Neurological impairment in rats after transient middle cerebral artery occlusion: a comparative study under various treatment paradigms

Abstract

The assessment of the functional outcome - in addition to the conventional endpoints as histomorphometry of the ischemic brain damage - for the evaluation of cerebroprotective therapies is increasingly recommended, although there is little consensus on appropriate procedures. We evaluated a battery of sensorimotor tasks in rats after transient middle cerebral artery occlusion (MCAO) to select those with the highest potential to discriminate between various degrees of neuronal damage. A total of 40 Sprague-Dawley rats were subjected to 90 min of MCAO and assigned to one of four treatment arms: (1) sham-operated controls, (2) vehicle-treated controls, (3) moderately effective neuroprotection by 2x100 mg/kg alpha-phenyl-N-tert-butyl nitrone (PBN), (4) highly effective neuroprotection by mild hypothermia (33 degrees C). Functional deficits were daily quantified using the beam balance task (1.5 cm, 2.5 cm diameter rectangular and 2.5 cm diameter cylindrical beam), the prehensile traction task, the rotarod, and a six-point neuro-score. Infarction of cerebral cortex and basal ganglia was assessed one week after ischemia. Treatment with PBN significantly reduced cortical infarction (-31%), while treatment with hypothermia resulted in a significantly smaller infarct volume of cortex (-94%) and basal ganglia (-27%). Beam balance, prehensile traction and rotarod failed to demonstrate any difference in motor performance. The six-point neuro-score showed a significant correlation with cortical infarction from day 2 and with total infarct volume from day 3. The smaller the reduction of infarct volume, the later the corresponding difference in neuro-score became apparent. Functional outcome after MCAO in rats can be assessed by a relatively simple measurement of neurological deficit. The slope of functional recovery is closely related with the degree of the morphological, particularly cortical damage. If expected treatment effects are small, an observation period of at least 3 days should be planned for the study design. The functional impairment from focal brain ischemia and its subsequent recovery could provide valuable information for future studies evaluating the neuroprotective potential of novel agents and procedures.