Neuroprotective effects of zonisamide on cerebral ischemia injury via inhibition of neuronal apoptosis

He, Jianbin; Zhang, Xiangjian; He, Weiliang; Xie, Yanzhao; Chen, Yanxia; Yang, Yang; Chen, Rong

doi:10.1590/1414-431x202010498

Cited by 7 publications

(4 citation statements)

References 36 publications

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“…In a rodent model of ischemic stroke, acute treatment with edaravone was neuroprotective in transient focal ischemia, and the mechanism involved suppression of the Fas/FasL signaling pathway ( Xiao et al, 2007 ). Recently, very early treatment with zonisamide was shown to decrease morbidity by suppressing the expression of caspase-3, caspase-8, and calpain-1, inhibiting the apoptosis of neuronal cells after cerebral ischemia ( He et al, 2021 ). Further, intranasal administration of a Fas-blocking peptide 12 h after ischemic stroke attenuated Fas-mediated apoptosis, decreased the volume of the infarcted area, and reduced neurological deficits ( Ullah et al, 2018 ).…”

Section: Discussionmentioning

confidence: 99%

Very early environmental enrichment protects against apoptosis and improves functional recovery from hypoxic–ischemic brain injury

Lee

Song

Hwang

et al. 2023

Front. Mol. Neurosci.

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Appropriate rehabilitation of stroke patients at a very early phase results in favorable outcomes. However, the optimal strategy for very early rehabilitation is at present unclear due to the limited knowledge on the effects of very early initiation of rehabilitation based on voluntary exercise (VE). Environmental enrichment (EE) is a therapeutic paradigm for laboratory animals that involves complex combinations of physical, cognitive, and social stimuli, as well as VE. Few studies delineated the effect of EE on apoptosis in very early stroke in an experimental model. Although a minimal benefit of early rehabilitation in stroke models has been claimed in previous studies, these were based on a forced exercise paradigm. The aim of this study is to determine whether very early exposure to EE can effectively regulate Fas/FasL-mediated apoptosis following hypoxic–ischemic (HI) brain injury and improve neurobehavioral function. C57Bl/6 mice were housed for 2 weeks in either cages with EE or standard cages (SC) 3 h or 72 h after HI brain injury. Very early exposure to EE was associated with greater improvement in motor function and cognitive ability, reduced volume of the infarcted area, decreased mitochondria-mediated apoptosis, and decreased oxidative stress. Very early exposure to EE significantly downregulated Fas/FasL-mediated apoptosis, decreased expression of Fas, Fas-associated death domain, cleaved caspase-8/caspase-8, cleaved caspase-3/caspase-3, as well as Bax and Bcl-2, in the cerebral cortex and the hippocampus. Delayed exposure to EE, on the other hand, failed to inhibit the extrinsic pathway of apoptosis. This study demonstrates that very early exposure to EE is a potentially useful therapeutic translation for stroke rehabilitation through effective inhibition of the extrinsic and intrinsic apoptotic pathways.

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Section: Discussionmentioning

confidence: 99%

Very early environmental enrichment protects against apoptosis and improves functional recovery from hypoxic–ischemic brain injury

Lee

Song

Hwang

et al. 2023

Front. Mol. Neurosci.

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“…The first is by avoid- ing neuronal excitotoxicity antagonizing glutamatergic actions in the CNS 17 ; it has been hypothesized that it acts similarly to zonisamide, a drug capable of inactivating voltage-gated calcium channels. 35 The second protective mechanism is related to its anti-inflammatory effect, whereby it acts as an irreversible inhibitor of myeloperoxidase, interferes with neutrophil migration and recruitment, blocks peroxidase activity in eosinophils, and inhibits the generation of 5-lipoxygenase products, reducing the generation of neurotoxic free radicals. Inflammation is very important in the genesis of cerebral vasospasm and in secondary ischemic damage.…”

Section: Discussionmentioning

confidence: 99%

“…Inflammation is very important in the genesis of cerebral vasospasm and in secondary ischemic damage. 17,25,35 We chose the dapsone dose of 100 mg per day, as we use in clinical practice, because it is well-tolerated and similar doses have demonstrated good blood-brain barrier penetration and CSF levels. 29…”

Section: Discussionmentioning

confidence: 99%

Neuroprotective effect of dapsone in patients with aneurysmal subarachnoid hemorrhage: a prospective, randomized, double-blind, placebo-controlled clinical trial

García-Pastor¹,

Llano²,

Balcázar-Padrón³

et al. 2022

Neurosurgical Focus

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OBJECTIVE In this study, the authors sought to define the differences in the incidence of delayed cerebral ischemia (DCI) between patients treated with dapsone and those treated with placebo. Secondary objectives were to define the clinical outcome at discharge and 3 months and the incidence of brain infarction. METHODS A prospective, randomized, double-blind, placebo-controlled study was performed and included patients with aneurysmal subarachnoid hemorrhage (SAH) within 5 days from ictus who were candidates for aneurysm occlusion, and who had a Fisher grade of 3 or 4. Patients with sulfa or sulfone drug allergies, hemoglobin < 11 g/dl, known G6PD deficiency, and those refusing informed consent were excluded. A minimal relevant effect decrease of 35% in the incidence of DCI was established. Patients were randomly assigned to receive a regimen of dapsone 2.5 ml (100 mg) daily or a placebo (aluminum hydroxide suspension, 2.5 ml daily). Both groups received validated treatment for aneurysmal SAH. The appearance of DCI on CT was assessed in every patient at discharge and 3 months later. We used the chi-square test to compare the DCI incidence between both groups, and the Student t-test or nonparametric tests to compare quantitative variables. RESULTS Overall, 48 patients (70.8% women and 29.2% men) were included. The mean age was 50 years (SD 14.28 years, range 18–72 years). Prerandomization and postrandomization characteristics were balanced, except for the necessity of intra-arterial nimodipine administration in patients treated with placebo (15.4% vs 45.5%, p = 0.029. The incidence of DCI, the primary endpoint, for the whole cohort was 43.8% and was significantly lower in the dapsone group (26.9% vs 63.6%, p = 0.011). In addition, the irreversible DCI incidence was lower in the dapsone group (11.5% vs 54.5%, p = 0.12). A favorable modified Rankin Scale score was more frequent in the dapsone group at discharge and at 3 months (76.9% vs 36.4%, p = 0.005 and 80% vs 38.9%, p = 0.019, respectively). Also, the brain infarction incidence was lower in the dapsone group (19.2% vs 63.6%, p = 0.001). There was no difference between groups regarding adverse events. CONCLUSIONS Dapsone seems to play a role as a prophylactic agent in patients at high risk of developing DCI after aneurysmal SAH. A multicenter investigation is necessary to increase the study population and confirm the consistency of the results observed in this study.

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“…Apoptosis is the main form of cell death in the pathogenesis of cerebral ischemia. 8 Autophagy is a lysosomal degradation pathway, which serves an important role in the removal of protein aggregates and the maintenance of cell homeostasis by damaged or excessive organelles. 9 A previous study demonstrated that autophagy and apoptosis usually occur in different types of brain injury.…”

Section: Introductionmentioning

confidence: 99%

Tricin attenuates cerebral ischemia/reperfusion injury through inhibiting nerve cell autophagy, apoptosis and inflammation by regulating the PI3K/Akt pathway

Liu

Yan³

et al. 2022

Hum Exp Toxicol

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To elucidate the effect of tricin in cerebral ischemia/reperfusion (I/R) injury and examine its possible underlying mechanisms. Rats were randomly divided into Sham (exposed the right internal carotid arteries), I/R, and tricin (administered at various doses) groups. After the cerebral I/R injury model was established, a Morris water maze test and a tetrazolium chloride assay were performed. Apoptosis and autophagy were assessed in the nerve cells of hippocampus tissue, and the levels of inflammatory markers within animal serum were detected. Proteins related to apoptosis and the PI3K/Akt pathway were evaluated. To further investigate the mechanisms by which tricin affects brain damage, mouse neuroblastoma cells N2a were divided into control, oxygen-glucose deprivation and reoxygenation (OGD/R), tricin, PI3K/Akt activator, and tricin + PI3K/Akt inhibitor groups. The cell viability, apoptosis, inflammatory factors, and PI3K/Akt pathway related proteins in N2a cells were also detected. The results revealed that I/R-induced learning and memory dysfunction was improved by tricin treatment. The area of cerebral infarction, the levels of apoptosis and autophagy in nerve cells, and the serum inflammatory marker content were all decreased following tricin treatment. Additionally, the expression of Beclin-1 protein was downregulated, while the expression of Bcl-2 protein, p-PI3K/PI3K and p-Akt/Akt was upregulated after tricin treatment. Mechanistically, tricin or PI3K/Akt activator ameliorated OGD/R-induced apoptosis, autophagy, and inflammation. However, these effects were reversed following PI3K/Akt inhibitor treatment in OGD/R-induced N2a cells. In summary, this study suggested that tricin can against I/R-induced brain injury by inhibiting autophagy, apoptosis and inflammation, and activating the PI3K/Akt signaling pathway.

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Neuroprotective effects of zonisamide on cerebral ischemia injury via inhibition of neuronal apoptosis

Cited by 7 publications

References 36 publications

Very early environmental enrichment protects against apoptosis and improves functional recovery from hypoxic–ischemic brain injury

Very early environmental enrichment protects against apoptosis and improves functional recovery from hypoxic–ischemic brain injury

Neuroprotective effect of dapsone in patients with aneurysmal subarachnoid hemorrhage: a prospective, randomized, double-blind, placebo-controlled clinical trial

Tricin attenuates cerebral ischemia/reperfusion injury through inhibiting nerve cell autophagy, apoptosis and inflammation by regulating the PI3K/Akt pathway

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