Chan Su Jing, Chai Chou, Lim Tze Wei, Yamamoto Mie, Lo Eng H, Lai Mitchell Kim Peng, Wong Peter Tsun Hon
Department of Pharmacology, Yong Loo Lin School of Medicine, National University Health System, National University of Singapore, Singapore.
Duke-NUS Graduate Medical School, Singapore.
ASN Neuro. 2015 Apr 13;7(2). doi: 10.1177/1759091415578711. Print 2015 Mar-Apr.
Hydrogen sulfide (H2S) has been reported to exacerbate stroke outcome in experimental models. Cystathionine β-synthase (CBS) has been implicated as the predominant H2S-producing enzyme in central nervous system. When SH-SY5Y cells were transfected to overexpress CBS, these cells were able to synthesize H2S when exposed to high levels of enzyme substrates but not substrate concentrations that may reflect normal physiological conditions. At the same time, these cells demonstrated exacerbated cell death when subjected to oxygen and glucose deprivation (OGD) together with high substrate concentrations, indicating that H2S production has a detrimental effect on cell survival. This effect could be abolished by CBS inhibition. The same effect was observed with primary astrocytes exposed to OGD and high substrates or sodium hydrosulfide. In addition, CBS was upregulated and activated by truncation in primary astrocytes subjected to OGD. When rats were subjected to permanent middle cerebral artery occlusion, CBS activation was also observed. These results imply that in acute ischemic conditions, CBS is upregulated and activated by truncation causing an increased production of H2S, which exacerbate the ischemic injuries. Therefore, CBS inhibition may be a viable approach to stroke treatment.
据报道，在实验模型中，硫化氢（H₂S）会加重中风后果。胱硫醚β-合酶（CBS）被认为是中枢神经系统中主要的H₂S生成酶。当SH-SY5Y细胞被转染以过表达CBS时，这些细胞在暴露于高水平酶底物而非可能反映正常生理条件的底物浓度时能够合成H₂S。同时，当这些细胞在高底物浓度下遭受氧糖剥夺（OGD）时，细胞死亡加剧，这表明H₂S生成对细胞存活具有有害影响。这种作用可通过抑制CBS来消除。在暴露于OGD和高底物或氢硫化钠的原代星形胶质细胞中也观察到了相同的作用。此外，在遭受OGD的原代星形胶质细胞中，CBS通过截短而上调并被激活。当大鼠遭受永久性大脑中动脉闭塞时，也观察到了CBS激活。这些结果表明，在急性缺血条件下，CBS通过截短而上调并被激活，导致H₂S生成增加，从而加重缺血性损伤。因此，抑制CBS可能是一种可行的中风治疗方法。
