Treatment with Isorhamnetin Protects the Brain Against Ischemic Injury in Mice

Abstract

Ischemic stroke is a major cause of morbidity and mortality, yet lacks effective neuroprotective treatments. The aim of this work was to investigate whether treatment with isorhamnetin protected the brain against ischemic injury in mice. Experimental stroke mice underwent the filament model of middle cerebral artery occlusion with reperfusion. Treatment with isorhamnetin or vehicle was initiated immediately at the onset of reperfusion. It was found that treatment of experimental stroke mice with isorhamnetin reduced infarct volume and caspase-3 activity (a biomarker of apoptosis), and improved neurological function recovery. Treatment of experimental stroke mice with isorhamnetin attenuated cerebral edema, improved blood-brain barrier function, and upregulated gene expression of tight junction proteins including occludin, ZO-1, and claudin-5. Treatment of experimental stroke mice with isorhamnetin activated Nrf2/HO-1, suppressed iNOS/NO, and led to reduced formation of MDA and 3-NT in ipsilateral cortex. In addition, treatment of experimental stroke mice with isorhamnetin suppressed activity of MPO (a biomarker of neutrophil infiltration) and reduced protein levels of IL-1β, IL-6, and TNF-α in ipsilateral cortex. Furthermore, it was found that treatment of experimental stroke mice with isorhamnetin reduced mRNA and protein expression of NMDA receptor subunit NR1 in ipsilateral cortex. In conclusion, treatment with isorhamnetin protected the brain against ischemic injury in mice. Isorhamnetin could thus be envisaged as a countermeasure for ischemic stroke but remains to be tested in humans.

Critical Role of Nrf2 in Experimental Ischemic Stroke

“…At 24 h after tMCAO, the total (Wang L. et al, 2012; Pang et al, 2016; Wang et al, 2016, 2018; Chumboatong et al, 2017; Janyou et al, 2017) and nuclear (Wicha et al, 2017) Nrf2 proteins were found to be downregulated, and the same was observed with HO1 (Wang L. et al, 2012; Pang et al, 2016; Wang et al, 2016, 2018; Chumboatong et al, 2017; Wicha et al, 2017) and NQO1 (Janyou et al, 2017). On the contrary to above findings, several reports found that no change was detected in the markers above (Wu L. et al, 2013; Zhao et al, 2016;Wu G. et al, 2017; Zhang W. et al, 2018).…”

“…Besides the candidate Nrf2 inducers above, many natural products, synthetic compounds and clinical drugs, such as ginkgo biloba (Tulsulkar and Shah, 2013), paeonol (Zhao et al, 2014), isoquercetin (Chen M. et al, 2017), tanshinone IIA (Cai et al, 2017), ursolic acid (Li et al, 2013), isorhamnetin (Zhao et al, 2016), docosahexaenoic acid (Chang et al, 2013), HP-1c (Wang et al, 2018), gastrodin (Peng et al, 2015), trichostatin A (Wang B. et al, 2012), bicyclol (Zhang J. et al, 2014), recombinant human erythropoietin (Meng et al, 2014), omega-3 fatty acids (Zhang M. et al, 2014), Tocovid (Shang et al, 2018), estradiol (Li et al, 2017), and more, have also been shown to benefit ischemic brain injury through mechanisms involving Nrf2.…”

Neuroprotective Potential of Secondary Metabolites from Melicope lunu-ankenda (Rutaceae)

“…In a study conducted on experimental stroke-induced mice to investigate the neuroprotective effects of this flavonoid, it was found that isorhamnetin at 5 mg/kg improved the blood brain barrier (BBB) function, upregulated Nrf2/HO-1, downregulated NR1, reduced oxidative stress, inflammation, cerebral edema, NO production and suppressed iNOS (Figure 4). This study also revealed that isorhamnetin protected the brain against ischemic injury in mice [46] (Table 1).…”

Salidroside attenuates hypoxia/reoxygenation‑induced human brain vascular smooth muscle cell injury by activating the SIRT1/FOXO3α pathway

“…Cerebral I/R-induced cytotoxicity and apoptosis serve a pivotal role in brain injury caused by I/R, in which apoptosis greatly contributes to the cell death that occurs following cerebral I/R injury ( 28 ). Caspase-3 has been identified as a pivotal mediator of apoptosis and previous studies have determined that the activity and expression of caspase-3 are upregulated in in vivo and in vitro models of ischemic stroke ( 29 – 31 ). Consistent with the above studies, the present study demonstrated that H/R-treated HBVSMCs, an appropriate and reproducible in vitro cell model of cerebral I/R injury, exhibited improved mimicking of the pathological conditions of I/R injury, including a decrease in cell viability and increases in caspase-3 activity and the cellular apoptosis rate.…”