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

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4 Citations (Scopus)

Abstract

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 peNOS 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. Cogentmechanisms would include attenuation of HMGB1/TLR-4-mediated inflammation and favorable modulation of the NOS.

Original languageEnglish
Article numbere0171147
JournalPloS one
Volume12
Issue number2
DOIs
Publication statusPublished - 2017 Feb

Fingerprint

stroke
Reperfusion
Rats
animal models
Stroke
hyperglycemia
Hyperglycemia
rats
Toll-Like Receptor 4
infarction
caspase-3
Cytochromes
cytochromes
Interleukin-1beta
Caspase 3
tumor necrosis factor-alpha
Cytochromes c2
Tumor Necrosis Factor-alpha
Cells
Rat control

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

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title = "Effect of pregabalin administration upon reperfusion in a rat model of hyperglycemic stroke: Mechanistic insights associated with high-mobility group box 1",
abstract = "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 peNOS 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. Cogentmechanisms would include attenuation of HMGB1/TLR-4-mediated inflammation and favorable modulation of the NOS.",
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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. / Song, Young; Jun, Ji Hae; Shin, Eun Jung; Kwak, Young Lan; Shin, Jeon Soo; Shim, Jae Kwang.

In: PloS one, Vol. 12, No. 2, e0171147, 02.2017.

Research output: Contribution to journalArticle

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