Journal
MOLECULES
Volume 27, Issue 5, Pages -Publisher
MDPI
DOI: 10.3390/molecules27051554
Keywords
SAC and gallic acid conjugate; H2S new donor; MTC; ischemia reperfusion; neuro-ischemic drug candidate
Funding
- National Natural Science Foundation of China [2019HD109, 31301116]
- Guangdong Science and Technology Project [2014750, 2017A070701013, 2114050001860]
- Major International Cooperation Projects in Universities in Guangdong Province [2015KGJHZ020]
- Guangzhou Science and Technology Project [20160299, 20200903, 202102010490]
- Foundation for Fostering the Scientific and Technical Innovation of Guangzhou University [20169203]
- key project of production and research of Guangzhou University [20180108, 20181208, RP2021034]
- Guangzhou University Innovation and Entrepreneurship Education Project [31171281]
- [31171281,31301116]
- [2014750,2017A070701013]
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In this paper, the design, synthesis, and biological evaluation of a novel compound MTC were reported. The results showed that MTC had protective effects on ischemia-reperfusion-induced neuronal injury, possibly through modulation of multiple signaling pathways and protein levels.
In this paper, we report the design, synthesis and biological evaluation of a novel S-allyl-l-cysteine (SAC) and gallic acid conjugate S-(4-fluorobenzyl)-N-(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.
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