Decompressive Craniectomy, VEGF Gene Transfer And Combined Therapy For Malignant Middle Cerebral Artery Infarction In Rats

There is still a subset of patients who deteriorate rapidly after hospital admission for cerebral infarction, with a mortality approaching 80% when treated conservatively. This occurs in 10 to 15% of supratentorial infarction cases and is involved in the entire middle cerebral artery (MCA) territory. Patients with this "malignant" MCA infarction suffer from coma or death because of large space-occupy brain edema and brain herniation. They may have concomitant anterior cerebral artery (ACA) or posterior cerebral artery (PCA) territory involvement. Thereby, this "malignant" MCA infarction is also called large space-occupy infarction. This patient subpopulation constitutes a particularly difficult challenge for clinicians charged with their cases. Decompressive craniectomy first described by Kocher can reduce intracranial pressure (ICP) and the vicious circle of extensive edema. However, craniectomy may not be effective in these infarcts of the basal ganglia because craniectomy only significantly improves cortical perfusion. Recently,some studies have shown that recombinant adenovirus-mediated human vascular endothelial growth factor (VEGF) gene (rAd-hVEGF) transfer may have foreground in the treatment of cerebral ischemic diseases. Up to date there is no report concerning the appliance of rAd-hVEGF in the animal model of malignant MCA infarction. Considering complex multifactoral process of malignant MCA infarction, microcosmic neuroprotection associated with macroscopical decompression may be ideal treatment. Therefore, the present study was designed to evaluate the singular and combined effects of decompressive craniectomy and/or rAd-hVEGF after permanent endovascular MCA occlusion (MCAO) in rats on mortality, neurological score, infarct volume and density of neurons. Immunoassaying for VEGF was also detected after cerebral infarction. These findings may offer abundant experimental data for the clinical management of malignant MCA infarction.MATERIALS AND METHODSExperimental animals:89 male Sprague-Dawley rats, weighing 290 to 340 g, were provided by Medical Animal Center of Zhejiang University.Methods:1. Groups: The 89 animals were allocated randomly to the following groups: (1) Sham operated group (Con, n=14, as controls); (2) MCAO group (MCAO, n=26, remained untreatment); (3) Decompressive craniectomy group (DC, n=15, received surgery at 1 hour after MCA occlusion); (4) rAd-hVEGF₁₆₅ group (rAd-hVEGF_l65, n=14, received VEGF gene transfer); (5) Combined group (combined, n=14, combined treatment of craniectomy and rAd-hVEGF₁₆₅). Meanwhile, we also set upgroup of sham + rAd-hVEGF₁₆₅ (n=6, sham animals treated with rAd-hVEGF₁₆₅ 7 days before the surgery). And this group was only designed for immunohistochemical observation of VEGF protein.2. Intracerebroventricular injection: Rats were anesthetized with chloral hydrate (10%), placed in a stereotaxic apparatus for intracerebroventricular injection. In Con group, MCAO group and DC group, 7 days before brain ischemia or sham-operation, animals were treated in the right lateral cerebral ventricle injection with physiological saline (20 ul). In rAd-hVEGF₁₆₅ group, sham+ rAd-hVEGF₁₆₅ group and combined group, 20 ul rAd-hVEGF₁₆₅ (4 X 10¹²pfu) was injected.3. MCAO model: The right MCA was permanently occluded via a transvascular approach by nylon suture. Animals with sham operations were as controls.4. Decompressive craniectomy: We performed craniectomy at 1 hour after MCA occlusion in DC group and combined group.5. Mortality, neurological score, infarct volume and neuronal density of different groups were evaluated and compared at 48 hours after brain ischemia or sham operation. Immunoassaying for VEGF was also detected after cerebral infarction.All values are expressed as means ± SD. Kruskal-Wallis test was applied to analysis the difference between groups. Statistical significance was assigned to P value of < 0.05.RESULTS1. Animal mortality at 48h after MCA occlusion was 46.2%. However, they were...