Noninvasive limb remote ischemic preconditioning contributes neuroprotective effects via activation of adenosine A1 receptor and redox status after transient focal cerebral ischemia in rats

• Published in: Brain research 2012-06, Vol.1459, p.81-90
• Main Authors: Hu, Sheng, Dong, Hailong, Zhang, Haopeng, Wang, Shiquan, Hou, Lichao, Chen, Shaoyang, Zhang, Jinsong, Xiong, Lize
• Format: Article
• Language: English
• Subjects: 2-Chloro-N6-cyclopentyladenosine (CCPA); 8-Cyclopentyl-1,3-dipropulxanthine (DPCPX); adenosine; Adenosine - administration & dosage; Adenosine - analogs & derivatives; Adenosine A1 receptor (A1R); Adenosine A1 receptors; agonists; Analysis of Variance; Animals; antagonists; Antioxidants; Biological and medical sciences; blood serum; Brain; Brain Infarction - etiology; Brain Infarction - prevention & control; Brain injury; Cerebral blood flow; Chloride; Diffusion Magnetic Resonance Imaging; Disease Models, Animal; Extremities - innervation; Glutathione - metabolism; image analysis; infarction; Infarction, Middle Cerebral Artery - therapy; Inflammation; Injuries; Ischemia; Ischemic Attack, Transient - prevention & control; Ischemic Preconditioning - methods; Ischemic tolerance; Limbs; Lipid Peroxidation - drug effects; Male; malondialdehyde; Manganese; Medical sciences; Nervous System Diseases - etiology; Nervous System Diseases - prevention & control; Neuroimaging; Neurology; Neuroprotection; Neuroprotective Agents - administration & dosage; neuroprotective effect; Nitric oxide; Nitrites - metabolism; Oxidation-Reduction; Oxidative stress; Preservation; Rats; Rats, Sprague-Dawley; Receptor, Adenosine A1 - metabolism; receptors; Remote ischemic preconditioning (RIPC); Reperfusion; Severity of Illness Index; Superoxide dismutase; Superoxide Dismutase - metabolism; Tumor necrosis factor; Tumor Necrosis Factor-alpha - blood; tumor necrosis factors; Vascular diseases and vascular malformations of the nervous system; Xanthines - administration & dosage
• ISSN: 0006-8993; 1872-6240
• DOI: 10.1016/j.brainres.2012.04.017

Abstract Purposes: To investigate whether activation of adenosine A1 receptor (A1R) through limb remote ischemic preconditioning (RIPC) by a noninvasive tourniquet contribute neuroprotective effects against rat focal cerebral ischemic injury induced by transient middle cerebral artery occlusion (MCAO). Methods: One hundred twenty-eight Sprague–Dawley (SD) rats were randomly assigned into eight groups ( n = 16 each ): MCAO, Control, 8-cyclopentyl-1,3-dipropulxanthine (DPCPX, Adenosine A1 receptor antagonist), RIPC, DPCPX + RIPC, Vehicle + RIPC, 2-chloro-N6 -cyclopentyladenosine (CCPA, Adenosine A1 receptor agonist) and CCPA + DPCPX groups. All animals underwent right middle cerebral artery occlusion (MCAO) for 2 h. Limb RIPC consisted of three cycles of 5-minute ischemia followed by 5-minute reperfusion in right hind-limb by tourniquet application. Neurological deficit scores were evaluated 24 h after reperfusion, and then the infarct volume was assessed with diffusion weighted imaging (DWI) and 2, 3, 5-triphenyltetrazolium chloride (TTC) staining. Inflammation was assessed by serum tumor necrosis factor α (TNF α ) and NO; oxidative stress was estimated by malondialdehyde (MDA) and 4-hydroxyalkenals (4-HAD), superoxide dismutase (SOD) activity and GSH. Results: Animals in the RIPC, Vehicle + RIPC and CCPA groups developed lower neurological deficit scores and smaller brain infarct volumes than the Control group ( P < 0.01). Animals in the DPCPX, DPCPX + RIPC and CCPA + DPCPX groups developed higher neurological deficit scores and larger brain infarct volumes than the RIPC, Vehicle + RIPC and CCPA groups ( P < 0.01 ). DPCPX abolished the protective effects of RIPC and CCPA. RIPC or CCPA induced a significant increase in brain MnSOD (manganese SOD) activity and NO generation, and this activity was abolished by DPCPX pretreatment. RIPC or CCPA induced a significant reduction ( P < 0.05) in the GSH and MDA + 4HDA concentration and an accumulation in the GSSG concentration in both compartments (serum and tissue) as compared with the MCAO group. Conclusions: The present study demonstrates that limb RIPC induced by noninvasive tourniquet reduces cerebral ischemic injury in rats, and the effect of neuroprotection may depend on the activation of adenosine A1 receptors. CCPA pretreatment can induce delayed ischemic tolerance against cerebral ischemia/reperfusion injury. These protective effects are associated with a reduction in oxidative stress, inflammation and end