Effect of pregabalin administration upon reperfusion in a rat model of hyperglycemic stroke: Mechanistic insights associated with high-mobility group box 1.
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.
Department of Anesthesiology and Pain Medicine, Yonsei University College of Medicine, Seodaemun-gu, Seoul, Republic of Korea.|Anesthesia and Pain Research Institute, Yonsei University College of Medicine, Seodaemun-gu, Seoul, Republic of Korea.
Young
Y
Song
Anesthesia and Pain Research Institute, Yonsei University College of Medicine, Seodaemun-gu, Seoul, Republic of Korea.
Ji-Hae
JH
Jun
Anesthesia and Pain Research Institute, Yonsei University College of Medicine, Seodaemun-gu, Seoul, Republic of Korea.
Eun-Jung
EJ
Shin
Department of Anesthesiology and Pain Medicine, Yonsei University College of Medicine, Seodaemun-gu, Seoul, Republic of Korea.|Anesthesia and Pain Research Institute, Yonsei University College of Medicine, Seodaemun-gu, Seoul, Republic of Korea.
Young-Lan
YL
Kwak
Department of Microbiology, Yonsei University College of Medicine, Seodaemun-gu, Seoul, Republic of Korea.|Brain Korea 21 PLUS for Medical Science, Yonsei University College of Medicine, Seodaemun-gu, Seoul, Republic of Korea.|Severance Biomedical Science Institute and Institute for Immunology and Immunological Diseases, Yonsei University College of Medicine, Seodaemun-gu, Seoul, Republic of Korea.
Jeon-Soo
JS
Shin
Department of Anesthesiology and Pain Medicine, Yonsei University College of Medicine, Seodaemun-gu, Seoul, Republic of Korea.|Anesthesia and Pain Research Institute, Yonsei University College of Medicine, Seodaemun-gu, Seoul, Republic of Korea.
Jae-Kwang
http://orcid.org/0000-0001-9093-9692
JK
Shim
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D020520:Brain Infarction / Q000150:complications / Q000378:metabolism / Q000628:therapy; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D024243:HMGB1 Protein / Q000378:metabolism*; D006943:Hyperglycemia / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism*; D007274:Injections, Intraperitoneal; D008297:Male; D016328:NF-kappa B / Q000378:metabolism; D018696:Neuroprotective Agents / Q000008:administration & dosage; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D000069583:Pregabalin / Q000008:administration & dosage*; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D020521:Stroke / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000378:metabolism
D016207:Cytokines; D024243:HMGB1 Protein; C104200:Hbp1 protein, rat; D016328:NF-kappa B; D018696:Neuroprotective Agents; C495347:Tlr4 protein, rat; D051197:Toll-Like Receptor 4; D000069583:Pregabalin; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496318:Nos2 protein, rat; C496316:Nos3 protein, rat