title: A novel reproducible model of neonatal stroke in mice: comparison with a hypoxia-ischemia model.
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, 24h 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.
authors: Department of Regenerative Medicine and Tissue Engineering, National Cerebral and Cardiovascular Center Research Institute, 5-7-1, Fujishiro-dai, Suita, Osaka, 565-8565, Japan. tsuji.masahiro.ri@mail.ncvc.go.jp
authors: Masahiro
authors: M
authors: Tsuji
authors: Makiko
authors: M
authors: Ohshima
authors: Akihiko
authors: A
authors: Taguchi
authors: Yukiko
authors: Y
authors: Kasahara
authors: Tomoaki
authors: T
authors: Ikeda
authors: Tomohiro
authors: T
authors: Matsuyama
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D001835:Body Weight; D001921:Brain / Q000473:pathology; D004195:Disease Models, Animal; D005106:Exploratory Behavior; D005260:Female; D020925:Hypoxia-Ischemia, Brain / Q000150:complications* / Q000473:pathology; D020244:Infarction, Middle Cerebral Artery / Q000150:complications*; D008297:Male; D051379:Mice; D009048:Motor Skills / Q000502:physiology; D012039:Regional Blood Flow / Q000502:physiology; D045442:Rotarod Performance Test; D020521:Stroke / Q000209:etiology* / Q000401:mortality / Q000473:pathology*; D013997:Time Factors
keywords: ANOVA; CB-17 mouse; CBF; Focal ischemia; HI; HIE; Hypoxic–ischemic encephalopathy; MCA; MCAO; Middle cerebral artery occlusion; NE; Neonatal encephalopathy; Neonatal stroke; Variability; analysis of variance; cerebral blood flow; hypoxic–ischemic encephalopathy; hypoxic–ischemic, hypoxia–ischemia; middle cerebral artery; middle cerebral artery occlusion; neonatal encephalopathy