The Role of Necroptosis in Cerebral Ischemic Stroke

Wang, Qingsong; Yang, Fan; Duo, Kun; Liu, Yue; Yu, Jianqiang; Wu, Qihui; Cai, Zhenyu

doi:10.1007/s12035-023-03728-7

Cited by 6 publications

(4 citation statements)

References 136 publications

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“…It is well recognized that no matter what mechanism is responsible for cerebral ischemic injury, death is the destiny for most injured brain cells when subjected to ischemia. Necroptosis, which is caspase-independent cell programmed necrosis, significantly contributes to the negative events that occur with ischemic brain stroke, and its inhibition has been proven to be protective both in vitro and in vivo [21,29,30]. The RIP1-RIP3-MLKL signaling pathway is generally considered to be a marker of cell necroptosis [31].…”

Section: Discussionmentioning

confidence: 99%

Luteolin-7-O-β-d-glucuronide Ameliorates Cerebral Ischemic Injury: Involvement of RIP3/MLKL Signaling Pathway

Fan,

Lin,

Chen

et al. 2024

Molecules

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Luteolin-7-O-β-d-glucuronide (LGU) is a major active flavonoid glycoside compound that is extracted from Ixeris sonchifolia (Bge.) Hance, and it is a Chinese medicinal herb mainly used for the treatment of coronary heart disease, angina pectoris, cerebral infarction, etc. In the present study, the neuroprotective effect of LGU was investigated in an oxygen glucose deprivation (OGD) model and a middle cerebral artery occlusion (MCAO) rat model. In vitro, LGU was found to effectively improve the OGD-induced decrease in neuronal viability and increase in neuronal death by a 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and a lactate dehydrogenase (LDH) leakage rate assay, respectively. LGU was also found to inhibit OGD-induced intracellular Ca2+ overload, adenosine triphosphate (ATP) depletion, and mitochondrial membrane potential (MMP) decrease. By Western blotting analysis, LGU significantly inhibited the OGD-induced increase in expressions of receptor-interacting serine/threonine-protein kinase 3 (RIP3) and mixed lineage kinase domain-like protein (MLKL). Moreover, molecular docking analysis showed that LGU might bind to RIP3 more stably and firmly than the RIP3 inhibitor GSK872. Immunofluorescence combined with confocal laser analyses disclosed that LGU inhibited the aggregation of MLKL to the nucleus. Our results suggest that LGU ameliorates OGD-induced rat primary cortical neuronal injury via the regulation of the RIP3/MLKL signaling pathway in vitro. In vivo, LGU was proven, for the first time, to protect the cerebral ischemia in a rat middle cerebral artery occlusion (MCAO) model, as shown by improved neurological deficit scores, infarction volume rate, and brain water content rate. The present study provides new insights into the therapeutic potential of LGU in cerebral ischemia.

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Section: Discussionmentioning

confidence: 99%

Luteolin-7-O-β-d-glucuronide Ameliorates Cerebral Ischemic Injury: Involvement of RIP3/MLKL Signaling Pathway

Fan,

Lin,

Chen

et al. 2024

Molecules

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“…Autophagy: Activation by AMP-activated protein kinase (AMPK), activation by phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt), inhibition by mammalian target of rapamycin (mTOR), activation by hypoxia-inducible factor (HIF)-1α/BCL2 interacting protein 3 (BNIP3), inhibition by the sequestration of Beclin1 by Bcl2, activation by p53, and inhibition by TIGAR [38] Apoptosis: Both the intrinsic (mitochondrial) and extrinsic (death receptors) pathways are involved [39] Ferroptosis: Iron-dependent accumulation of lipid peroxides and glutathione peroxidase 4 (GPX4) inactivation [22] Pyroptosis: The NLRP3 inflammasome is activated by ROS generated during IRI, thus triggering pyroptosis in brain cells. [40] Necroptosis: Mediated by receptor-interacting serine/threonine protein kinase-1 and -3 and mixed lineage kinase domain-like protein [41] ACSL4: Acyl-CoA synthetase long-chain family member 4; AMPK: AMP-activated protein kinase; Akt: protein kinase B; BBB: blood-brain barrier; BNIP3: BCL2 interacting protein 3; eNOS: endothelial NOS; GPX: glutathione peroxidase; JAK2: Janus kinase 2; HIF: hypoxia-inducible factor; iNOS: induced NOS; LDL: low-density lipoprotein; MMP: matrix metalloproteinase; mTOR: mammalian target of rapamycin; NADPH: nicotinamide adenine dinucleotide phosphate; NCOA4: nuclear receptor coactivator 4; NLRP3: NLR family pyrin domain containing 3; NMDAR: N-methyl-D-aspartate receptor; nNOS: nitric oxide synthase; NO: nitric oxide; Nrf2: nuclear factor erythroid 2-related factor 2; PI3K: phosphatidylinositol-3-kinase; TIGAR: TP53-induced glycolysis and apoptosis regulator; RNS: reactive nitrogen species; ROS: reactive oxygen species; STAT: signal transducer and activator of transcription; VEGF: vascular endothelial growth factor.…”

Section: Blood-brain Barrier (Bbb) Disruptionmentioning

confidence: 99%

Novel Multi-Antioxidant Approach for Ischemic Stroke Therapy Targeting the Role of Oxidative Stress

Briones-Valdivieso,

Briones,

Orellana-Urzúa

et al. 2024

Biomedicines

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Stroke is a major contributor to global mortality and disability. While reperfusion is essential for preventing neuronal death in the penumbra, it also triggers cerebral ischemia-reperfusion injury, a paradoxical injury primarily caused by oxidative stress, inflammation, and blood–brain barrier disruption. An oxidative burst inflicts marked cellular damage, ranging from alterations in mitochondrial function to lipid peroxidation and the activation of intricate signalling pathways that can even lead to cell death. Thus, given the pivotal role of oxidative stress in the mechanisms of cerebral ischemia-reperfusion injury, the reinforcement of the antioxidant defence system has been proposed as a protective approach. Although this strategy has proven to be successful in experimental models, its translation into clinical practice has yielded inconsistent results. However, it should be considered that the availability of numerous antioxidant molecules with a wide range of chemical properties can affect the extent of injury; several groups of antioxidant molecules, including polyphenols, carotenoids, and vitamins, among other antioxidant compounds, can mitigate this damage by intervening in multiple signalling pathways at various stages. Multiple clinical trials have previously been conducted to evaluate these properties using melatonin, acetyl-L-carnitine, chrysanthemum extract, edaravone dexborneol, saffron, coenzyme Q10, and oleoylethanolamide, among other treatments. Therefore, multi-antioxidant therapy emerges as a promising novel therapeutic option due to the potential synergistic effect provided by the simultaneous roles of the individual compounds.

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“…MLKLs then translocate to the plasma membrane, disrupting membrane integrity and cell death [ 35 ]. Necroptosis has been shown to contribute to neuronal death in ischemic stroke [ 36 , 37 , 38 , 39 , 40 ]. Inhibition of necroptosis through RIPK1 pharmacologic and genetic inhibition has been found to reduce neuronal damage and improve functional outcomes in animal models of ischemic stroke [ 41 ].…”

Section: Etiology and Pathophysiology Of Ischemic Strokementioning

confidence: 99%

Understanding the Pathophysiology of Ischemic Stroke: The Basis of Current Therapies and Opportunity for New Ones

Salaudeen,

Bello,

Danraka

et al. 2024

Biomolecules

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The majority of approved therapies for many diseases are developed to target their underlying pathophysiology. Understanding disease pathophysiology has thus proven vital to the successful development of clinically useful medications. Stroke is generally accepted as the leading cause of adult disability globally and ischemic stroke accounts for the most common form of the two main stroke types. Despite its health and socioeconomic burden, there is still minimal availability of effective pharmacological therapies for its treatment. In this review, we take an in-depth look at the etiology and pathophysiology of ischemic stroke, including molecular and cellular changes. This is followed by a highlight of drugs, cellular therapies, and complementary medicines that are approved or undergoing clinical trials for the treatment and management of ischemic stroke. We also identify unexplored potential targets in stroke pathogenesis that can be exploited to increase the pool of effective anti-stroke and neuroprotective agents through de novo drug development and drug repurposing.

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The Role of Necroptosis in Cerebral Ischemic Stroke

Cited by 6 publications

References 136 publications

Luteolin-7-O-β-d-glucuronide Ameliorates Cerebral Ischemic Injury: Involvement of RIP3/MLKL Signaling Pathway

Luteolin-7-O-β-d-glucuronide Ameliorates Cerebral Ischemic Injury: Involvement of RIP3/MLKL Signaling Pathway

Novel Multi-Antioxidant Approach for Ischemic Stroke Therapy Targeting the Role of Oxidative Stress

Understanding the Pathophysiology of Ischemic Stroke: The Basis of Current Therapies and Opportunity for New Ones

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