The Vannucci Model of Hypoxic-Ischemic Injury in the Neonatal Rodent: 40 years Later

Abstract

Perinatal hypoxic-ischemic (HI) brain damage has long been a major cause of acute mortality and chronic neurologic morbidity in infants and children. Experimental animal models are essential to gain insights into the pathogenesis and management of perinatal HI brain damage. Prior to 1980 only large animal models were available. The first small animal model was developed in the postnatal 7 (P7) rat in 1981, now known as the Vannucci model. This model combines unilateral carotid artery ligation with subsequent hypoxia to produce transient hemispheric hypoxia-ischemia in the hemisphere ipsilateral to the ligation while the contralateral hemisphere is exposed to hypoxia only. This model has been characterized with studies of cerebral hemodynamics, cerebral metabolic changes, and acute and chronic neuropathology. Over the past 40 year this animal model has been utilized in numerous laboratories around the world, has been adapted to the immature mouse, as well as to immature rodents at various stages of development. This brief review describes the validation and characterization studies of the original model and some of the adaptations. A discussion of all of the studies focused on specific cell types is beyond the scope of this review. Rather, we present the application of the model to the study of a specific cell type, the pre-oligodendrocyte, and the role this cell plays in the development of white matter injury in the preterm brain.

A Novel Murine Multi-Hit Model of Perinatal Acute Diffuse White Matter Injury Recapitulates Major Features of Human Disease

“…In this model, the combination of hypoxia and ischemia is required to produce brain injury. Rats are able to survive periods of hypoxia without brain damage, and the unilateral induction of ischemia through carotid artery ligation can be compensated for by contralateral circulation thanks to the rats’ complete Circle of Willis [ 27 ]. This model has been modified in recent years to optimize injury timing relative to the time course of oligodendrocyte lineage development in rodent white matter [ 27 ].…”

“…Rats are able to survive periods of hypoxia without brain damage, and the unilateral induction of ischemia through carotid artery ligation can be compensated for by contralateral circulation thanks to the rats’ complete Circle of Willis [ 27 ]. This model has been modified in recent years to optimize injury timing relative to the time course of oligodendrocyte lineage development in rodent white matter [ 27 ]. Steps to adapt this model to mice have revealed significant strain-specific differences in sensitivity to hypoxic–ischemic injury [ 28 ].…”

Therapeutic hypercapnia. Review

“…The effectiveness of the use of hypoxia has been proven both as a preventive and therapeutic agent. It has been established that hypoxic training for a month reduces the incidence of cystic infarction in the brain of rats associated with compression of the common carotid artery, and also positively affects the energy metabolism of the nervous tissue, increasing its resistance to ischemia [31,32]. Interval highaltitude hypoxia has been successfully used to prevent the development of ischemic necrosis of the rat myocardium [33].…”

Restraint stress during neonatal hypoxia‐ischemia alters brain injury following normothermia and hypothermia

“…Perinatal hypoxic–ischemic (HI) brain injury is a major cause of neonatal mortality and neurodevelopmental morbidity (Kurinczuk et al, 2010 ). The Vannucci model (Vannucci & Back, 2022 ; Vannucci & Vannucci, 1997 , 2005 ) in postnatal day 7 rats (P7) (Semple et al, 2013 ; Yager et al, 1996 ) is a widely‐used experimental model of neonatal HI injury and is based on the Levine model (Levine, 1960 ) in adult rats. The Vannucci model has become the animal model of choice in exploring therapeutic treatments for HI injury (Vannucci & Vannucci, 2005 ), such as hypothermia (HT), with which our group has 30 years of experience (Thoresen, Bagenholm, et al, 1996 ).…”