Human tissue kallikrein ameliorates cerebral vasospasm in a rabbit model of subarachnoid hemorrhage

Objectives: Cerebral vasospasm (CVS) and early brain injury are major causes of morbidity and mortality following subarachnoid hemorrhage (SAH). We investigated the efficiency of human tissue kallikrein (HTK) to prevent CVS in a rabbit model of SAH. Methods: Forty-eight Japanese white rabbits were randomly divided into four groups (n = 12 each): control (sham-operated), SAH, SAH + phosphate-buffered saline (PBS, vehicle), and SAH + HTK. Basilar artery (BA) diameters were measured by three-dimensional computed tomography angiography at three time points. Endothelin-1 (ET-1) and nitric oxide (NO) levels in the cerebrospinal fluid (CSF) were assayed 24 h before and 5 and 7 days after SAH. After the last measurement, the animals were killed, and endothelial cell apoptosis was assessed. Bax and Bcl-2 levels in the BA were measured by western blotting. Results: HTK was found to significantly reduce CVS following SAH in rabbits. Inverse changes were observed in ET-1 and NO levels in the CSF collected from the SAH group. HTK increased levels of NO, which has a vasodilatory effect, but did not affect levels of ET-1, which has a vasoconstrictive effect. CTA revealed that HTK treatment significantly increased BA diameter. Moreover, HTK treatment reduced the number of apoptotic cells following SAH, presumably by increasing and decreasing Bcl-2 and Bax expression, respectively. Conclusion: HTK ameliorated CVS and inhibited apoptosis in the BA in a rabbit model of SAH.

[1]  A. Siddiqui,et al.  Endothelial Nitric Oxide Synthase and Superoxide Mediate Hemodynamic Initiation of Intracranial Aneurysms , 2014, PloS one.

[2]  Xiaohong Wang,et al.  Inhibition of protein kinase C signal reduces ET receptor expression and basilar vasospasm after subarachnoid hemorrhage in rats. , 2012, Journal of integrative neuroscience.

[3]  S. Howng,et al.  Atorvastatin preconditioning attenuates the production of endothelin-1 and prevents experimental vasospasm in rats , 2010, Acta Neurochirurgica.

[4]  S. Howng,et al.  17Beta-estradiol activates adenosine A(2a) receptor after subarachnoid hemorrhage. , 2009, The Journal of surgical research.

[5]  Renliang Zhang,et al.  Tissue kallikrein protects cortical neurons against in vitro ischemia-acidosis/reperfusion-induced injury through the ERK1/2 pathway , 2009, Experimental Neurology.

[6]  Ji-Xin Shi,et al.  Effects of recombinant human erythropoietin (rhEPO) on JAK2/STAT3 pathway and endothelial apoptosis in the rabbit basilar artery after subarachnoid hemorrhage. , 2009, Cytokine.

[7]  Wei-jian Chen,et al.  [Effects of human tissue kallikrein on cerebral vasospasm: experiment with rabbits]. , 2008, Zhonghua yi xue za zhi.

[8]  M. Wintermark,et al.  Prospective Evaluation of Multidetector-Row CT Angiography for the Diagnosis of Vasospasm following Subarachnoid Hemorrhage: A Comparison with Digital Subtraction Angiography , 2007, Cerebrovascular Diseases.

[9]  F. Ringel,et al.  Molecular mechanisms of cerebral vasospasm following aneurysmal SAH , 2007, Neurological research.

[10]  Leslie A. Smith,et al.  Endothelial Progenitor Cells Stimulate Cerebrovascular Production of Prostacyclin By Paracrine Activation of Cyclooxygenase-2 , 2007, Circulation research.

[11]  E. Oldfield,et al.  Analysis of nitric oxide (NO) in cerebral vasospasm after aneursymal bleeding. , 2007, Reviews on recent clinical trials.

[12]  L. Chao,et al.  Experimental therapy with tissue kallikrein against cerebral ischemia. , 2006, Frontiers in bioscience : a journal and virtual library.

[13]  L. Chao,et al.  Kallikrein/kinin protects against gentamicin-induced nephrotoxicity by inhibition of inflammation and apoptosis. , 2006, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[14]  Ting-Yim Lee,et al.  Dynamic CT Perfusion imaging in subarachnoid hemorrhage related vasospasm , 2005, AJNR. American journal of neuroradiology.

[15]  S. Lozzi,et al.  Endothelin-1 levels in plasma and cerebrospinal fluid of patients with cerebral vasospasm after aneurysmal subarachnoid hemorrhage. , 2005, Surgical neurology.

[16]  L. Chao,et al.  Kallikrein Gene Transfer Protects Against Ischemic Stroke by Promoting Glial Cell Migration and Inhibiting Apoptosis , 2004, Hypertension.

[17]  P. Ho,et al.  Measurement of basilar artery diameter in dogs: CT evaluation correlated with arteriography , 1988, Neuroradiology.

[18]  L. Chao,et al.  Kallikrein Gene Delivery Improves Cardiac Reserve and Attenuates Remodeling After Myocardial Infarction , 2002, Hypertension.

[19]  John H. Zhang,et al.  Oxyhemoglobin induces caspase‐mediated cell death in cerebral endothelial cells , 2001, Journal of neurochemistry.

[20]  F. Sellke,et al.  Microvascular Endothelial Dysfunction and its Mechanism in a Rat Model of Subarachnoid Hemorrhage , 2001, Anesthesia and analgesia.

[21]  John H. Zhang,et al.  Oxyhemoglobin produces apoptosis and necrosis in cultured smooth muscle cells , 2001, Brain Research.

[22]  J. M. Findlay,et al.  CT angiography for the detection of cerebral vasospasm in patients with acute subarachnoid hemorrhage. , 2000, AJNR. American journal of neuroradiology.

[23]  John H. Zhang,et al.  Apoptosis of endothelial cells in vessels affected by cerebral vasospasm. , 2000, Surgical neurology.

[24]  A. Pasqualin.  Epidemiology and pathophysiology of cerebral vasospasm following subarachnoid hemorrhage. , 1998, Journal of neurosurgical sciences.

[25]  S. Endo,et al.  Experimental model of symptomatic vasospasm in rabbits. , 1988, Stroke.