N-acetyl-L-Cysteine amide (NACA) is a novel antioxidant, the amide form of N-acetylcysteine (NAC), due to its permeability through both cellular and mitochondrial membranes [1]. N-acetylcysteine amide permeates cellular and mitochondrial membranes, crosses the blood-brain barrier [1,2] and has higher radical scavenging ability, metal chelating activity and reducing power than NAC [3].
N-acetyl-L-Cysteine amide protects neurons and dopaminergic cells from oxidative stress in tissue cultures and lipid peroxidation in neuronal cell lines [4,5]. N-acetyl-L-Cysteine amide (750 μM) protected the PC12 cells from glutamate toxicity by slightly decreasing the bleb formation on neurites, and increased the PC12 cell GSH level [5]. N-acetyl-L-Cysteine amide protected PC12 cells against glutamate cytotoxicity by decreasing the glutamate-induced ROS accumulation [5]. N-acetylcysteine amide (1 mM) prevents METH-induced oxidative stress in human brain microvascular endothelial (HBMVEC) cells [6].
In moderate TBI, N-acetyl-L-Cysteine amide treatment improves mitochondrial bioenergetics, cognitive function, cortical tissue sparing and reduces lipid peroxidation product 4-hydroxynonenal compared to NAC or vehicle treated rats [7]. In acute spinal cord injury, N-acetyl-L-Cysteine amide (150 or 300 mg/kg/day) treatment improves mitochondrial bioenergetics, maintains mitochondrial glutathione and improves tissue sparing and hind limb function [8].
参考文献:
[1]. Grinberg L, Fibach E, Amer J, et al. N-acetylcysteine amide, a novel cell-permeating thiol, restores cellular glutathione and protects human red blood cells from oxidative stress[J]. Free Radical Biology and Medicine, 2005, 38(1): 136-145.
[2]. Offen D, Gilgun?\Sherki Y, Barhum Y, et al. A low molecular weight copper chelator crosses the blood-brain barrier and attenuates experimental autoimmune encephalomyelitis[J]. Journal of neurochemistry, 2004, 89(5): 1241-1251.
[3]. Ates B, Abraham L, Ercal N. Antioxidant and free radical scavenging properties of N-acetylcysteine amide (NACA) and comparison with N-acetylcysteine (NAC)[J]. Free radical research, 2008, 42(4): 372-377.
[4]. Bahat?\Stroomza M, Gilgun?\Sherki Y, Offen D, et al. A novel thiol antioxidant that crosses the blood brain barrier protects dopaminergic neurons in experimental models of Parkinson's disease[J]. European Journal of Neuroscience, 2005, 21(3): 637-646.
[5]. Penugonda S, Mare S, Goldstein G, et al. Effects of N-acetylcysteine amide (NACA), a novel thiol antioxidant against glutamate-induced cytotoxicity in neuronal cell line PC12[J]. Brain research, 2005, 1056(2): 132-138.
[6]. Zhang X, Banerjee A, Banks W A, et al. N-Acetylcysteine amide protects against methamphetamine-induced oxidative stress and neurotoxicity in immortalized human brain endothelial cells[J]. Brain research, 2009, 1275: 87-95.
[7]. Pandya J D, Readnower R D, Patel S P, et al. N-acetylcysteine amide confers neuroprotection, improves bioenergetics and behavioral outcome following TBI[J]. Experimental neurology, 2014, 257: 106-113.
[8]. Patel S P, Sullivan P G, Pandya J D, et al. N-acetylcysteine amide preserves mitochondrial bioenergetics and improves functional recovery following spinal trauma[J]. Experimental neurology, 2014, 257: 95-105.
N-乙酰-L-半胱氨酸酰胺 (NACA) 是一种新型抗氧化剂，它是 N-乙酰半胱氨酸 (NAC) 的酰胺形式，因为它可渗透细胞膜和线粒体膜[1] . N-乙酰半胱氨酸酰胺可透过细胞膜和线粒体膜，穿过血脑屏障[1,2]，具有比NAC更高的自由基清除能力、金属螯合活性和还原能力[3]。
N-乙酰-L-半胱氨酸酰胺保护神经元和多巴胺能细胞免受组织培养物中的氧化应激和神经元细胞系中的脂质过氧化 [4,5]。 N-乙酰基-L-半胱氨酸酰胺 (750 μM) 通过略微减少神经突上的气泡形成来保护 PC12 细胞免受谷氨酸毒性，并增加 PC12 细胞 GSH 水平 [5]。 N-乙酰-L-半胱氨酸酰胺通过减少谷氨酸诱导的 ROS 积累来保护 PC12 细胞免受谷氨酸细胞毒性 [5]。 N-乙酰半胱氨酸酰胺 (1 mM) 可防止 METH 诱导的人脑微血管内皮 (HBMVEC) 细胞氧化应激 [6]。
在中度 TBI 中，N-乙酰-L-半胱氨酸酰胺治疗可改善线粒体生物能量学、认知功能、皮质组织保护和减少脂质过氧化产物 4-hydroxynonenal 与 NAC 或载体处理的大鼠相比 [7]。在急性脊髓损伤中，N-乙酰基-L-半胱氨酸酰胺（150 或 300 mg/kg/天）治疗可改善线粒体生物能量学，维持线粒体谷胱甘肽并改善组织保护和后肢功能[8]。
| Cell experiment [1]: | |
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Cell lines |
PC12 cells |
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Preparation Method |
PC12 cells were plated at a density of 25 × 103 cells/well in a 24-well collagen-coated plate for morphological assessment. The plate was divided into five groups in triplicate: (1) control: no glutamate, no N-acetyl-L-Cysteine amide (NACA); (2) Nerve growth factor (NGF) control: NGF (100 ng/ml), no glutamate, no NACA; (3) NACA only: NGF (100 ng/ml), no glutamate, NACA (750 μM); (4) glutamate only: NGF (100 ng/ml), glutamate (10 mM), no NACA; and (5) Glu + NACA: NGF (100 ng/ml), glutamate (10 mM), NACA (750 μM). All wells received 100 ng/ml NGF every other day, except Group I. After 1 week, cells were treated or not (control) with 10 mM glutamate, with or without NACA, for 24 h. Twenty-four hours later, the cells were fixed with 0.5% (v/v) glutaraldehyde in PBS and micropictures were taken. |
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Reaction Conditions |
750 μM for 24 h |
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Applications |
The addition of N-acetyl-L-Cysteine amide protected the PC12 cells from glutamate toxicity by slightly decreasing the bleb formation on neurites. |
| Animal experiment [2]: | |
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Animal models |
Adult male Sprague-Dawley rats |
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Preparation Method |
In order to access tissue sparing following Traumatic brain injury (TBI), rats were randomly divided into three groups: (I.) N-acetyl-L-Cysteine amide (NACA) loaded pump (18.5 mg/kg/hr) and a single 150 mg/kg bolus intraperitoneal (IP) injection of NACA given (30 min post-injury) (II.) N-acetylcysteine (NAC) (18.5 mg/kg/hr) loaded pump and a single 150 mg/kg bolus injection of NAC given IP (30 min post-injury) (III.) Vehicle loaded pump and single vehicle bolus injection given IP (30 min post-injury). Following random distribution of all animals into one of the three previous groups, experimenters were blinded to treatment group. |
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Dosage form |
loaded pump (18.5 mg/kg/hr) and a single 150 mg/kg, IP |
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Applications |
N-acetyl-L-Cysteine amide treatment improved cognitive outcome following TBI as demonstrated by the significant improvements in distance traveled to goal as measured using the Morris Water Maze task. |
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参考文献: [1]: Penugonda S, Mare S, Goldstein G, et al. Effects of N-acetylcysteine amide (NACA), a novel thiol antioxidant against glutamate-induced cytotoxicity in neuronal cell line PC12[J]. Brain research, 2005, 1056(2): 132-138. | |
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