The Protective Effects of Hydrogen Sulfide New Donor Methyl S -(4-Fluorobenzyl)- N -(3,4,5-Trimethoxybenzoyl)-l-Cysteinate on the Ischemic Stroke

• Published in: Molecules (Basel, Switzerland) Vol. 27; no. 5; p. 1554
• Main Authors: Fan, Jing, Du, Junxi, Zhang, Zhongwei, Shi, Wenjing, Hu, Binyan, Hu, Jiaqin, Xue, Yan, Li, Haipeng, Ji, Wenjin, Zhuang, Jian, Lv, Pengcheng, Cheng, Kui, Chen, Kun
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 25.02.2022; MDPI
• Subjects: 1-Phosphatidylinositol 3-kinase; Acids; AKT protein; Alzheimer's disease; Animals; Antioxidants; Apoptosis; Apoptosis - drug effects; BAX protein; Bcl-2 protein; BIM protein; Caspase-3; Caspase-9; Cysteine - analogs & derivatives; Cysteine - chemistry; Cysteine - pharmacology; Disease Models, Animal; Drug dosages; Endoplasmic reticulum; Endoplasmic Reticulum Stress - drug effects; Gallic acid; H2S new donor; Hydrogen; Hydrogen sulfide; Hydrogen Sulfide - pharmacology; Inflammation; Inhibitors; Injury prevention; Ischemia; ischemia reperfusion; Ischemic Stroke - drug therapy; Ischemic Stroke - metabolism; Ischemic Stroke - pathology; Male; Metabolic pathways; Mitochondria; MTC; Neonates; Nervous system; neuro-ischemic drug candidate; Neurons; Neurons - drug effects; Neurons - metabolism; Neurons - pathology; Neuroprotection; Neuroprotective Agents - chemistry; Neuroprotective Agents - pharmacology; Oxidative stress; Oxidative Stress - drug effects; PC12 Cells; Pheochromocytoma cells; Phosphatidylinositol 3-Kinases - metabolism; Physiology; Potassium channels; Proteins; Proto-Oncogene Proteins c-akt - metabolism; Rats; Rats, Sprague-Dawley; Regeneration; Reperfusion; Reperfusion Injury - drug therapy; Reperfusion Injury - metabolism; Reperfusion Injury - prevention & control; SAC and gallic acid conjugate; Signal transduction; Signal Transduction - drug effects; Survival; ischemia reperfusion; H2S new donor; SAC and gallic acid conjugate; MTC; neuro-ischemic drug candidate
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules27051554

In this paper, we report the design, synthesis and biological evaluation of a novel -allyl-l-cysteine (SAC) and gallic acid conjugate -(4-fluorobenzyl)- -(3,4,5-trimethoxybenzoyl)-l-cysteinate (MTC). We evaluate the effects on ischemia-reperfusion-induced PC12 cells, primary neurons in neonatal rats, and cerebral ischemic neuronal damage in rats, and the results showed that MTC increased SOD, CAT, GPx activity and decreased LDH release. PI3K and p-AKT protein levels were significantly increased by activating PI3K/AKT pathway. Mitochondrial pro-apoptotic proteins Bax and Bim levels were reduced while anti-apoptotic protein Bcl-2 levels were increased. The levels of cleaved caspase-9 and cleaved caspase-3 were also reduced in the plasma. The endoplasmic reticulum stress (ERS) was decreased, which in turns the survival rate of nerve cells was increased, so that the ischemic injury of neurons was protected accordingly. MTC activated the MEK-ERK signaling pathway and promoted axonal regeneration in primary neurons of the neonatal rat. The pretreatment of MEK-ERK pathway inhibitor PD98059 and PI3K/AKT pathway inhibitor LY294002 partially attenuated the protective effect of MTC. Using a MCAO rat model indicated that MTC could reduce cerebral ischemia-reperfusion injury and decrease the expression of proinflammatory factors. The neuroprotective effect of MTC may be due to inhibition of the over-activation of the TREK-1 channel and reduction of the current density of the TREK1 channel. These results suggested that MTC has a protective effect on neuronal injury induced by ischemia reperfusion, so it may have the potential to become a new type of neuro-ischemic drug candidate.