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Effect of pregabalin administration upon reperfusion in a rat model of hyperglycemic stroke: Mechanistic insights associated with high-mobility group box 1

 Young Song  ;  Ji-Hae Jun  ;  Eun-Jung Shin  ;  Young-Lan Kwak  ;  Jeon-Soo Shin  ;  Jae-Kwang Shim 
 PLoS One, Vol.12(2) : e0171147, 2017 
Journal Title
 PLoS One 
Issue Date
Animals ; Apoptosis/drug effects ; Brain/drug effects ; Brain/metabolism ; Brain/pathology ; Brain Infarction/complications ; Brain Infarction/metabolism ; Brain Infarction/therapy ; Cytokines/metabolism Disease Models, Animal ; HMGB1 Protein/metabolism* ; Hyperglycemia/complications ; Hyperglycemia/drug therapy* ; Hyperglycemia/metabolism* ; Injections, Intraperitoneal ; Male ; NF-kappa B/metabolism ; Neuroprotective Agents/administration & dosage ; Nitric Oxide Synthase Type II/metabolism ; Nitric Oxide Synthase Type III/metabolism ; Pregabalin/administration & dosage* ; Rats ; Rats, Wistar ; Reperfusion Injury/drug therapy* ; Reperfusion Injury/metabolism* ; Reperfusion Injury/pathology ; Stroke/complications ; Stroke/drug therapy* ; Stroke/metabolism* ; Toll-Like Receptor 4/metabolism
Hyperglycemia, which reduces the efficacy of treatments and worsens clinical outcomes, is common in stroke. Ability of pregabalin to reduce neuroexcitotoxicity may provide protection against stroke, even under hyperglycemia. We investigated its protective effect against hyperglycemic stroke and its possible molecular mechanisms. Male Wistar rats administered dextrose to cause hyperglycemia, underwent middle cerebral artery occlusion for 1 h and subsequent reperfusion. Rats were treated with an intraperitoneal injection of 30 mg/kg pregabalin or an equal amount of normal saline at the onset of reperfusion (n = 16 per group). At 24 h after reperfusion, neurological deficit, infarct volume, and apoptotic cell count were assessed. Western blot analysis was performed to determine protein expression of high-mobility group box 1 (HMGB1), toll-like receptor-4 (TLR-4), phosphorylated nuclear factor-kappa B (p-NF-κB), interleukin-1beta (IL-1β), tumor necrosis factor-alpha (TNF-α), phosphorylated inducible and endothelial nitric oxide synthase (p-iNOS, p-eNOS), Bcl-2, Bax, Cytochrome C, and caspase-3 in the brain. Pregabalin-treated rats showed significantly improved neurological function (31% decrease in score), reduced infarct size (by 33%), fewer apoptotic cells (by 63%), and lower expression levels of HMGB1, TLR4, p-NF-κB, IL-1β, and TNF- α, compared with control rats. Decreased p-iNOS and increased p-eNOS expressions were also observed. Expression of Bax, Cytochrome C, and cleaved caspase-3/caspase3 was significantly downregulated, while Bcl-2 expression was increased by pregabalin treatment. Pregabalin administration upon reperfusion decreased neuronal death and improved neurological function in hyperglycemic stroke rats. Cogent mechanisms would include attenuation of HMGB1/TLR-4-mediated inflammation and favorable modulation of the NOS.
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1. College of Medicine (의과대학) > Dept. of Anesthesiology and Pain Medicine (마취통증의학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Microbiology (미생물학교실) > 1. Journal Papers
Yonsei Authors
곽영란(Kwak, Young Lan) ORCID logo https://orcid.org/0000-0002-2984-9927
송영(Song, Young) ORCID logo https://orcid.org/0000-0003-4597-387X
신전수(Shin, Jeon Soo) ORCID logo https://orcid.org/0000-0002-8294-3234
심재광(Shim, Jae Kwang) ORCID logo https://orcid.org/0000-0001-9093-9692
전지혜(Jun, Ji Hae) ORCID logo https://orcid.org/0000-0002-8080-0715
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