Cerebral hemorrhage therapy by targeting VEGF and HGF in a preclinical trial in rats

Li,Xueqing; Cao,Ruiqi; Lu,Huaihai; Tian,Wenbin; Yu,Ning; Zhang,Pei; Dong,Zhenming

doi:10.3892/mmr.2017.6355

Cerebral hemorrhage therapy by targeting VEGF and HGF in a preclinical trial in rats

Authors:
- Xueqing Li
- Ruiqi Cao
- Huaihai Lu
- Wenbin Tian
- Ning Yu
- Pei Zhang
- Zhenming Dong
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Affiliations: Department of Intensive Care Unit of Anesthesiology, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, P.R. China
Published online on: March 22, 2017 https://doi.org/10.3892/mmr.2017.6355
Pages: 3093-3098

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Abstract

Cerebral hemorrhage is the most common type of human cerebrovascular disease and frequently causes paralysis, vegetative state and mortality. The modulatory actions of vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF) are vital in the human nervous system. The present study investigated the association between cerebral hemorrhage and the expression of VEGF and HGF in a rat model of cerebral hemorrhage. The therapeutic potential of cerebral hemorrhage was also evaluated using targeted drugs for VEGF and HGF in the cerebral hemorrhage rat model. Behavioral and preclinical changes and the survival rates of rats were assessed after treatment with VEGF receptor (VEGFR) and HGF receptor (HGFR). The results of Tarlov scores demonstrated that movement of limbs and coordination when walking were significantly improved in moderate and severe hemorrhage lesions in the VEGFR plus HGFR‑treated group and mainly alleviated in primary hemorrhage lesions compared with rats in the single VEGFR or HGFR‑treated groups and the control group (**P<0.01). Decreasing expression levels of VEGF and HGF were observed in the neural tissue of animals treated with VEGFR plus HGFR compared with the control group (**P<0.01). These preclinical observations indicated that VEGF and HGF serve a function in the pathological injury and repair of cerebral tissue in rats with cerebral hemorrhages. The therapeutic benefits of VEGFR plus HGFR suggested that VEGFR plus HGFR may be candidate drugs for cerebral hemorrhage, and thus offer a promising treatment for clinicians and doctors.

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1	Sussman ES and Connolly ES Jr: Hemorrhagic transformation: A review of the rate of hemorrhage in the major clinical trials of acute ischemic stroke. Front Neurol. 4:692013. View Article : Google Scholar : PubMed/NCBI
2	Kobayashi T, Tadokoro H, Odai T, Hibino T and Waki K: A delayed cerebral vasospasm with infarction is secondary to listeria monocytogenes meningitis: MRI and MRA are diagnostically useful. Intern Med. 54:2935–2938. 2015. View Article : Google Scholar : PubMed/NCBI
3	Lee WJ, Yeon JY, Jo KI, Kim JS and Hong SC: Reversible cerebral vasoconstriction syndrome and posterior reversible encephalopathy syndrome presenting with deep intracerebral hemorrhage in young women. J Cerebrovasc Endovasc Neurosurg. 17:239–245. 2015. View Article : Google Scholar : PubMed/NCBI
4	Kanamaru K, Suzuki H and Taki W: Cerebral infarction after aneurysmal subarachnoid hemorrhage. Acta Neurochir Suppl. 121:167–172. 2016.PubMed/NCBI
5	Brown RJ, Epling BP, Staff I, Fortunato G, Grady JJ and McCullough LD: Polyuria and cerebral vasospasm after aneurysmal subarachnoid hemorrhage. BMC Neurol. 15:2012015. View Article : Google Scholar : PubMed/NCBI
6	Jenson AV, Rodriguez GJ, Alvarado LA, Cruz-Flores S and Maud A: Higher rate of intracerebral hemorrhage in hispanic patients with cerebral cavernous malformation. J Vasc Interv Neurol. 8:1–4. 2015.PubMed/NCBI
7	Dabus G and Nogueira RG: Current options for the management of aneurysmal subarachnoid hemorrhage-induced cerebral vasospasm: A comprehensive review of the literature. Interv Neurol. 2:30–51. 2013. View Article : Google Scholar : PubMed/NCBI
8	Sehba FA, Pluta RM and MacDonald RL: Brain injury after transient global cerebral ischemia and subarachnoid hemorrhage. Stroke Res Treat. 2013:8271542013.PubMed/NCBI
9	Matsumoto H and Yoshida Y: Rapid progression of cerebral infarction after intraventricular hemorrhage in adult moyamoya disease. J Korean Neurosurg Soc. 54:411–414. 2013. View Article : Google Scholar : PubMed/NCBI
10	Wu L and Chen G: Signaling pathway in cerebral vasospasm after subarachnoid hemorrhage: News update. Acta Neurochir Suppl. 121:161–165. 2016.PubMed/NCBI
11	Kidwell CS, Chalela JA, Saver JL, Starkman S, Hill MD, Demchuk AM, Butman JA, Patronas N, Alger JR, Latour LL, et al: Comparison of MRI and CT for detection of acute intracerebral hemorrhage. JAMA. 292:1823–1830. 2004. View Article : Google Scholar : PubMed/NCBI
12	Roever L and Levine SR: Cerebral hemorrhage following thrombolytic therapy for stroke: Are neutrophils really neutral? Neurology. 85:1360–1361. 2015. View Article : Google Scholar : PubMed/NCBI
13	Wang DN, Hou XW, Yang BW, Lin Y, Shi JP and Wang N: Quantity of cerebral microbleeds, antiplatelet therapy, and intracerebral hemorrhage outcomes: A systematic review and meta-analysis. J Stroke Cerebrovasc Dis. 24:2728–2737. 2015. View Article : Google Scholar : PubMed/NCBI
14	Li X, Wang R, Wang X, Xue X, Ran D and Wang S: Relevance of IL-6 and MMP-9 to cerebral arteriovenous malformation and hemorrhage. Mol Med Rep. 7:1261–1266. 2013.PubMed/NCBI
15	Yang T, Gu J, Kong B, Kuang Y, Cheng L, Cheng J, Xia X, Ma Y and Zhang J: Gene expression profiles of patients with cerebral hematoma following spontaneous intracerebral hemorrhage. Mol Med Rep. 10:1671–1678. 2014.PubMed/NCBI
16	Chu SH, Feng DF, Ma YB, Zhang H, Zhu ZA, Li ZQ and Zhang ZH: Expression of HGF and VEGF in the cerebral tissue of adult rats with chronic hydrocephalus after subarachnoid hemorrhage. Mol Med Rep. 4:785–791. 2011.PubMed/NCBI
17	Rozman A, Silar M and Kosnik M: Angiogenin and vascular endothelial growth factor expression in lungs of lung cancer patients. Radiol Oncol. 46:354–359. 2012. View Article : Google Scholar : PubMed/NCBI
18	Liu CZ, Zhang L, Chang XH, Cheng YX, Cheng HY, Ye X, Fu TY, Chen J and Cui H: Overexpression and immunosuppressive functions of transforming growth factor 1, vascular endothelial growth factor and interleukin-10 in epithelial ovarian cancer. Chin J Cancer Res. 24:130–137. 2012. View Article : Google Scholar : PubMed/NCBI
19	Hodorowicz-Zaniewska D, Kibil W, Malek A, Szpor J, Kulig J and Sztefko K: Evaluation of serum concentrations of vascular endothelial growth factor (VEGF) in breast cancer patients. Pol J Pathol. 63:255–260. 2012. View Article : Google Scholar : PubMed/NCBI
20	Dahlberg SE, Sandler AB, Brahmer JR, Schiller JH and Johnson DH: Clinical course of advanced non-small-cell lung cancer patients experiencing hypertension during treatment with bevacizumab in combination with carboplatin and paclitaxel on ECOG 4599. J Clin Oncol. 28:949–954. 2010. View Article : Google Scholar : PubMed/NCBI
21	Kim CH, Qi G, Dahlberg K and Li W: Strontium-doped perovskites rival platinum catalysts for treating NOx in simulated diesel exhaust. Science. 327:1624–1627. 2010. View Article : Google Scholar : PubMed/NCBI
22	Palma J, Macedonia C, Deuster P, Olsen C, Mozayeni BR and Crutchfield KE: Cerebrovascular dynamics and vascular endothelial growth factor in acute mountain sickness. Wilderness Environ Med. 17:1–7. 2006. View Article : Google Scholar : PubMed/NCBI
23	Ding Y, Adachi H, Katsuno M, Huang Z, Jiang YM, Kondo N, Iida M, Tohnai G, Nakatsuji H, Funakoshi H, et al: Overexpression of hepatocyte growth factor in SBMA model mice has an additive effect on combination therapy with castration. Biochem Biophys Res Commun. 468:677–683. 2015. View Article : Google Scholar : PubMed/NCBI
24	Chu SH, Feng DF, Ma YB, Zhu ZA, Zhang H and Qiu JH: Stabilization of hepatocyte growth factor mRNA by hypoxia-inducible factor 1. Mol Biol Rep. 36:1967–1975. 2009. View Article : Google Scholar : PubMed/NCBI
25	He QS, Yang LF, Wang WB, Yuan B, Zhang LY and Guo XJ: Vascular endothelial growth factor gene is associated with hypertensive cerebellar hemorrhage and rehabilitative treatment. Genet Mol Res. 14:9849–9857. 2015. View Article : Google Scholar : PubMed/NCBI
26	Committee for the Update of the Guide for the Care and Use of Laboratory Animals: Guide for the Care and Use of Laboratory Animals. 8th. National Academies Press; Washington, DC: 2011
27	Chamnanvanakij S, Margraf LR, Burns D and Perlman JM: Apoptosis and white matter injury in preterm infants. Pediatr Dev Pathol. 5:184–189. 2002. View Article : Google Scholar : PubMed/NCBI
28	Riggs AJ and Riggs JE: Epilepsy's role in the historical differentiation of religion, magic and science. Epilepsia. 46:452–453. 2005. View Article : Google Scholar : PubMed/NCBI
29	Gao F, Guo Y, Zhang H, Wang S, Wang J, Wu JM, Chen Z and Ding MP: Anterior thalamic nucleus stimulation modulates regional cerebral metabolism: An FDG-MicroPET study in rats. Neurobiol Dis. 34:477–483. 2009. View Article : Google Scholar : PubMed/NCBI
30	Aliparasti MR, Almasi S, Sanaat Z, Movasaghpoor A, Khalili-Dizaji R and Sadeghi-Bazargani H: Gene expression of VEGF-A and VEGF-C in peripheral blood mononuclear cells of iranian patients with acute myeloid leukemia. Turk J Haematol. 30:137–143. 2013. View Article : Google Scholar : PubMed/NCBI
31	Ramezani A, Nägga K, Hansson O, Lönn J, Sjöwall J, Katoozian F, Mansouri S and Nayeri F: Hepatocyte growth factor in cerebrospinal fluid differentiates community-acquired or nosocomial septic meningitis from other causes of pleocytosis. Fluids Barriers CNS. 12:222015. View Article : Google Scholar : PubMed/NCBI
32	Zhou X and He QH: Hepatocyte growth factor and male reproduction. Zhonghua Nan Ke Xue. 21:747–752. 2015.(In Chinese). PubMed/NCBI
33	Ishibashi H, Tonomura H, Ikeda T, Nagae M, Sakata M, Fujiwara H, Tanida T, Mastuda K, Kawata M and Kubo T: Hepatocyte growth factor/c-met promotes proliferation, suppresses apoptosis, and improves matrix metabolism in rabbit nucleus pulposus cells in vitro. J Orthop Res. 34:709–716. 2016. View Article : Google Scholar : PubMed/NCBI