Chronic Neurological Deficits in Mice after Perinatal Hypoxia and Ischemia Correlate with Hemispheric Tissue Loss and White Matter Injury Detected by MRI

Abstract

We investigated the effects of perinatal hypoxia-ischemia (HI) on brain injury and neurological functional outcome at postnatal day (P)30 through P90. HI was induced by exposing P9 mice to 8% O₂ for 55 min using the Vannucci HI model. Following HI, mice were treated with either vehicle control or Na⁺/H⁺ exchanger isoform 1 (NHE1) inhibitor HOE 642. The animals were examined by the accelerating rotarod test at P30 and the Morris water maze (MWM) test at P60. T₂-weighted MRI was conducted at P90. Diffusion tensor imaging (DTI) was subsequently performed in ex vivo brains, followed by immunohistochemical staining for changes in myelin basic protein (MBP) and neurofilament protein expression in the corpus callosum (CC). Animals at P30 after HI showed deficits in motor and spatial learning. T₂ MRI detected a wide spectrum of brain injury in these animals. A positive linear correlation was observed between learning deficits and the degree of tissue loss in the ipsilateral hemisphere and hippocampus. Additionally, CC DTI fractional anisotropy (FA) values correlated with MBP expression. Both FA and MBP values correlated with performance on the MWM test. HOE 642-treated mice exhibited improved spatial learning and memory, and less white matter injury in the CC. These findings suggest that HI-induced cerebral atrophy and CC injury contribute to the development of deficits in learning and memory, and that inhibition of NHE1 is neuroprotective in part by reducing white matter injury. T₂-weighted MRI and DTI are useful indicators of functional outcome after perinatal HI.

Monitoring ischemic cerebral injury in spontaneously hypertensive rats by diffusion tensor imaging

“…70); fixation has also been reported to decrease FA, however (47). Even if fixation may alter absolute diffusivity parameters, ex vivo DTI can still provide useful indications of white matter injury that are supported by histological evaluation (8,27,30,48). The good agreement between the pattern of FA reduction that we observe in our ex vivo study with that in human stroke patients assessed by in vivo DTI (64,66) supports the general applicability of the ex vivo approach.…”

“…Similarly, tractography (instead of FA) has been used to assess involvement of specific fiber regions in stroke patients and here too, damage to the IC or other portions of the corticospinal tract is predictive of poor motor outcome at 3 months (46). Likewise, studies in animal models have shown correspondence between DTI measures and behavioral outcomes (8,10,62). chronic stages after ischemic injury (7,15,32,53).…”

Chondroitin sulfate proteoglycans impede myelination by oligodendrocytes after perinatal white matter injury

“…The functions of the hippocampus are interrupted by the damaged fiber connections and pathways that run through the fimbria and fornix, and disconnecting rather than destroying brain regions that contribute to the spatial learning may affect the MWM acquisition as well. WMI in the corpus callosum was reported to be associated with impaired learning and memory (Cengiz et al, 2011;Huang et al, 2009). The degradation of CSPGs with cABC was observed to restore sensory function and promote behavior recovery after SCI (Cafferty et al, 2008;Starkey et al, 2012).…”

The Na+/H+ Exchanger-1 as a New Molecular Target in Stroke Interventions

“…These findings suggest that NHE-1 mediated disruption of ionic homeostasis can contribute to CA1 pyramidal neuronal injury after neonatal HI. Moreover, T2 weighted and Diffusion Tensor (DTI) MRI revealed that NHE-1 inhibition with HOE 642 after HI resulted in improved white matter injury in the corpus callosum, which correlated with improvements in memory and learning (Cengiz et al, 2011).…”