Therapeutic Potential of Novel Twin Compounds Containing Tetramethylpyrazine and Carnitine Substructures in Experimental Ischemic Stroke

Abstract

Although studies have seen dramatic advances in the understanding of the pathogenesis of stroke such as oxidative stress, inflammation, excitotoxicity, calcium overload and apoptosis, the delivery of stroke therapies is still a great challenge. In this study, we designed and synthesized a series of novel twin compounds containing tetramethylpyrazine and carnitine substructures and explored their therapeutic potential and mechanism in stroke-related neuronal injury. We first screened the neuroprotective effects of candidate compounds and found that among the tested compounds, LR134 and LR143 exhibited significant neuroprotection as evidenced by reducing cerebral infarct and edema, improving neurological function as well as blood-brain barrier integrity in rats after cerebral ischemia/reperfusion injury. We further demonstrated that the neuroprotective effects of compounds LR134 and LR143 were associated with the reduced inflammatory responses and NADPH oxidase- (NOX2-) mediated oxidative stress and the protection of mitochondria accompanied by the improvement of energy supply. In summary, this study provides direct evidence showing that the novel twin compounds containing tetramethylpyrazine and carnitine substructures have neuroprotective effects with multiple therapeutic targets, suggesting that modulation of these chemical structures may be an innovative therapeutic strategy for treating patients with stroke.

Tetramethylpyrazine (TMP) protects rats against acute pancreatitis through NF-κB pathway

“…Pharmacologic studies have demonstrated that Tetramethylpyrazine (TMP, also known as Ligustrazine), an intravenous drug made from traditional Chinese herbs, is able to reduce inflammatory responses [39] and activation of apoptosis [40]. It is capable of attenuating the severity of AP and protecting multiple organ injury in rats with AP [41].…”

Mitochondrial MPTP: A Novel Target of Ethnomedicine for Stroke Treatment by Apoptosis Inhibition

“…Considering the short in vivo half-life of tetramethylpyrazine, a novel compound containing tetramethylpyrazine and carnitine structures was synthesized. Further in vivo and in vitro results also confirmed that its anti-hypoxic brain protective effect was related to anti-oxidative stress and anti-inflammatory, ultimately maintaining the morphology and function of neurons and inhibiting neuronal apoptosis (Wang et al, 2017). Of course, there are other natural compounds that antagonize ischemiainfuriated morphological and functional disorders of brain mitochondria by regulating oxidative stress signals such as leonurine (Loh et al, 2010) and neferine .…”

Maresin 1 protects the liver against ischemia/reperfusion injury via the ALXR/Akt signaling pathway

“…Previous studies have demonstrated that pro-resolving lipid mediators such as maresins can protect tissues by suppressing damaging inflammation (Sun et al 2017 ). Therefore, we examined the serum levels of inflammatory cytokines.…”

“…In our study, the level of tissue MDA, a main product of lipid peroxidation, was markedly decreased in the MaR1-treated mouse livers following hepatic I/R insult. The eradication of reactive free radicals is dependent on many different antioxidant enzymes, such as superoxide dismutase (SOD), glutathione peroxidase (GPX) and catalase (CAT), which keep the balance between antioxidative effects and oxidative stress responses (Sun et al 2017 ). Loss of antioxidant enzymes causes accumulation of free radicals, which further exacerbates I/R-induced injury (Han et al 2016 ).…”