Chinese Herbal Preparation SaiLuoTong Alleviates Brain Ischemia Via Nrf2 Antioxidation Pathway Dependent Cerebral Microvascular Protection

Abstract

Background: Stroke is one of the most devastating diseases worldwide. Chinese herbal preparation SaiLuoTong capsule (SLT) showed outstanding therapeutic effects over stroke and its sequelae. This study is to elucidate the mechanism. Methods: We duplicated cerebral ischemia model in rats by permanent MCAO, and simulated ischemia injury in cultured hCMEC/D3 cells with oxygen and glucose deprivation/reoxia (OGD/R); we treated them with SLT. Brain infarction volumes and micromorphology were examined with TTC and HE stainings, respectively; neurological function injuries were valued with deficits scoring; brain water contents were measured with the wet-dry method; and expressions of claudin-1, occludin, Nrf2 and HO-1 were examined with western blot assay and immunohistochemstry or immunocytofluorescnce stainings; activities of SOD and contents of GSH were measured by colorimetric method; cell viabilities were measured by CCK8 method; cell monolayer permeabilities were assessed by FITC-dextran diffusion method. Results: SLT (33 mg/kg) significantly decreased infarction volumes, relieved neuron degenerations and neuron loss, and ameliorated neurological functions; SLT also significantly inhibited elevations in brain water content and decreases of claudin-1 and occludin expressions; additionally SLT significantly increased the nucleus translocation of Nrf2, elevated expression of HO-1, and raised activity of SOD and content of GSH (p<0.05 or 0.01, compared with the model group, in quantitative data). These testified SLT’s anti-stroke effect, and hint the possible key role of cerebral blood vascular endothelial cells (CBVEC) protection and Nrf2 pathway in SLT’s therapy. In hCMEC/D3 cells, SLT significantly inhibited the drop in cell viabilities; SLT also significantly facilitated the nucleus translocation of Nrf2, and increased the expression of HO-1, the activity of SOD, and the content of GSH (in comparison to the model group, p<0.05 or 0.01). Lastly, the anti-OGD/R effects of SLT in hCMEC/D3 cells, including raising cell viabilities, inhibiting the elevation in cell monolayer permeabilities, and preserving the expressions of claudin-1 and occludin, were all abolished by Nrf2 siRNA interference. These undoubtedly confirmed SLT’s protective effect on CBVEC and the obligatory role of Nrf2 pathway in it. Conclusion: SLT’s therapeutic effect on brain ischemia is related to its protection on CBVEC, which is dependent on the activation of Nrf2 pathway.

Crocins for Ischemic Stroke: A Review of Current Evidence

“…Another study found that pretreatment with CR followed by I/R (2 h hypoxia, 4 h reoxygenation) protected myocardial ischemic injury and regulated autophagy AMP-activated protein kinase (AMPK) mechanistic pathway (Zeng et al, 2016). Fan et al (2021) showed CR protected myocardial mitochondria injury and acute myocardial infarction in rats (Leijiao Fan, 2021b). CR (15 and 30 mg/kg) significantly attenuated mitochondrial damage by increasing the membrane potential and reducing the mitochondrial permeability transition pore openness.…”

“…Due to the limitations of the aforementioned therapies, there have been continuing efforts to discover, develop, research, and implement new therapies for IS (Marquez-Romero et al, 2020;Williams et al, 2020). A number of natural ingredients and traditional herbal medicines have been investigated as potential therapies for IS, including ginsenoside Rg1 and Rb1 (Gao, Bai et al, 2020), Naoxinqing (NXQ) (Bei et al, 2004), Buyang Huanwu Decoction (Hao et al, 2012), saffron (SF) (Sharma et al, 2020) and related formulas including Naodesheng (Sugawara and Chan, 2003;Hao et al, 2015), Weinaokang (Zhang et al, 2010), also known as Sailoutong (SLT) (Fan et al, 2021). SLT is a standardized combination of SF that has been shown to be effective for vascular dementia in Phase I and Phase II clinical trials and is currently under the phase III trial for vascular dementia (Chang et al, 2016;Jia et al, 2018;Steiner et al, 2018).…”

“…SLT is a standardized combination of SF that has been shown to be effective for vascular dementia in Phase I and Phase II clinical trials and is currently under the phase III trial for vascular dementia (Chang et al, 2016;Jia et al, 2018;Steiner et al, 2018). NXQ and SLT have shown vigorous antioxidant activity that may play a role in their neuroprotective effects (Bei et al, 2004;Bei et al, 2009;Fan et al, 2021). Ginsenoside Rg1 was demonstrated with a protective effect in animal models against ischemia/reperfusion (I/R) induced injuries (Xie et al, 2015b;Chen et al, 2019;Gao et al, 2020) possibly via alleviating blood-brain barrier (BBB) disruption (Zhou et al, 2014), downregulating inflammatory mediators (Zheng et al, 2019) and ameliorating protease-activated receptor-1 expression (Xie et al, 2015a).…”