Dataset Information

Transcranial Direct-Current Stimulation Regulates MCT1-PPA-PTEN-LONP1 Signaling to Confer Neuroprotection After Rat Cerebral Ischemia-Reperfusion Injury.

ABSTRACT: Propionic acid (PPA) is a critical metabolite involved in microbial fermentation, which functions to reduce fat production, inhibit inflammation, and reduce serum cholesterol levels. The role of PPA in the context of cerebral ischemia-reperfusion (I/R) injury has yet to be clarified. Increasing evidence indicate that transcranial direct-current stimulation (tDCS) is a safe approach that confers neuroprotection in cerebral ischemia injury. Here, we show that the levels of PPA were reduced in the ischemic brain following a rat cerebral I/R injury and in the cultured rat cortical neurons after oxygen-glucose deprivation (OGD), an in vitro model of ischemic injury. We found that the decreased levels of transporter protein monocarboxylate transporter-1 (MCT1) were responsible for the OGD-induced reduction of PPA. Supplementing PPA reduced ischemia-induced neuronal death after I/R. Moreover, our results revealed that the neuroprotective effect of PPA is mediated through downregulation of phosphatase PTEN and subsequent upregulation of Lon protease 1 (LONP1). We demonstrated that direct-current stimulation (DCS) increased MCT1 expression and PPA level in OGD-insulted neurons, while tDCS decreased the brain infarct volume in the MCAO rats via increasing the levels of MCT1 expression and PPA. This study supports a potential application of tDCS in ischemic stroke.

SUBMITTER: Kong X

PROVIDER: S-EPMC9616768 | biostudies-literature | 2022 Dec

REPOSITORIES: biostudies-literature

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Transcranial Direct-Current Stimulation Regulates MCT1-PPA-PTEN-LONP1 Signaling to Confer Neuroprotection After Rat Cerebral Ischemia-Reperfusion Injury.

Kong Xiangyi X Hu Wenjie W Cui Yu Y Gao Jingchen J Yao Xujin X Ren Jinyang J Lin Tao T Sun Jiangdong J Gao Yunyi Y Li Xiaohua X Wang Hui H Li Huanting H Che Fengyuan F Wan Qi Q

Molecular neurobiology 20221003 12

Propionic acid (PPA) is a critical metabolite involved in microbial fermentation, which functions to reduce fat production, inhibit inflammation, and reduce serum cholesterol levels. The role of PPA in the context of cerebral ischemia-reperfusion (I/R) injury has yet to be clarified. Increasing evidence indicate that transcranial direct-current stimulation (tDCS) is a safe approach that confers neuroprotection in cerebral ischemia injury. Here, we show that the levels of PPA were reduced in the ...[more]

PMID: 36190692

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Project description:Background and purposeAquaporin-4(AQP4) is an abundant water channel protein in brain that regulates water transport to maintain homeostasis. Cerebral edema resulting from AQP4 over expression is considered to be one of the major determinants for progressive neuronal insult during cerebral ischemia. Although, both upregulation and downregulation of AQP4 expression is associated with brain pathology, over expression of AQP4 is one of the chief contributors of water imbalance in brain during ischemic pathology. We have found that Piroxicam binds to AQP4 with optimal binding energy value. Thus, we hypothesized that Piroxicam is neuroprotective in the rodent cerebral ischemic model by mitigating cerebral edema via AQP4 regulation.MethodsRats were treated with Piroxicam OR placebo at 30 min prior, 2 h post and 4 h post 60 minutes of MCAO followed by 24 hour reperfusion. Rats were evaluated for neurological deficits and motor function just before sacrifice. Brains were harvested for infarct size estimation, water content measurement, biochemical analysis, RT-PCR and western blot experiments.ResultsPiroxicam pretreatment thirty minutes prior to ischemia and four hour post reperfusion afforded neuroprotection as evident through significant reduction in cerebral infarct volume, improvement in motor behavior, neurological deficit and reduction in brain edema. Furthermore, ischemia induced surge in levels of nitrite and malondialdehyde were also found to be significantly reduced in ischemic brain regions in treated animals. This neuroprotection was found to be associated with inhibition of acid mediated rise in intracellular calcium levels and also downregulated AQP4 expression.ConclusionsFindings of the present study provide significant evidence that Piroxicam acts as a potent AQP4 regulator and renders neuroprotection in focal cerebral ischemia. Piroxicam could be clinically exploited for the treatment of brain stroke along with other anti-stroke therapeutics in future.

Project description:ObjectiveL-3-n-Butylphthalide (NBP) is used to treat moderate and severe acute ischemia stroke. A previous screening study indicates that XY03-EA, a novel derivative of NBP, is more potent than NBP in the oxyradical scavenging capacity. In this study, in vivo and in vitro ischemia/reperfusion (I/R) models were used to test whether the XY03-EA offered therapeutic benefits in the ischemic stroke and explore the underlying mechanism of action.MethodsFor this purpose, behavioral scores, cerebral infarct volume, cerebral blood flow, oxidative stress levels, inflammatory factor expression, energy metabolism levels, and autophagy activation were estimated in the rat middle cerebral artery occlusion and reperfusion (MCAO/R) model. The nonhuman primate MCAO/R model was conducted to validate the therapeutic effect of XY03-EA applied for 3 weeks. The neurological deficit score (NDS) progression rate and the infarct volume were continuously recorded on days 3, 7, 14, and 21. The PC-12 cell OGD/R model was used to assess the cell survival rate, reactive oxygen species (ROS) levels, the expression of autophagy execution molecules, and the activation of autophagy-related signaling pathways.ResultsXY03-EA decreased the cerebral injuries and NDS by increasing cerebral blood flow, improving brain energy metabolism, accelerating ROS clearance, suppressing inflammatory responses, and inhibiting autophagy in the MCAO/R model rats. In the nonhuman primate MCAO/R model, the treatment of XY03-EA for 3 weeks could significantly inhibit the NDS progression rate and indicate a positive trend to reduce the infarct volume in a dose-dependent way. Mechanistically, XY03-EA inhibited ROS-dependent autophagy activation and thereby protected the PC-12 cells from the autophagic cell death induced by OGD/R.ConclusionsIn this study, we found that XY03-EA alleviated the cerebral I/R injuries in rats and nonhuman primates. Our results demonstrated that XY03-EA exerted neuroprotective effects against the ROS-mediated autophagic neurocyte death and had great potential for the treatment of ischemic stroke.

Project description:Selective brain hypothermia is considered an effective treatment for neuronal injury after stroke, and avoids the complications of general hypothermia. However, the mechanisms by which selective brain hypothermia affects mitochondrial fission remain unknown. In this study, we investigated the effect of selective brain hypothermia on the expression of fission 1 (Fis1) protein, a key factor in the mitochondrial fission system, during focal cerebral ischemia/reperfusion injury. Sprague-Dawley rats were divided into four groups. In the sham group, the carotid arteries were exposed only. In the other three groups, middle cerebral artery occlusion was performed using the intraluminal filament technique. After 2 hours of occlusion, the filament was slowly removed to allow blood reperfusion in the ischemia/reperfusion group. Saline, at 4°C and 37°C, were perfused through the carotid artery in the hypothermia and normothermia groups, respectively, followed by restoration of blood flow. Neurological function was assessed with the Zea Longa 5-point scoring method. Cerebral infarct volume was assessed by 2,3,5-triphenyltetrazolium chloride staining, and apoptosis was assessed by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling staining. Fis1 and cytosolic cytochrome c levels were assessed by western blot assay. Fis1 mRNA expression was assessed by quantitative reverse transcription-polymerase chain reaction. Mitochondrial ultrastructure was evaluated by transmission electron microscopy. Compared with the sham group, apoptosis, Fis1 protein and mRNA expression and cytosolic cytochrome c levels in the cortical ischemic penumbra and cerebral infarct volume were increased after reperfusion in the other three groups. These changes caused by cerebral ischemia/reperfusion were inhibited in the hypothermia group compared with the normothermia group. These findings show that selective brain hypothermia inhibits Fis1 expression and reduces apoptosis, thereby ameliorating focal cerebral ischemia/reperfusion injury in rats. Experiments were authorized by the Ethics Committee of Qingdao Municipal Hospital of China (approval No. 2019008).

Dataset Information

Transcranial Direct-Current Stimulation Regulates MCT1-PPA-PTEN-LONP1 Signaling to Confer Neuroprotection After Rat Cerebral Ischemia-Reperfusion Injury.

Publications

Transcranial Direct-Current Stimulation Regulates MCT1-PPA-PTEN-LONP1 Signaling to Confer Neuroprotection After Rat Cerebral Ischemia-Reperfusion Injury.

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