Stroke: Molecular mechanisms and therapies: Update on recent developments

Shehjar, Faheem; Maktabi, Briana; Rahman, Zainab; Bahader, Ghaith A.; James, Antonisamy William; Naqvi, Ahmed; Mahajan, Reetika; Shah, Zahoor A.

doi:10.1016/j.neuint.2022.105458

Cited by 31 publications

(31 citation statements)

References 196 publications

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“…EPZ‐6438, GSK‐J4, and AKT inhibitor (LY294002) were dissolved in 10% PBS. The rats with confirmed MCAO were randomly divided into the following groups with 6 rats in each group 1 : PBS group treated with vehicle 2 ; EPZ‐6438 group treated with 100 mg/kg EPZ‐6438 which was injected once every 2 days by intraperitoneal injection 3 ; GSK‐J4 group treated with 10 mg/kg GSK‐J4 once every 3 days by intraperitoneal injection; and 4 AKT inhibitor group: the LY294002 (10 mg/kg, intraperitoneal injection) was injected once every 2 days. The treatment lasted for 14 days.…”

Section: Methodsmentioning

confidence: 99%

“…Due to limited therapeutic options, stroke remains among the foremost causes of death worldwide. [1][2][3] Thus, improving our knowledge on the pathogenesis of stroke and uncovering efficient therapeutic targets for this disease is of paramount necessity. Histone modification epigenetics is known to alter brain developmental processes and the cerebral function by controlling the expression and function of important proteins, [4][5][6][7] and are, thus, considered as potential therapeutic targets for diseases of the nervous system.…”

Section: Introductionmentioning

confidence: 99%

“…Due to limited therapeutic options, stroke remains among the foremost causes of death worldwide 1–3 . Thus, improving our knowledge on the pathogenesis of stroke and uncovering efficient therapeutic targets for this disease is of paramount necessity.…”

Section: Introductionmentioning

confidence: 99%

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Histone methyltransferase enzyme enhancer of zeste homolog 2 counteracts ischemic brain injury via H3K27me3‐mediated regulation of PI3K/AKT/mTOR signaling pathway

Chen

Fan

Wu³

et al. 2023

Environmental Toxicology

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BackgroundEpigenetic histone methylation plays a crucial role in cerebral ischemic injury, particularly in the context of ischemic stroke. However, the complete understanding of regulators involved in histone methylation, such as Enhancer of Zeste Homolog 2 (EZH2), along with their functional effects and underlying mechanisms, remains incomplete.MethodsHere, we employed a rat model of MCAO (Middle cerebral artery occlusion) and an OGD (Oxygen‐Glucose Deprivation) model of primary cortical neurons to study the role of EZH2 and H3K27me3 in cerebral ischemia‐reperfusion injury. The infarct volume was measured through TTC staining, while cell apoptosis was detected using TUNEL staining. The mRNA expression levels were quantified through quantitative real‐time polymerase chain reaction (qPCR), whereas protein expressions were evaluated via western blotting and immunofluorescence experiments.ResultsThe expression levels of EZH2 and H3K27me3 were upregulated in OGD; these expression levels were further enhanced by GSK‐J4 but reduced by EPZ‐6438 and AKT inhibitor (LY294002) under OGD conditions. Similar trends were observed for mTOR, AKT, and PI3K while contrasting results were noted for UTX and JMJD3. The phosphorylation levels of mTOR, AKT, and PI3K were activated by OGD, further stimulated by GSK‐J4, but inhibited by EPZ‐6438 and AKT inhibitor. Inhibition of EZH2 or AKT effectively counteracted OGD‐/MCAO‐induced cell apoptosis. Additionally, inhibition of EZH2 or AKT mitigated MCAO‐induced infarct size and neurological deficit in vivo.ConclusionsCollectively, our results demonstrate that EZH2 inhibition exerts a protective effect against ischemic brain injury by modulating the H3K27me3/PI3K/AKT/mTOR signaling pathway. The results provide novel insights into potential therapeutic mechanisms for stroke treatment.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Histone methyltransferase enzyme enhancer of zeste homolog 2 counteracts ischemic brain injury via H3K27me3‐mediated regulation of PI3K/AKT/mTOR signaling pathway

Chen

Fan

Wu³

et al. 2023

Environmental Toxicology

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“…The progression of ischemic stroke pathology is closely connected to dysregulated ROS. The most common ROS are superoxide (O 2 − ), hydrogen peroxide (H 2 O 2 ), hydroxyl radical (HO − ), hypochlorous acid (HOCl − ), nitric oxide (NO), and peroxynitrite (ONOO − ) that are produced by either intracellular responses (mitochondria) or extracellular inflammation [ 3 , 15 ]. The intracellular production of ROS is mainly due to the altered metabolic activity of the mitochondrial respiratory chain, whereas extracellularly it is a result of inflammasome activation and the immune response [ 16 , 17 ].…”

Section: Ros and Oxidative Stress In Strokementioning

confidence: 99%

Reverse Electron Transport at Mitochondrial Complex I in Ischemic Stroke, Aging, and Age-Related Diseases

Chavda

2023

Antioxidants

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Stroke is one of the leading causes of morbidity and mortality worldwide. A main cause of brain damage by stroke is ischemia-reperfusion (IR) injury due to the increased production of reactive oxygen species (ROS) and energy failure caused by changes in mitochondrial metabolism. Ischemia causes a build-up of succinate in tissues and changes in the mitochondrial NADH: ubiquinone oxidoreductase (complex I) activity that promote reverse electron transfer (RET), in which a portion of the electrons derived from succinate are redirected from ubiquinol along complex I to reach the NADH dehydrogenase module of complex I, where matrix NAD+ is converted to NADH and excessive ROS is produced. RET has been shown to play a role in macrophage activation in response to bacterial infection, electron transport chain reorganization in response to changes in the energy supply, and carotid body adaptation to changes in the oxygen levels. In addition to stroke, deregulated RET and RET-generated ROS (RET-ROS) have been implicated in tissue damage during organ transplantation, whereas an RET-induced NAD+/NADH ratio decrease has been implicated in aging, age-related neurodegeneration, and cancer. In this review, we provide a historical account of the roles of ROS and oxidative damage in the pathogenesis of ischemic stroke, summarize the latest developments in our understanding of RET biology and RET-associated pathological conditions, and discuss new ways to target ischemic stroke, cancer, aging, and age-related neurodegenerative diseases by modulating RET.

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“…In the past 3 years, several excellent articles have reviewed pathophysiology of IS and therapeutic medicines for the treatment of IS based on the pathophysiology. 2,[8][9][10][11][12] Regretfully, there are lack of a comprehensive overview to summarize all categories of anti-IS drugs/agents designed and synthesized based on molecular mechanisms of IS pathophysiology by using medicinal chemistry strategies. In this review, we first give a brief presentation of IS pathophysiology and its molecular mechanisms, and special emphasis is then directed to introduce several types of anti-IS drugs and agents (small molecule compounds, natural products, peptides, and others) developed by targeting the molecular mechanisms, including the research and development processes, mechanism of action and application of these drugs/agents.…”

Section: Introductionmentioning

confidence: 99%

Drugs/agents for the treatment of ischemic stroke: Advances and perspectives

Jia,

Jiao,

Wang

et al. 2023

Medicinal Research Reviews

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Ischemic stroke (IS) poses a significant threat to global human health and life. In recent decades, we have witnessed unprecedented progresses against IS, including thrombolysis, thrombectomy, and a few medicines that can assist in reopening the blocked brain vessels or serve as standalone treatments for patients who are not eligible for thrombolysis/thrombectomy therapies. However, the narrow time windows of thrombolysis/thrombectomy, coupled with the risk of hemorrhagic transformation, as well as the lack of highly effective and safe medications, continue to present big challenges in the acute treatment and long‐term recovery of IS. In the past 3 years, several excellent articles have reviewed pathophysiology of IS and therapeutic medicines for the treatment of IS based on the pathophysiology. Regretfully, there is no comprehensive overview to summarize all categories of anti‐IS drugs/agents designed and synthesized based on molecular mechanisms of IS pathophysiology. From medicinal chemistry view of point, this article reviews a multitude of anti‐IS drugs/agents, including small molecule compounds, natural products, peptides, and others, which have been developed based on the molecular mechanism of IS pathophysiology, such as excitotoxicity, oxidative/nitrosative stresses, cell death pathways, and neuroinflammation, and so forth. In addition, several emerging medicines and strategies, including nanomedicines, stem cell therapy and noncoding RNAs, which recently appeared for the treatment of IS, are shortly introduced. Finally, the perspectives on the associated challenges and future directions of anti‐IS drugs/agents are briefly provided to move the field forward.

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Stroke: Molecular mechanisms and therapies: Update on recent developments

Cited by 31 publications

References 196 publications

Histone methyltransferase enzyme enhancer of zeste homolog 2 counteracts ischemic brain injury via H3K27me3‐mediated regulation of PI3K/AKT/mTOR signaling pathway

Histone methyltransferase enzyme enhancer of zeste homolog 2 counteracts ischemic brain injury via H3K27me3‐mediated regulation of PI3K/AKT/mTOR signaling pathway

Reverse Electron Transport at Mitochondrial Complex I in Ischemic Stroke, Aging, and Age-Related Diseases

Drugs/agents for the treatment of ischemic stroke: Advances and perspectives

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