Rodent Hypoxia-Ischemia Models for Cerebral Palsy Research: A Systematic Review

Abstract

Cerebral palsy (CP) is a complex multifactorial disorder, affecting approximately 2.5-3/1000 live term births, and up to 22/1000 prematurely born babies. CP results from injury to the developing brain incurred before, during, or after birth. The most common form of this condition, spastic CP, is primarily associated with injury to the cerebral cortex and subcortical white matter as well as the deep gray matter. The major etiological factors of spastic CP are hypoxia/ischemia (HI), occurring during the last third of pregnancy and around birth age. In addition, inflammation has been found to be an important factor contributing to brain injury, especially in term infants. Other factors, including genetics, are gaining importance. The classic Rice-Vannucci HI model (in which 7-day-old rat pups undergo unilateral ligation of the common carotid artery followed by exposure to 8% oxygen hypoxic air) is a model of neonatal stroke that has greatly contributed to CP research. In this model, brain damage resembles that observed in severe CP cases. This model, and its numerous adaptations, allows one to finely tune the injury parameters to mimic, and therefore study, many of the pathophysiological processes and conditions observed in human patients. Investigators can recreate the HI and inflammation, which cause brain damage and subsequent motor and cognitive deficits. This model further enables the examination of potential approaches to achieve neural repair and regeneration. In the present review, we compare and discuss the advantages, limitations, and the translational value for CP research of HI models of perinatal brain injury.

Keywords: HI rodent model; hypoxia–ischemia; myelination; oligodendrocyte; perinatal brain injury; periventricular leukomalacia; spastic hemiplegic cerebral palsy; white matter damage.

Figure 1

Multiple-hit hypothesis of cerebral palsy: a combination of two or more factors is more likely to trigger and modulate lesions in the brain, causing CP. Adapted from Ref. (10, 15).

Figure 2

Tri-phasic hypothesis of the perinatal brain damage: major action elements and processes. The acute phase occurs minutes after the insult, while the secondary phase happens hours after. A tertiary phase, which can last for months/years and result in developmental disturbances has also been proposed. The secondary phase can be skipped in some situations. Adapted from Ref. (15).

Figure 3

Cellular and molecular mechanisms to PVL onset: upstream mechanisms (cerebral hypoxia/ischemia and maternal infection/fetal inflammation) activate downstream mechanisms (glutamate excitotoxicity and free radical release) leading to cellular deficiencies, in particular oligodendrocyte maturation impairment and myelination deficit. Pre-OL, pre-oligodendrocyte; Rc, receptor; AMPA, α-3-amino-hydroxy-5-methyl-4-isoxazole propionic acid; KA, kainate; NMDA, N-methyl-D-aspartate; ROS, reactive oxygen species; RNS, reactive nitrogen species [adapted from Ref. (23, 47, 50, 68, 69)].