Cerebral blood flow during reperfusion predicts later brain damage in a mouse and a rat model of neonatal hypoxic-ischemic encephalopathy

Abstract

Children with severe neonatal hypoxic-ischemic encephalopathy (HIE) die or develop life-long neurological impairments such as cerebral palsy and mental retardation. Decreased regional cerebral blood flow (CBF) is believed to be the predominant factor that determines the level of tissue injury in the immature brain. However, the spatio-temporal profiles of CBF after neonatal HIE are not well understood. CB17 mouse and Wistar rat pups were exposed to a unilateral hypoxic-ischemic (HI) insult at eight or seven days of age. Laser speckle imaging sequentially measured the cortical surface CBF before the hypoxic exposure and until 24h after the hypoxic exposure. Seven days after the HI insult, brain damage was morphologically assessed by measuring the hemispheric volumes and by semi-quantitative scoring for neuropathologic injury. The mean CBF on the ipsilateral hemisphere in mice decreased after carotid artery ligation. After the end of hypoxic insult (i.e., the reperfusion phase), the mean CBF level gradually rose and nearly attained its pre-surgery level by 9h of reperfusion. It then decreased. The degree of reduced CBF during reperfusion was well correlated with the degree of later morphological brain damage. The correlation was the strongest when the CBF was measured in the ischemic core region at 24h of reperfusion in mice (R²=0.89). A similar trend in results was found in rats. These results suggest that the CBF level during reperfusion may be a useful predictive factor for later brain damage in immature mice. This may enable optimizing brain damage for detail analyses.