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Abstract
Brain damage resulting from perinatal cerebral hypoxia and ischemia is a major cause of acute mortality and neurological disabilities, including cerebral palsy (CP) and cognitive dysfunction. In order to establish an experimental hypoxia-ischemia (HI) model of CP for the screening of therapeutics, we operated bilateral common carotid artery ligation (BCAO) and monolateral carotid artery occlusion (MCAO), followed by 15 min of hypoxia (8% oxygen) in 4-day-old rats, and evaluated neurobehavioral disorders. After surgery, the survival rates of male and female BCAO rats were 33.3 and 7.1%, respectively, whereas 100% and 82.4% MCAO rats survived. In neurobehavioral performances, both male and female BCAO rats showed delayed achievement of righting reflex, in contrast to a negligible effect in MACO animals. However, both BCAO and MCAO rats exhibited impairment of cliff avoidance performances, although the physical dysfunction was more severe in BCAO than in MCAO. In global locomotor activity, MCAO rats also displayed decreased fast-moving time comparable BCAO animals, and increased resting and slow-moving times. In addition, MCAO rats showed marked learning and memory deficit in passive avoidance performances, similar to BCAO animals. From immunostaining analyses, severe degradation and loss of myelin basic proteins were observed in the brain of BCAO rats, in contrast to a mild aggregation in MCAO animals. Therefore, it is suggested that MCAO should be a more suitable CP model than BCAO, based on the high survival rate, relatively-mild brain injury, and enough neurobehavioral disorders for the research on preventive and therapeutic compounds.
References
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Figure 1.
Righting reflex of normal (●), monolateral carotid artery occlusion (MCAO, ▼) and bilateral carotid artery occlusion (BCAO, ■) rats. Rats were subjected to hypoxia-ischemia operation on postnatal day 4 (PND4), and to righting reflex performances on PND8–21. A, male; B, female.
Figure 2.
Cliff avoidance reflex of normal (●), monolateral carotid artery occlusion (MCAO, ▼) and bilateral carotid artery occlusion (BCAO, ■) rats. Rats were subjected to hypoxia-ischemia operation on postnatal day 4 (PND4), and to cliff avoidance performances on PND8–21. Cut-off time was set at 60 sec. A, male; B, female.
Figure 3.
Locomotor activity of normal (●), monolateral carotid artery occlusion (MCAO, ▼) and bilateral carotid artery occlusion (BCAO, ■) rats. Rats were subjected to hypoxia-ischemia operation on postnatal day 4 (PND4), and locomotor activity was monitored for 5 min on PND9–12.
Figure 4.
Learning and memory function of normal (●), monolateral carotid artery occlusion (MCAO, ▼) and bilateral carotid artery occlusion (BCAO, ■) rats. Rats were subjected to hypoxia-ischemia operation on postnatal day 4 (PND4), and to passive avoidance performances on PND18–21. Cut-off time was set at 300 sec. A, male; B, female.
Figure 5.
Representative photomicrographs of myelin basic protein (MBP) immunostaining in the periventricular regions of monolateral carotid artery occlusion (MCAO, A) and bilateral carotid artery occlusion (BCAO, B) rats. Note the red fluorescence of MBP, showing mild aggregation in MCAO and severe degradation and loss in BCAO rats.
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