Ryanodine receptor inhibitor dantrolene reduces hypoxic-ischemic brain injury in neonatal mice

Ovcjak, Andrea; Xiao, Aiping; Kim, Jisun; Xu, Baofeng; Szeto, Vivian; Turlova, Ekaterina; Abussaud, Ahmed; Chen, Nai‐Hong; Miller, Steven P.; Sun, Hong‐Shuo; Feng, Zhong‐Ping

doi:10.1016/j.expneurol.2022.113985

Cited by 9 publications

(3 citation statements)

References 102 publications

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“…The inositol trisphosphate receptor (IP 3 R) and ryanodine receptor (RyR) are major calcium release channels in the endoplasmic reticulum and are essential in the regulation of calcium homeostasis [ 15 ]. The voltage-gated calcium channel blockers as well as the endoplasmic reticulum calcium channel blockers, 2-aminoethoxydiphenyl borate (2-APB), and thapsigargin (TG) have yielded beneficial results in basic studies [ 16 – 18 ]. However, an early clinical study found that nimodipine, an L-type calcium channel blocker, showed no benefit in TBI patients, adding confusion to the mechanism of calcium influx mediated neuronal damage [ 19 ].…”

Section: Introductionmentioning

confidence: 99%

NS1619 Alleviate Brain-Derived Extracellular Vesicle-Induced Brain Injury by Regulating BKca Channel and Nrf2/HO-1/NF-ĸB Pathway

Gao

Zhang

et al. 2022

Oxidative Medicine and Cellular Longevity

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Brain induced extracellular vesicle (BDEV) elevates after traumatic brain injury (TBI) and contributes to secondary brain injury. However, the role of BDEV in TBI remains unclear. In this study, we determined the mechanisms of BDEV in brain injury and explored whether neuroprotective drug BKca channel opener NS1619 may attenuate BDEV-induced brain injury. We injected BDEV and lactadherin, respectively, to mimic the up and downregulation of BDEV after TBI and illustrated the role of BDEV in vivo. In vitro, the membrane potential and calcium concentration of HT-22, bEnd3, and BV-2 were measured by fluorescent staining. The effects of BDEV and NS1619 on HT-22 were evaluated by CCK-8, LDH release assay, Na+/k+-ATPase activity, JC-1 staining, DHE staining, and 4-HNE staining, respectively. The role of BDEV and NS1619 on the Nrf2/HO-1/p65 pathway was also evaluated in HT-22. Finally, we administrated TBI mice with NS1619 to clarify the role of NS1619 against BDEV in vivo. Our results suggested that BDEV aggravated and lactadherin mitigated TBI-induced EB leakage, brain edema, neuronal degeneration, apoptosis, ROS level, microgliosis, MMP-9 activity, and NF-κB activation. In vitro, BDEV-caused depolarized membrane potential and calcium overload were significantly attenuated by NS1619 in HT-22, bEnd3, and BV-2. BDEV markedly decreased cell viability, Na+/k+-ATPase activity, and caused mitochondrial dysregulation, oxidative stress, and NF-ĸB activation. NS1619 pretreatment alleviated above process and enhanced antioxidant system Nrf2/HO-1 in HT-22. Finally, NS1619 administration significantly inhibited neuroinflammation response and improved TBI outcome after TBI. NS1619 treatment also reduced 4-HNE content and NF-ĸB activation and enhanced Nrf2/HO-1 pathway. Our data showed that BDEV aggravated brain injury by perturbing cell membrane potential, calcium homeostasis, oxidative stress, and neuroinflammation. The BKca channel opener NS1619 attenuated BDEV-induced pathological process in vitro and in vivo by modulating the BKca channel and Nrf2/HO-1/NF-ĸB pathway.

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Section: Introductionmentioning

confidence: 99%

NS1619 Alleviate Brain-Derived Extracellular Vesicle-Induced Brain Injury by Regulating BKca Channel and Nrf2/HO-1/NF-ĸB Pathway

Gao

Zhang

et al. 2022

Oxidative Medicine and Cellular Longevity

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“…Ischemia-induced axonal degeneration of the spinal cord is also attributed to increased calcium release from ER-mediated by the RyR [ 93 ], which was proved in the model of VH neuronal injury in rats, and it is proposed that inhibition of RyRs for attenuating glutamate excitotoxicity induced by the CICR mechanism is a novel targeting strategy [ 94 ]. Recent studies show that the application of RyR antagonist dantrolene in the HI model of mice and the OGD model of the cortical neuron can reduce brain injury and nerve cell death [ 95 ]. Interestingly, in another study in vivo and in vitro, although the RyR itself decreased during ischemic precondition (PC), administration of dantrolene confronted ischemic tolerance (IT) induced by PC in a dose-dependent manner [ 96 ].…”

Section: Excessive Synaptic or Extra-synaptic Glutamate Release Resul...mentioning

confidence: 99%

Excitatory Synaptic Transmission in Ischemic Stroke: A New Outlet for Classical Neuroprotective Strategies

Fan

Xie

Xing

et al. 2022

IJMS

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Stroke is one of the leading causes of death and disability in the world, of which ischemia accounts for the majority. There is growing evidence of changes in synaptic connections and neural network functions in the brain of stroke patients. Currently, the studies on these neurobiological alterations mainly focus on the principle of glutamate excitotoxicity, and the corresponding neuroprotective strategies are limited to blocking the overactivation of ionic glutamate receptors. Nevertheless, it is disappointing that these treatments often fail because of the unspecificity and serious side effects of the tested drugs in clinical trials. Thus, in the prevention and treatment of stroke, finding and developing new targets of neuroprotective intervention is still the focus and goal of research in this field. In this review, we focus on the whole processes of glutamatergic synaptic transmission and highlight the pathological changes underlying each link to help develop potential therapeutic strategies for ischemic brain damage. These strategies include: (1) controlling the synaptic or extra-synaptic release of glutamate, (2) selectively blocking the action of the glutamate receptor NMDAR subunit, (3) increasing glutamate metabolism, and reuptake in the brain and blood, and (4) regulating the glutamate system by GABA receptors and the microbiota–gut–brain axis. Based on these latest findings, it is expected to promote a substantial understanding of the complex glutamate signal transduction mechanism, thereby providing excellent neuroprotection research direction for human ischemic stroke (IS).

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“…Many studies have been carried on the occurrence, progress, regulation, and other mechanisms of hypoxic-ischemic brain damage (4,5). The main pathophysiological changes are necrosis of nerve cells in the acute phase and apoptosis of nerve cells after reperfusion injury, mainly involving mitochondrial injury and endoplasmic reticulum (ER) stress, production of free radicals, inflammation, and immune response (6)(7)(8)(9). Although researchers are continuing to explore the treatment strategy for HIE, it has been found that 40-50% of children who receive treatment for HIE die or experience adverse sequelae of the nervous system, such as cerebral palsy, visual and auditory impairment, epilepsy, developmental retardation, autism, and so on (10)(11)(12).…”

Section: Introductionmentioning

confidence: 99%

The protective effect of MiR-27a on the neonatal hypoxic-ischemic encephalopathy by targeting FOXO1 in rats

Cai¹,

Zhang²,

Shen³

et al. 2022

Transl Pediatr

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Background: Neonatal hypoxic-ischemic encephalopathy (HIE), a kind of hypoxic-ischemic brain damage caused by perinatal asphyxia, is the most crucial cause of neonatal death and long-term neurological dysfunction in children. We aimed to investigate the protective effects of micro (mi)R-27a on HIE in neonatal rats.Methods: A rat model of neonatal HIE was constructed by modification of the Rice-Vannucci model.Real-time quantitative polymerase chain reaction (RT-qPCR) was used to test the expressions of miR-27a, FOXO1 messenger RNA (mRNA), interleukin-1β (IL-1β) mRNA, and tumor necrosis factor-α (TNF-α) mRNA, and western blot was applied to test the expression of FOXO1. In order to overexpress miR-27a, an intracerebroventricular injection (i.c.v) of miR-27a mimic was administered. We adopted 2,3,5-triphenytetrazolium chloride (TTC) staining and brain water content measurement to test the effects of miR-27a on the infarcted volume and edema in brain after HIE. Flow cytometry (FCM) analysis was applied to test the effects of miR-27a on the infiltrated peripheral immune cells in the rat brains after HIE. Results:We successfully established a rat model of neonatal HIE. It was revealed that the expressions of miR-27a decreased gradually after HIE, however, the expressions of FOXO1 mRNA increased. After injection of the miR-27a mimic, the expression of miR-27a in the rat HIE model brains was significantly upregulated, however, the expression of FOXO1 was robustly downregulated. Both TTC staining and brain water content showed that the infarcted volume and brain edema was markedly increased after HIE. Interestingly, the overexpression of miR-27a reduced the infarcted volume and edema induced by HIE. Additionally, RT-qPCR and FCM analysis showed that HIE lead to increases of IL-1β, TNF-α, and infiltrated immune cells. Overexpression of miR-27a could reduce the expressions of IL-1β mRNA and TNF-α mRNA, and the cell numbers of infiltrated peripheral macrophages and neutrophils in the brain.Conclusions: MiR-27a plays protective roles by reducing infarct volume and brain edema, and inhibiting inflammatory factors and infiltrated peripheral immune cells by targeting FOXO1 in neonatal HIE rats.

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Ryanodine receptor inhibitor dantrolene reduces hypoxic-ischemic brain injury in neonatal mice

Cited by 9 publications

References 102 publications

NS1619 Alleviate Brain-Derived Extracellular Vesicle-Induced Brain Injury by Regulating BKca Channel and Nrf2/HO-1/NF-ĸB Pathway

NS1619 Alleviate Brain-Derived Extracellular Vesicle-Induced Brain Injury by Regulating BKca Channel and Nrf2/HO-1/NF-ĸB Pathway

Excitatory Synaptic Transmission in Ischemic Stroke: A New Outlet for Classical Neuroprotective Strategies

The protective effect of MiR-27a on the neonatal hypoxic-ischemic encephalopathy by targeting FOXO1 in rats

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