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

Date Published: February 2, 2017

Publisher: Public Library of Science

Author(s): Young Song, Ji-Hae Jun, Eun-Jung Shin, Young-Lan Kwak, Jeon-Soo Shin, Jae-Kwang Shim, Thiruma V. Arumugam.

http://doi.org/10.1371/journal.pone.0171147

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 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.

Partial Text

Irrespective of a history of diabetes, approximately 30–40% of patients that present with acute ischemic stroke exhibit hyperglycemia, which is known to exacerbate clinical outcomes [1]. Unfortunately, the application of intensive glycemic control does not improve outcomes leaving clinicians with an additional burden, whilst already being confronted with limited therapeutic options against stroke in general [2, 3].

In the present study, we observed the functional and histological neuroprotective effects of pregabalin administration upon reperfusion after 1 h of MCAO in a rat model of hyperglycemic stroke. It reduced infarct size by 33%, improved neurological deficits (31% decrease in score), presented with fewer apoptotic cells (by 63%), and demonstrated favorable expression of apoptosis-regulatory molecules in the brain tissue. Activation of HMGB1/TLR-4 signaling and NF-κB-mediated pro-inflammatory cascades was attenuated by pregabalin treatment. Favorable modulation of NOS isoforms was also revealed.

Pregabalin administration upon reperfusion conveyed significant functional and histological neuroprotection after 1 h of MCAO under hyperglycemia. These beneficial influences were observed to be associated with major regulators of inflammation, HMGB1, and subsequently, NF-κB and anti-apoptotic pathways, as well as NOS.

 

Source:

http://doi.org/10.1371/journal.pone.0171147