和MK801治疗可改善小鼠脑血脑屏障破坏、CBF和突触功能。这些结果表明H2S通过NMDA受体对Hcy诱导的脑血管病理具有神经保护作用。我们目前的研究清楚地表明H2S对阿尔茨海默病等脑血管疾病的治疗效果。
Elevated plasma total homocysteine (Hcy) level is associated with an increased risk of Alzheimer's disease (AD). During transsulfuration pathways, Hcy is metabolized into hydrogen sulfide (H2S), which is a synaptic modulator, as well as a neuro-protective agent. However, the role of hydrogen sulfide, as well as NMDAR activation, in hyperhomocysteinemia (HHcy) induced blood-brain barrier (BBB) disruption and synaptic dysfunction, leading to AD pathology is not clear. Therefore, we hypothesized that the inhibition of neuronal NMDA-R by H2S and MK801; mitigate the Hcy-induced BBB disruption and synapse dysfunction, in part by decreasing neuronal matrix degradation. Hcy intracerebral (IC) treatment significantly impaired cerebral blood flow (CBF), and cerebral circulation and memory function. Hcy treatment also decreases the expression of CBS and CSE in the brain along with increased expression of NMDA-R (NR1) and synaptosomal Ca2+ indicating excitotoxicity. Additionally, we found Hcy treatment increased protein and mRNA expression of ICAM-1, MMP-2 and MMP-9 and also increased MMP-2,-9 activity in the brain. The increased expression of ICAM-1, GFAP, and the decreased expression of VE-Cadherin, Claudin-5 indicates BBB disruption and vascular inflammation. Moreover, we also found decreased expression of MAP-2, PSD-95, SAP-97, SNAP-25, synaptophysin, and BDNF showing synapse dysfunction in the hippocampus. Furthermore, NaHS and MK801 treatment ameliorates BBB disruption, CBF, and synapse functions in the mice brain. These results demonstrate a neuro-protective effect of H2S over Hcy induced cerebrovascular pathology through the NMDA receptor. Our present study clearly signifies the therapeutic ramifications of H2S for cerebrovascular diseases such as Alzheimer's disease.