Artemether confers neuroprotection on cerebral ischemic injury through stimulation of the Erk1/2-P90rsk-CREB signaling pathway

Abstract

Ischemic stroke is one of the leading causes of death and disability among adults. Despite the economic burden of the disease, available treatment options are still very limited. With the exception of anti-thrombolytics and hypothermia, current therapies fail to reduce neuronal injury, neurological deficits and mortality rates, suggesting that the development of novel and more effective therapies against ischemic stroke is urgent. In the present study, we found that artemether, which has been used in the clinic as an anti-malarial drug, was able to improve the neurological deficits, attenuate the infarction volume and the brain water content in a middle cerebral artery occlusion (MCAO) animal model. Furthermore, artemether treatment significantly suppressed cell apoptosis, stimulated cell proliferation and promoted the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2), P90 rsk and cAMP responsive element-binding protein (CREB). Artemether protective effect was attenuated by PD98059, an ERK1/2 inhibitor, administration. Similarly, in oxygen-glucose deprivation/reperfusion (OGD/RP) cell models, artemether pre-treatment induced the suppression of the intracellular ROS, the down-regulation of LDH activity, the reduction of caspase 3 activity and of the apoptosis cell rate and reversed the decrease of mitochondrial membrane potential. As with MCAO animal model, artemether promoted the activation of Erk1/2-P90 rsk -CREB signaling pathway. This effect was blocked by the inhibition or knock-down of ERK1/2. The present study provides evidences of the neuroprotective effect of artemether unravelling its potential as a new therapeutic candidate for the prevention and treatment of stroke.

Crocetin antagonizes parthanatos in ischemic stroke via inhibiting NOX2 and preserving mitochondrial hexokinase-I

“…5A, B ), supporting that the early ROS was derived from NOX2 but not mitochondria. To further support the ROS measurements, we detected the level of malondialdehyde (MDA), a lipid peroxidation marker [ 26 ] and glutathione (GSH), a major intracellular antioxidant [ 27 ]. The results showed that crocetin pretreatment not only reduced the MDA levels, but also increased the GSH level (Fig.…”

Aquilariperoxide A, a Sesquiterpene Dimer from Agarwood of Aquilaria sinensis with Dual Antitumor and Antimalarial Effects

“…Natural products bearing a peroxide nucleus have been isolated from Artemisia annua, Rhododendron latoucheae, Emericella nidulans, and Salvia officinalis . They have been proven to have antimalaria, HSV-1 inhibition, and NO inhibitory activities. , Artemisinin, a typical anti-malaria natural agent with the peroxide bridge, has been found to have a broad range of biological properties such as neural protection, antitumor activity, and antiviruses. − Sesquiterpenoids are a type of compound with diverse structures. Oxidation and cyclization are driving forces of structural diversity.…”

Traditional Chinese medicine in treating ischemic stroke by modulating mitochondria: A comprehensive overview of experimental studies

“…Ginsenoside Rd and piperine pretreatment improved mitochondrial energy metabolism after cerebral I/R injury ( Ye et al, 2011 ; Kaushik et al, 2021 ) whereas notoginsenoside R1 and notoginseng leaf triterpene pretreatment improved mitochondrial energy metabolism after OGD/R injury ( Xie et al, 2020 ; Zhu et al, 2021 ; Liu et al, 2022 ). In vivo ( Ye et al, 2011 ; Mukherjee et al, 2019 ; Zhang et al, 2019 ; Huang et al, 2021 ; Kaushik et al, 2021 ) and in vitro ( Li et al, 2017 ; Wu et al, 2017 ; Zhou et al, 2017 ; Huang et al, 2020 ; Xie et al, 2020 ; Li et al, 2021 ; Huang et al, 2021 ; Li et al, 2022b ; Ni et al, 2022 ; Peng et al, 2022 ) studies have reported that TCM compounds (e.g., piperine, ginsenoside Rd, hydroxysafflor yellow A, β-patchoulene, curcumin, ginsenoside Rb1, artemether, notoginseng leaf triterpenes, ginkgolide k, ginsenoside monomer compound k, tanshinone IIA, artemisinin, and kaempferol) inhibited oxidative stress and mPTP and upregulated MMP levels. In vitro studies show that atractylenolide III, ginkgolide K, calenduloside E, and kaempferol decreased Drp1 translocation from the cytosol to the outer mitochondrial membrane, reduced its phosphorylation at Ser616, and enhanced its phosphorylation at Ser637 ( Wu et al, 2017 ; Zhou et al, 2017 ; Zhou et al, 2019 ; Li et al, 2022b ).…”

“…Curcumin could also alleviate OGD injury by improving mitochondrial energy metabolism ( Wang and Xu, 2020 ). Evidence from in vivo studies ( Zhang et al, 2017 ; Zhao et al, 2018b ; Mondal et al, 2019 ; Wang and Xu, 2020 ; Li et al, 2021 ; Cen et al, 2022 ; Mao et al, 2022 ; Peng et al, 2022 ) and in vitro studies ( Feng et al, 2018 ; Liu et al, 2018 ; Chen et al, 2019 ; Xiang et al, 2019 ; Xue et al, 2019 ; Wang and Xu, 2020 ; Wei et al, 2021 ; Ye et al, 2021 ; Mao et al, 2022 ) demonstrated that, following cerebral I/R injury or OGD injury, TCM compounds (e.g., curcumin, bilobalide, artemether, quercetin, artemisinin, tetrahydrocurcumin, rhein, ligustilide, icariside II, hydroxysafflor yellow A, oxymatrine, ginkgolide K, resveratrol, and astragaloside IV) alleviated oxidative stress, inhibited mPTP, and upregulated MMP levels. Mfn-1 and Drp-1 downregulation after cerebral I/R injury was restored by tetrahydrocurcumin treatment ( Mondal et al, 2019 ) whereas Drp-1 downregulation and Opa1 upregulation after OGD injury were restored by hydroxysafflor yellow A treatment ( Chen et al, 2019 ).…”

“…Additionally, picroside II attenuated cerebral I/R injury by inhibiting EndoG release from the mitochondria into the cytoplasm ( Li et al, 2018 ) Similarly, baicalein treatment decreased cerebral I/R injury by inhibiting nuclear translocation of AIF in cerebral I/R rats ( Li et al, 2020 ). Many in vivo ( Zhang et al, 2017 ; Zhao et al, 2018b ; Cheng et al, 2019 ; Yin et al, 2020 ; Li et al, 2021 ; Zhang et al, 2021 ; Li et al, 2022b ; Peng et al, 2022 ) and in vitro ( Zhao et al, 2018a ; Feng et al, 2018 ; Liu et al, 2018 ) studies have shown that TCM compounds (e.g., curcumin, artemether, ferulic acid, artemisinin, rhein, astragaloside IV, l-borneol, calenduloside E, ginkgolide K, dehydrocostus lactone, and icariside II) exert protective effects in MCAO animal models or OGD/R cell models by inhibiting BAX/BCL2, caspase-9, caspase-3, cleaved caspase-3, caspase-8, Cyt-c, Bid, Apaf-1, Bad, and p53 ( Figure 4 ).…”