Animal Models of Neonatal Stroke/Ischemia

Sources of Funding

NINDS_NS80015, NINDS_NS44025, NINDS_NS76726, The Leducq Foundation DSRR_P34404.

Introduction

Development of age-appropriate models of cerebral ischemia and/or hypoxia has allowed knowledge that brain immaturity at the time of injury plays a key role in the pattern of brain damage. Furthermore, studies of ischemia in immature animals of differing ages have made apparent how rapidly changing the injury response is within the “immaturity spectrum,” in part due to different developmental steps of individual brain regions at any given time and the existence of cell type–specific susceptibility to injury. We will summarize available models of at-term ischemic brain injury in rodents and in larger species and discuss how the maturational stage of the brain at the time of an insult affects the underlying injury components with regard to the mechanisms of hypoxic-ischemic encephalopathy (HIE) and stroke in human infants.

Developmental Patterns of Ischemia-Associated Brain Damage in Preterm and Term Infants

Hemorrhage and periventricular white matter injury, including periventricular leukomalacia, are the most common types of ischemia-related injuries in preterm human babies. These injury patterns predominate largely due to a weak germinal matrix and the immaturity of oligodendrocyte progenitors. Unlike in preterm, at term ischemia-related injury is no longer diffuse and is manifested focally in gray matter regions, most commonly in the striatum, thalamus, and cortex. Perinatal arterial ischemic stroke is frequent, up to 1 in 2300 live infant births, and produces significant morbidity and severe long-term neurological and cognitive deficits, including cerebral palsy, neurodevelopmental disabilities, and impaired vision . Although injury types are different in preterm and at term, infection and inflammation are the major predisposing and/or modulatory factors in ischemic injury in both age groups .

Large Animal Models of Ischemia-Related Injury

Various models of hypoxia, hypoxia-ischemia (H-I), and focal stroke have been developed in rodents and in larger species to mimic an array of injuries seen in the human infant. Sheep, pigs, and rabbits are the most commonly used nonrodent mammal species to induce H-I in the immature brain. The advantages of these models are that these species have a white/gray matter ratio closer to the human brain than rodents. Cerebral H-I models in fetal sheep induced by bilateral transient occlusion of the carotid arteries during midgestation and in late gestation demonstrated predominant white matter lesions and deep gray matter injury following H-I during midgestation but cortical laminar necrosis in the late-gestation fetus, vulnerability patterns that correlate well with human pathology. At the same time, findings in sheep are relevant to preterm stages in the human because sheep are precocial species. Nevertheless, studies in sheep and in newborn piglets have helped in the development of therapeutic hypothermia for infants with HIE. In rabbits, intrauterine ischemia induced by the Tan lab around 22 days gestation mimicked injury in preterm, whereas intrauterine ischemia at the end of gestation, at 29 days, mimicked injury at term, demonstrating predictive value of animal modeling.

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