A novel reproducible model of neonatal stroke in mice: Comparison with a hypoxia–ischemia model

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Abstract

Neonatal stroke occurs in 1/4000 live births and leaves life-long neurological impairments, such as cerebral palsy and epilepsy. Currently, the rodent models of neonatal stroke that are available exhibit significant inter-animal variability, which makes it difficult to accurately assess the mechanisms of brain injury and the efficacy of candidate treatments. We aimed to introduce a novel, highly reproducible model of stroke, middle cerebral artery occlusion (MCAO), in immature mice, and to evaluate the reproducibility of this model compared with a conventional hypoxia–ischemia (HI) model. Postnatal day 12 CB-17 mice underwent left MCAO by direct electrocoagulation. The MCAO model exhibited excellent long-term survival; 85% up to 8 weeks after the insult. Infarct was evident in every animal with MCAO (n = 27) and was confined to the cortex, with the exception of some mild thalamic injury. While the % stroke volume 48 h after the insult was consistent in the MCAO group, range: 17.8–30.4% (minimum–maximum), it was substantially less consistent in the HI group, range: 3.0–70.1%. This contrasting variability between the two models was also evident in the cerebral blood flow, 24 h after the insult, and in the ipsilateral hemispheric volume, as assessed at 8 weeks after the insult. Mice with MCAO exhibited significant neurofunctional deficits in the rotarod and open-field tests. Preclinical studies for neonatal stroke could become more reliable using this model, with even a potential reduction in the number of pups required for statistical significance. The contrasting variability between the two models may provide insights into the factors that contribute to inter-animal variability in brain injury.

Graphical abstract

Our new neonatal stroke model with middle cerebral artery occlusion (MCAO) is highly reproducible, as compared with a conventional hypoxia–ischemia (HI) model.

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