Strain Variability, Injury Distribution, and Seizure Onset in a Mouse Model of Stroke in the Immature Brain

Abstract

Neonatal stroke is an important cause of neurologic morbidity and cerebral palsy. Recently, we have determined that in postnatal day 12 CD1 mice unilateral carotid ligation alone results in seizures and brain injury. We have shown that, in this model, seizure scores correlate with brain injury scores. We have applied this model to another strain of mice to assess strain-related differences in vulnerability to seizures and brain injury after unilateral carotid ligation. Under isoflurane anesthesia, unilateral right-sided carotid ligation was performed in postnatal day 12 C3HeB/FeJ mice followed by a 4-hour period of observation in a 35°C incubator. Seizure scores and brain jury scores were assigned and compared to scores in mice receiving sham surgery. Timing of seizure onset and regional distribution of brain injury were compared in the CD1 and C3HeB/FeJ mice. Unilateral carotid ligation in postnatal day 12 C3HeB/FeJ mice resulted in seizure behavior and brain injury in some animals, with similar time to seizure onset and regional injury distribution, but affected a significantly smaller percentage of C3HeB/FeJ pups than that observed in postnatal day 12 CD1 mice, indicating strain-related vulnerability in this model.

Recombinant Erythropoietin Is Neuroprotective in a Novel Mouse Oxidative Injury Model

“…This model, which results in consistent brain injury with acceptable mortality rates, adds another approach by which investigators can transfer the study of neonatal brain injury from rats to mice. Several neonatal mouse models of brain injury are now available, including carotid artery ligation alone [27] , photothrombosis injury [35] , and excitotoxicity [21] . The postnatal mouse brain development is comparable to that of rats, but there is the added advantage of the availability of transgenic strains which are critical to improving our understanding of both normal development and pathophysiology [36] .…”

“…Unfortunately, mice tend to be more sensitive to hypoxia than rats and have a strainrelated susceptibility to hypoxia-ischemia [26,27] . We, therefore, developed a neonatal mouse model of unilateral brain injury by combining the unilateral carotid artery ligation methods developed by Vannucci and Vannucci [28] in neonatal rats with our novel approach using alternating periods of hypoxia and hyperoxia in order to expose mice to hypoxia for an interval sufficient to trigger brain injury, but in a manner that minimizes the hypoxia-induced mortality.…”

Impact of age and strain on ischemic brain injury and seizures after carotid ligation in immature mice

“…Mice were immediately placed in an incubator at 35 °C. Previously reported data for P12 CD1 mice ( n = 28 ligated and 5 shams from 3 litters) and for P12 C3HeB/FeJ mice ( n = 22 ligated and 3 shams from 3 litters) (Comi et al, 2004; Comi et al, 2005) are included here for direct comparison to the new data.…”

“…Seizure severity was strongly correlated with the extent of brain injury. Furthermore, we have shown that vulnerability to ischemic seizures and injury is less in P12 C3HeB/FeJ mice than in P12 CD1 mice (Comi et al, 2005).…”

Neuroprotection for Ischemic Injury in the Immature Brain

“…The 129Sv mice had the highest mortality (46%) with 30 minutes of hypoxia; of the animals that survived, however, only 17% were injured (Sheldon et al 1998). We also found strain-related variation in susceptibility in the brain injury demonstrated in the unilateral mouse carotid ligation ischemia model [33]. In the P12 C3HeB/FeJ mice, 18% of animals had gross brain injury at 7 days compared to 71% of the P12 CD1 mice.…”