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.
Highlights
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]
The adverse influence of acute hyperglycemia has been confirmed in animal models of middle cerebral artery occlusion (MCAO) [4]
Experimental studies have revealed that hyperglycemia exacerbates metabolic deterioration, intensifies the inflammatory response and oxidative stress, augments blood-brain barrier (BBB) disruption, and lowers the availability of NO, leading to increased infarct volume, edema, and hemorrhagic transformation [7, 8, 22, 23]
Summary
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]. Ischemic injury universally starts with presynaptic neuronal discharge leading to activation of voltage-gated calcium channels (VGCC) and release of excitatory neurotransmitters in the ischemic core [5]. This excitotoxicity is followed by delayed inflammatory responses in the penumbra, with high-mobility group box 1 (HMGB1) recently identified as the key pro-inflammatory molecule linking these two successive events [6]. Hyperglycemia has been shown to abolish the experimentally proven protective effects of certain agents, such as volatile anesthetic, against cerebral ischemia-reperfusion (I-R) injury [10, 11]
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