Differential effects of N-acetylcysteine on retinal degeneration in two mouse models of normal tension glaucoma
Differential effects of N-acetylcysteine on retinal degeneration in two mouse models of normal tension glaucoma
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DOI：
10.1038/s41419-019-1365-z
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发表时间：
2019-01-28
影响因子：
9
通讯作者：
Harada, Takayuki
中科院分区：
文献类型：
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作者：
Sano, Hiroki;Namekata, Kazuhiko;Harada, Takayuki
N-乙酰半胱氨酸（NAC）被广泛用作粘液溶解剂和对乙酰氨基酚过量的解毒剂。NAC作为半胱氨酸的前体，刺激神经细胞合成谷胱甘肽。抑制视网膜中的氧化应激可能是青光眼的有效治疗策略，青光眼是视网膜神经节细胞（RGC）和视神经的慢性神经变性疾病。在这里，我们研究了NAC在两种正常眼压性青光眼小鼠模型中的治疗潜力，其中兴奋性氨基酸载体1（EAAC 1）或谷氨酸/天冬氨酸转运体（GLAST）基因被删除。EAAC 1在视网膜神经元包括RGC中表达，而GLAST主要在Muller神经胶质细胞中表达。腹腔内注射NAC可预防EAAC 1缺陷（敲除; KO）小鼠的RGC变性和视力损害，但在GLAST KO小鼠中则不然。在EAAC 1 KO小鼠中，NAC治疗可通过增加谷胱甘肽水平抑制氧化应激和自噬。我们的研究结果表明，NAC的全身管理的可能性，可用于某些类型的青光眼患者。
N-acetylcysteine (NAC) is widely used as a mucolytic agent and as an antidote to paracetamol overdose. NAC serves as a precursor of cysteine and stimulates the synthesis of glutathione in neural cells. Suppressing oxidative stress in the retina may be an effective therapeutic strategy for glaucoma, a chronic neurodegenerative disease of the retinal ganglion cells (RGCs) and optic nerves. Here we examined the therapeutic potential of NAC in two mouse models of normal tension glaucoma, in which excitatory amino-acid carrier 1 (EAAC1) or glutamate/aspartate transporter (GLAST) gene was deleted. EAAC1 is expressed in retinal neurons including RGCs, whereas GLAST is mainly expressed in Muller glial cells. Intraperitoneal administration of NAC prevented RGC degeneration and visual impairment in EAAC1-deficient (knockout; KO) mice, but not in GLAST KO mice. In EAAC1 KO mice, oxidative stress and autophagy were suppressed with increased glutathione levels by NAC treatment. Our findings suggest a possibility that systemic administration of NAC may be available for some types of glaucoma patients.