Pretreatment with simvastatin upregulates expression of BK-2R and CD11b in the ischemic penumbra of rats

Abstract

Inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductases, collectively known as statins, have been shown to minimize cerebral ischemic events in patients. We assessed the mechanisms of simvastatin pretreatment in preventing cerebral ischemia/reperfusion injury in rats using a model of middle cerebral artery occlusion (MCAO). Rats were pretreated with simvastatin 14 days prior to MCAO induction. At 3, 24, and 48 hours after reperfusion, bradykinin levels in the ischemic penumbra were assayed by ELISA, mRNA levels of bradykinin B2 receptors (BK-2Rs) and CD11b were measured by fluorescent quantitative real-time PCR (RT-PCR), and co-expression of microglia and BK-2Rs was determined by immunofluorescence. Simvastatin had no effect on bradykinin expression in the ischemic penumbra at any time point. However, the levels of BK-2R and CD11b mRNA in the ischemic penumbra, which were significantly decreased 3 hours after ischemia-reperfusion, were increased in simvastatin-pretreated rats. Moreover, the co-expression of BK-2Rs and microglia was confirmed by immunofluorescence analysis. These results suggest that the beneficial effects of simvastatin pretreatment before cerebral ischemia/reperfusion injury in rats may be partially due to increased expression of BK-2R and CD11b in the ischemic penumbra.

Keywords

simvastatin / cerebral ischemia/reperfusion / bradykinin B2 receptors / CD11b

References

[1] Van Der Putten C, Kuipers HF, Zuiderwijk-Sick EA, Statins amplify TLR-induced responses in microglia via inhibition of cholesterol biosynthesis[J]. Glia, 2012, 60(1): 43–52

[2] Bertrand MJ, Tardif JC. Inflammation and beyond: new directions and emerging drugs for treating atherosclerosis[J]. Expert Opin Emerg Drugs, 2017, 22(1): 1–26

[3] Ziedén B, Olsson AG. The role of statins in the prevention of ischemic stroke[J]. Curr Atheroscler Rep, 2005, 7(5): 364–368

[4] Kogure K, Yamasaki Y, Matsuo Y, Inflammation of the brain after ischemia[J]. Acta Neurochir Suppl, 1996, 66: 40–43

[5] Campbell DJ. The kallikrein-kinin system in humans[J]. Clin Exp Pharmacol Physiol, 2001, 28(12): 1060–1065

[6] Marceau F, Bachvarov DR. Kinin receptors[J]. Clin Rev Allergy Immunol, 1998, 16(4): 385–401

[7] Viel TA, Lima Caetano A, Nasello AG, Increases of kinin B1 and B2 receptors binding sites after brain infusion of amyloid-beta 1-40 peptide in rats[J]. Neurobiol Aging, 2008, 29(12): 1805–1814

[8] de Sousa Buck H, Ongali B, Thibault G, Autoradiographic detection of kinin receptors in the human medulla of control, hypertensive, and diabetic donors[J]. Can J Physiol Pharmacol, 2002, 80(4): 249–257

[9] Xia CF, Smith RS Jr, Shen B, Postischemic brain injury is exacerbated in mice lacking the kinin B2 receptor[J]. Hypertension, 2006, 47(4): 752–761

[10] Noda M, Kariura Y, Amano T, Expression and function of bradykinin receptors in microglia[J]. Life Sci, 2003, 72(14): 1573–1581

[11] Davalos D, Grutzendler J, Yang G, ATP mediates rapid microglial response to local brain injury in vivo[J]. Nat Neurosci, 2005, 8(6): 752–758

[12] Nimmerjahn A, Kirchhoff F, Helmchen F. Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo[J]. Science, 2005, 308(5726): 1314–1318

[13] Xing C, Wang X, Cheng C, Neuronal production of lipocalin-2 as a help-me signal for glial activation[J]. Stroke, 2014, 45(7): 2085–2092

[14] Gelosa P, Lecca D, Fumagalli M, Microglia is a key player in the reduction of stroke damage promoted by the new antithrombotic agent ticagrelor[J]. J Cereb Blood Flow Metab , 2014, 34(6): 979–988

[15] Hossmann KA. Viability thresholds and the penumbra of focal ischemia[J]. Ann Neurol, 1994, 36(4): 557–565

[16] Obrenovitch TP. The ischaemic penumbra: twenty years on[J].Cerebrovasc Brain Metab Rev , 1995, 7(4): 297–323

[17] Siesjö BK. Pathophysiology and treatment of focal cerebral ischemia. Part I: Pathophysiology[J]. J Neurosurg, 1992, 77(2): 169–184

[18] Siesjö BK. Pathophysiology and treatment of focal cerebral ischemia. Part II: Mechanisms of damage and treatment[J]. J Neurosurg, 1992, 77(3): 337–354

[19] Back T, Ginsberg MD, Dietrich WD, Induction of spreading depression in the ischemic hemisphere following experimental middle cerebral artery occlusion: effect on infarct morphology[J]. J Cereb Blood Flow Metab, 1996, 16(2): 202–213

[20] Longa EZ, Weinstein PR, Carlson S, Reversible middle cerebral artery occlusion without craniectomy in rats[J]. Stroke, 1989, 20(1): 84–91

[21] Lu J, Zhang Y, Shi J. Effects of intracerebroventricular infusion of angiotensin-(1-7) on bradykinin formation and the kinin receptor expression after focal cerebral ischemia-reperfusion in rats[J]. Brain Res, 2008, 1219: 127–135

[22] Ashwal S, Tone B, Tian HR, Core and penumbral nitric oxide synthase activity during cerebral ischemia and reperfusion[J]. Stroke, 1998, 29(5): 1037–1046., discussion 1047

[23] Delmas P, Wanaverbecq N, Abogadie FC, Signaling microdomains define the specificity of receptor-mediated InsP(3) pathways in neurons[J]. Neuron, 2002, 34(2): 209–220

[24] Noda M, Kariura Y, Pannasch U, Neuroprotective role of bradykinin because of the attenuation of pro-inflammatory cytokine release from activated microglia[J]. J Neurochem, 2007, 101(2): 397–410

[25] Leeb-Lundberg LM, Marceau F, Müller-Esterl W, International union of pharmacology. XLV. Classification of the kinin receptor family: from molecular mechanisms to pathophysiological consequences[J]. Pharmacol Rev, 2005, 57(1): 27–77

[26] Sang H, Liu L, Wang L, Opposite roles of bradykinin B1 and B2 receptors during cerebral ischaemia-reperfusion injury in experimental diabetic rats[J]. Eur J Neurosci, 2016, 43(1): 53–65

[27] Gröger M, Lebesgue D, Pruneau D, Release of bradykinin and expression of kinin B2 receptors in the brain: role for cell death and brain edema formation after focal cerebral ischemia in mice[J]. J Cereb Blood Flow Metab, 2005, 25(8): 978–989

[28] Xia CF, Yin H, Borlongan CV, Kallikrein gene transfer protects against ischemic stroke by promoting glial cell migration and inhibiting apoptosis[J]. Hypertension, 2004, 43(2): 452–459

[29] Ding-Zhou L, Margaill I, Palmier B, LF 16-0687 Ms, a bradykinin B2 receptor antagonist, reduces ischemic brain injury in a murine model of transient focal cerebral ischemia[J]. Br J Pharmacol, 2003, 139(8): 1539–1547

[30] Aloisi F. Immune function of microglia[J]. Glia, 2001, 36(2): 165–179

[31] Largo C, Cuevas P, Herreras O. Is glia disfunction the initial cause of neuronal death in ischemic penumbra[J]? Neurol Res, 1996, 18(5): 445–448

RIGHTS & PERMISSIONS

2018 2018 by the Journal of Biomedical Research.