Abstract
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.
Highlights
Cerebral infarction, known as ischemic stroke, is a blood supply disorder caused by various reasons such as hypertension, smoking, improper diet, lack of physical exercise, diabetes and excessive drinking
We demonstrated that the PI3K/AKT pathway plays a role in inhibiting apoptosis and promoting cell proliferation
The present study shows that MTC post-treatment reduces the expression of Bim, cleavedcaspase-12, IP3, glucoseregulated protein-78 (GRP78) and C/EBP homologous protein (CHOP) protein levels (Figure 7b,c), and the results are consistent with previous studies
Summary
Known as ischemic stroke, is a blood supply disorder caused by various reasons such as hypertension, smoking, improper diet, lack of physical exercise, diabetes and excessive drinking. It causes ischemic brain damage, and activates a series of cascade reactions in the cell, including various signaling pathways and causes irreversible brain tissue damage [1,2]. The mechanism has not yet been fully elucidated, how to reduce cerebral ischemia/reperfusion injury has become a hot topic in global clinical medicine development. It is of great theoretical and practical significance to investigate the pathology and treatment strategies of cerebral ischemia-reperfusion injury [10]
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