We established mouse models of periventricular leukomalacia (PVL), the predominant brain injury in premature infants characterized by periventricular white matter lesions. Hypoxia/ischemia with/without systemic infection are the primary causes of PVL. Unilateral carotid ligation and hypoxia exposure with/without lipopolysaccharide injection creates PVL-like lesions in P6 mice.
Injury to the developing brain leads to devastating neurological consequences. Strikingly, the pattern of perinatal brain injury is highly age-dependent. In term infants, it predominantly affects cerebral cortex with characteristic neuronal loss. However, in premature infants, it selectively affects cerebral white matter with prominent injury to developing oligodendrocytes, a disorder termed periventricular leukomalacia (PVL). The magnitude of the problem of brain injury in the premature infant is extraordinary. Premature delivery and improved neonatal intensive care have led to nearly 90% of survival of the 13 million premature infants worldwide (approximately 56,000 in the United States) born yearly with a birthweight under 1500 grams, i.e., very low-birth-weight infants. Approximately 10% of the survivors subsequently exhibit cerebral palsy and approximately 50% have cognitive and behavioral deficits. PVL is the most important brain pathology underlying cerebral palsy in premature infants. No specific therapy for PVL presently exists, in part because the pathogenesis has not been well understood1,2.
Although the etiology of PVL is multifactorial, perinatal hypoxia/ischemia with maternal intrauterine infection is thought to be a primary cause of PVL. A hypoxic/ischemic model of PVL in the rat at P7 has been previously established3. This model is unique in that it resembles PVL in premature infants. The hallmark of this model is selective white matter pathology, in contrast to the majority of the stroke models that are characterized by gray matter infarction. However, the limitations of the hypoxic-ischemic model in the rat should not be overlooked. First, the etiology of PVL is often multifactorial. In addition to hypoxia/ischemia, maternal-fetal infection/inflammation is strongly associated with PVL. Thus, combined hypoxia/ischemia and infection/inflammation would likely create more PVL-like models. The rodent age that best correlates with the human developmental period of greatest risk for PVL lesions (24-32 weeks of gestation) is postnatal because oligodendroglial differentiation is predominantly a postnatal event in rodents. As it is impossible to produce a maternal-fetal infection/inflammation in postnatal ages, it would be reasonable to simulate an infection at a relevant postnatal developmental stage to create a rodent model of PVL. We have sought to combine LPS injection with the hypoxic/ischemic model in mice at P6, to produce more clinically relevant PVL lesions. Second, the optimal proof-of-concept experimental approach for a causative role of a molecule necessitates the use of transgenic mice; genetic manipulations are much harder in the rat than in the mouse. Thus, we have sought to convert our experimental model of PVL from the rat to the mouse.
Mouse models of PVL will greatly facilitate 1) the study of disease biology and pathogenesis using available transgenic mouse strains; 2) conduction of drug trials to discover candidate agents with therapeutic potential; 3) testing of the utility of stem cells using immunodeficient mouse strains.
The authors have nothing to disclose.
This work is in part supported by grants from National Institutes of Health (RO1 NS059043 and RO1 ES015988), National Multiple Sclerosis Society, Roche Foundation for Anemia Research, Feldstein Medical Foundation, and Shriners Hospitals for Children.
We would like to thank Dr. David Pleasure for his suggestions. This work was in part supported by grants to W.D. from National Institutes of Health (RO1 NS059043 and RO1 ES015988), National Multiple Sclerosis Society, and Shriners Hospitals for Children. We declare no competing interests related to this article.
Material Name | Tipo | Company | Catalogue Number | Comment |
---|---|---|---|---|
LPS | Sigma | L4130 | ||
Hypoxia Chamber | BioSpherix | A-30274 | ||
Surgical hook | F.S.T. | 10064-14 |