Middle occlusion model

Table 5.1 Effects of compound 231617 on infarct volume in the middle cerebral occlusion model of focal stroke...

KawasakiYatsugi S, Ichiki C, Yatsugi S, et al (2000) Neuroprotective effects of an AMPA receptor antagonist YM872 in a rat transient middle cerebral artery occlusion model. Neuropharmacology 39 211-217... 

Young W., RappaportZ. H., Chalif D. J., and Flamm E. S. (1987) Regional brain sodium, potassium, and water changes in the rat middle cerebral artery occlusion model of ischemia. Stroke 18, 751-759. 

The middle cerebral artery occlusion model (MCAO) is commonly used in experimental focal cerebral ischemia. This technique causes hypothalamic injury resulting in hyperthermia, worsening outcome and possibly masking neuroprotective effects. Thus, careful temperature monitoring is needed in those preclinical studies. Recently, Gerriets et al. (10) introduced a new MCAO model that involves intraarterial embolizationusing macrospheres. Unlike the traditional MCAO suture model, this macrosphere model does not result in hyperthermia and yet provides reproducible infarcts. 

Kurozumi K, Nakamura K, Tamiya T, et al. (2004). BDNF gene-modified mesenchymal stem ceils promote functional recovery and reduce infarct size in the rat middle cerebral artery occlusion model. Mol. Ther. 9 189-197. 

Sinha K, Chaudhary G, Kumar Gupta Y. Protective effect of resveratrol against oxidative stress in middle cerebral artery occlusion model of stroke in rats. Life Sci 2002 71 655-665. 

Ebselen (Fig. 3.5), a selenium compound with glutathione peroxidase-like activity, is a modestly effective neuroprotectant in a rat transient middle cerebral artery occlusion model when given before the start of ischemia, but not when the insult is severe. Data from the permanent middle cerebral artery occlusion model and an embolic stroke model result in a bell-shaped dose-response curve. This weak pre-clinical profile explains the lack of success in clinical trials in humans (Green and Ashwood, 2005). 

Methyl-l-phenyl-2-pyrazolin-5-one (MCI-186) is a potent scavenger of hydroxyl radicals inhibiting not only hydroxyl radicals but iron-induced per-oxidative injury (Watanabe etal. 1988, Muroto et al. 1990). After the reaction with peroxy radicals, MCI-186 changes into 2-oxo-3-(phenylhydrazone)-butanoic acid (Yamamoto et al. 1996, Kawai et al. 1997). In a thrombotic rat distal middle cerebral artery occlusion model, 3-methyl-l-phenyl-2-pyrazolin-5-one (3 mg/kg) significantly P < 0.05) decreased the size of the cerebral infarct 1 day after artery occlusion (Kawai et al. 1997). 

Since the early 1980s, much effort has focused on animal models of acute and chronic neurodegeneration in search of therapeutics for stroke. Neuronal cell death follows strokes, acute ischemic insults, and chronic neurodegeneration, such as Parkinson s disease, Alzheimer s disease (AD), epilepsy, and Huntington s disease. Up to 80% of all strokes result from focal infarcts and ischemia in the middle cerebral artery (MCA), so the commonly used animal models for neuroprotection are produced by temporary or permanent occlusion of the MCA.5 Lesions of the MCA include occlusion by electrocoagulation, intraluminal monofilaments, photochemical effects, thrombosis, and endothelin-1, but all of these models necessitate studying reperfusion events and validating MCA occlusion by behavioral assessments. 

In states of focal cerebral ischemia, repetitive MRI has elucidated the natural course of brain lesions which - as a regular phenomenon - show considerable lesion enlargement over time. This observation was made by using DWI in animal models with occlusion of the middle cerebral artery. To date, we have little information on the natural course of ischemic lesions that are of hemodynamic origin or the result... 

Kohno K, Back T, Hoehn-Berlage M, Hossmann K-A (1995a) A modified rat model of middle cerebral artery thread occlusion under electrophysiological control for magnetic resonance investigations. Magn Reson Imag 13 65-71... 

A number of animal models have been developed to mimic cerebral ischemia experimentally. They can be roughly categorized into global (bilateral arterial occlusion) and focal (unilateral arterial occlusion) cerebral ischemia models. Probably the widest applied method is the middle cerebral artery occlusion (MCAO), performed by transiently blocking the arterial blood flow with a removable thread or... 

Nagai S., Irikura K., Maruyama S., and Miyasaka Y. (1999) The significance of hypothermic acid-base management induced before ischemia in a rat model of transient middle cerebral artery occlusion. Neurol. Res. 21, 204-208. 

Gerriets T., Li F., Silva M. D., Meng X., Brevard M., Sotak C. H., and Fisher M. (2003) The macrosphere model. Evaluation of a new stroke model for permanent middle cerebral artery occlusion in rats. J. Neurosci. Methods 122, 201-211. 

In a study using spontaneously hypertensive rats, a dose of 12 mg kg-1 of compound X was also neuroprotective [these rats were subjected to 2h of focal ischemia by occlusion of the right middle cerebral artery (MCA), followed by 22 h of reperfusion]. With the assumption of 100% systemic absorption, the expected plasma Cmax at this dose was 2000ng ml In this model, there was a significant reduction (greater than 30%) in cortical infarct volume, compared with saline controls, when the drug was given at the time of occlusion and at 0, 0.5, 1 and 1.5 h post-MCA occlusion. 

Takasago T, Peters EE, Graham DI, et al. 1997. Neuroprotective efficacy of ebselen, an anti-oxidant with anti-inflammatory actions, in a rodent model of permanent middle cerebral artery occlusion. Br J Pharmacol 122 1251-1256. 

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