Neuroimaging and histopathological evaluation of delayed neurological damage produced by artificial occlusion of the middle cerebral artery in Cynomolgus monkeys: establishment of a monkey model for delayed cerebral ischemia.

A monkey model (Cynomolgus) was established to evaluate the delayed neurological damage evident at areas distant from ischemic cerebral foci. In addition to proton magnetic resonance spectroscopy (MRS) monitoring in life, histological examinations of specimens of the brain was conducted on lesions produced 6h and 1, 2, 4 and 8 weeks after unilateral (left) permanent middle cerebral artery occlusion (pMCO) on five monkeys. In addition to the typical images evident at primary ischemic foci around the middle cerebral artery, MRS revealed and enhanced, clearer region, due to edema extending into the reticular and compact area of the left substantia nigra one week after pMCO, inducing right hemiparesis caused by focal cerebral ischemia. Similar histological lesions were also induced in the left thalamus 4 weeks after pMCO. Thereafter, a variety of histological findings including astrocytic activation, reduced number of nerve cells and gliosis were found in the above described areas far apart from the original ischemic cerebral foci. Our monkey model should be suitable for studies elucidating the pathological process in cerebral ischemia as well as for investigating therapeutic strategies involving ischemic stroke in humans.

A third-generation, long-acting, dihydropyridine calcium antagonist, azelnidipine, attenuates stent-associated neointimal formation in non-human primates.

BACKGROUND: Calcium antagonists have been shown to reduce atherogenesis and improve clinical outcomes in atherosclerotic vascular disease. No study has so far, however, addressed the effects of calcium antagonists on stent-associated neointimal formation. We therefore investigated whether a third-generation calcium antagonist, azelnidipine, attenuates in-stent neointimal formation in non-human primates. METHOD: Male cynomolgus monkeys were fed a high cholesterol diet for 4 weeks, and were randomly assigned to three groups: a vehicle group and two other groups treated with azelnidipine at 3 and 10 mg/kg per day for an additional 24 weeks (n = 12 each). Multi-link stents were then implanted in the iliac artery. RESULTS: Azelnidipine at the high dose reduced neointimal thickness (0.25 +/- 0.02 versus 0.19 +/- 0.02 mm; P < 0.05). Azelnidipine also reduced local oxidative stress and monocyte chemoattractant protein 1 (MCP-1) expression. No difference was found between the three groups in the degrees of injury score, inflammation score, plaque neovascularization, or plasma lipid levels. Azelnidipine also reduced MCP-1-induced proliferation/migration of vascular smooth muscle cells in vitro. CONCLUSIONS: This study demonstrated for the first time that azelnidipine attenuates in-stent neointimal formation associated with the reduced expression of MCP-1 and smooth muscle proliferation/migration in the neointima. These data in non-human primates suggest potential clinical benefits of azelnidipine as a 'vasculoprotective calcium antagonist' in patients undergoing vascular interventions.

Cholesterol-lowering independent regression and stabilization of atherosclerotic lesions by pravastatin and by antimonocyte chemoattractant protein-1 therapy in nonhuman primates.

OBJECTIVE: Anti-atherosclerotic effects of statins might be mediated partly by pleiotropic cholesterol-lowering independent mechanisms. We used nonhuman primates and examined whether treatment with pravastatin or antimonocyte chemoattractant protein-1 (MCP-1) therapy can induce regression and stabilization of established atherosclerotic lesions through cholesterol-lowering independent mechanisms. METHODS AND RESULTS: Advanced atherosclerosis was induced in the abdominal aorta and the common iliac artery of cynomolgus monkeys by undergoing balloon injury and giving atherogenic diet for 6 months. At 6 months, the diet was changed to normal chow, and the animals were allocated to 4 treatment groups: control vehicle group and other groups treated with pravastatin (1 or 10 mg/kg) or with mutant MCP-1 gene transfection for additional 6 months. Each compound was treated instead of the atherogenic diet, and cholesterol contents in pravastatin-treated groups were adjusted to equalize plasma cholesterol level among groups. Pravastatin reduced neointimal formation in the aorta, but not in the common iliac artery. Pravastatin reduced intimal macrophage area and other markers of plaque destabilization in the common iliac artery. Equivalent inhibitory effects were observed in animals that received mutant MCP-1 gene transfection. No serious side effects were noted by 2 therapeutic modalities. CONCLUSIONS: This study demonstrated cholesterol-lowering independent regression and stabilization of established atherosclerotic lesions by pravastatin and by anti-MCP-1 therapy in nonhuman primates. An anti-inflammatory mechanism may be involved in the beneficial effects of pravastatin.