Protective effects of Dimethyl malonate on neuroinflammation and blood-brain barrier after ischemic stroke

Zhang, Zhen; Lu, Zhaoming; Liu, Chang; Jiang, Man; Li, Xiang; Cui, Kefei; Lü, Hong; Wang, Jianping

doi:10.1097/wnr.0000000000001704

Cited by 6 publications

(8 citation statements)

References 25 publications

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“…Recent data has shown that succinate accumulates in both the human and mouse brain upon ischemia, and that inhibiting its oxidation via delivery of SDH inhibitors before stroke induction 31 or before stroke reperfusion 32 can lead to a dose-dependent decrease in brain injury.…”

Section: Previous Approaches Centred On the Detection Of Metabolic Al...mentioning

confidence: 99%

Integrative transcriptomic and metabolic analyses of the mammalian hibernating brain identifies a key role for succinate dehydrogenase in ischemic tolerance

Bernstock

Willis

Garcia‐Segura

et al. 2023

Preprint

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Ischemic stroke results in a loss of tissue homeostasis and integrity, the underlying pathobiology of which stems primarily from the depletion of cellular energy stores and perturbation of available metabolites1. Hibernation in thirteen-lined ground squirrels (TLGS), Ictidomys tridecemlineatus, provides a natural model of ischemic tolerance as these mammals undergo prolonged periods of critically low cerebral blood flow without evidence of central nervous system (CNS) damage2. Studying the complex interplay of genes and metabolites that unfolds during hibernation may provide novel insights into key regulators of cellular homeostasis during brain ischemia. Herein, we interrogated the molecular profiles of TLGS brains at different time points within the hibernation cycle via RNA sequencing coupled with untargeted metabolomics. We demonstrate that hibernation in TLGS leads to major changes in the expression of genes involved in oxidative phosphorylation and this is correlated with an accumulation of the tricarboxylic acid (TCA) cycle intermediates citrate, cis-aconitate, and α-ketoglutarate-αKG. Integration of the gene expression and metabolomics datasets led to the identification of succinate dehydrogenase (SDH) as the critical enzyme during hibernation, uncovering a break in the TCA cycle at that level. Accordingly, the SDH inhibitor dimethyl malonate (DMM) was able to rescue the effects of hypoxia on human neuronal cells in vitro and in mice subjected to permanent ischemic stroke in vivo. Our findings indicate that studying the regulation of the controlled metabolic depression that occurs in hibernating mammals may lead to novel therapeutic approaches capable of increasing ischemic tolerance in the CNS.

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Section: Previous Approaches Centred On the Detection Of Metabolic Al...mentioning

confidence: 99%

Integrative transcriptomic and metabolic analyses of the mammalian hibernating brain identifies a key role for succinate dehydrogenase in ischemic tolerance

Bernstock

Willis

Garcia‐Segura

et al. 2023

Preprint

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“…6 Dimethyl malonate inhibits accumulation of SI, which prevents rapid oxidization of SI to form mitochondrial reactive oxygen species. Dimethyl malonate has been shown to protect several different tissue beds in the presence of ischemia-reperfusion, including the brain, 23,24 liver, 25 and perhaps most studied, the heart. 22,26,27 Whether DMM can be therapeutic after severe HS is unknown.…”

mentioning

confidence: 99%

Dimethyl malonate slows succinate accumulation and preserves cardiac function in a swine model of hemorrhagic shock

Taghavi

Abdullah

Toraih

et al. 2022

J Trauma Acute Care Surg

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BACKGROUND: Succinate (SI) is a citric acid cycle metabolite that accumulates in tissues during hemorrhagic shock (HS) due to electron transport chain uncoupling. Dimethyl malonate (DMM) is a competitive inhibitor of SI dehydrogenase, which has been shown to reduce SI accumulation and protect against reperfusion injury. Whether DMM can be therapeutic after severe HS is unknown. We hypothesized that DMM would prevent SI buildup during resuscitation (RES) in a swine model of HS, leading to better physiological recovery after RES. METHODS:The carotid arteries of Yorkshire pigs were cannulated with a 5-Fr catheter. After placement of a Swan-Ganz catheter and femoral arterial line, the carotid catheters were opened and the animals were exsanguinated to a mean arterial pressure (MAP) of 45 mm. After 30 minutes in the shock state, the animals were resuscitated to a MAP of 60 mm using lactated ringers. A MAP above 60 mm was maintained throughout RES. One group received 10 mg/kg of DMM (n = 6), while the control received sham injections (n = 6). The primary end-point was SI levels. Secondary end-points included cardiac function and lactate. RESULTS:Succinate levels increased from baseline to the 20-minute RES point in control, while the DMM cohort remained unchanged. The DMM group required less intravenous fluid to maintain a MAP above 60 (450.0 vs. 229.0 mL; p = 0.01). The DMM group had higher pulmonary capillary wedge pressure at the 20-minute and 40-minute RES points. The DMM group had better recovery of cardiac output and index during RES, while the control had no improvement. While lactate levels were similar, DMM may lead to increased ionized calcium levels. DISCUSSION:Dimethyl malonate slows SI accumulation during HS and helps preserve cardiac filling pressures and function during RES. In addition, DMM may protect against depletion of ionized calcium. Dimethyl malonate may have therapeutic potential during HS.

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“…Microglia are important in maintaining brain microenvironment homeostasis, and to a large extent, microglial activation contributes to the inflammatory response in the setting of stroke 27 . Therefore, we stained Iba1 at the peri‐infarction area to explore microglial activation.…”

Section: Resultsmentioning

confidence: 99%

Transplantation of Roxadustat‐preconditioned bone marrow stromal cells improves neurological function recovery through enhancing grafted cell survival in ischemic stroke rats

et al. 2022

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Aims:The therapeutic effect of bone marrow stromal cell (BMSC) transplantation for ischemic stroke is limited by its low survival rate. The purpose of this study was to evaluate whether Roxadustat (FG-4592) pretreatment could promote the survival rate of grafted BMSCs and improve neurological function deficits in ischemia rats.Methods: Oxygen-glucose deprivation (OGD) and permanent middle cerebral artery occlusion (pMCAO) were constructed as stroke models in vitro and in vivo. Flow cytometry analysis and expression of Bax and Bcl-2 were detected to evaluate BMSCs apoptosis. Infarct volume and neurobehavioral score were applied to evaluate functional recovery. Inflammatory cytokine expression, neuronal apoptosis, and microglial M1 polarization were assessed to confirm the enhanced neurological recovery after FG-4592 pretreatment.Results: FG-4592 promoted autophagy level to inhibit OGD-induced apoptosis through HIF-1α/BNIP3 pathway. GFP and Ki67 double staining showed an improved survival rate of BMSCs in the FG-4592 group, whereas infarct volume and neurobehavioral score verified its enhanced neurological recovery activity simultaneously.NeuN and Iba-1 fluorescence staining showed improved neural survival and decreased microglial activation, along with decreased IL-1β, IL-6, and TNFα levels through the TLR-4/NF-kB pathway.Conclusions: FG-4592 pretreated BMSCs improve neurological function recovery after stroke and are likely to be a promising strategy for stroke management.

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Protective effects of Dimethyl malonate on neuroinflammation and blood-brain barrier after ischemic stroke

Cited by 6 publications

References 25 publications

Integrative transcriptomic and metabolic analyses of the mammalian hibernating brain identifies a key role for succinate dehydrogenase in ischemic tolerance

Integrative transcriptomic and metabolic analyses of the mammalian hibernating brain identifies a key role for succinate dehydrogenase in ischemic tolerance

Dimethyl malonate slows succinate accumulation and preserves cardiac function in a swine model of hemorrhagic shock

Transplantation of Roxadustat‐preconditioned bone marrow stromal cells improves neurological function recovery through enhancing grafted cell survival in ischemic stroke rats

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