title: 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% O(2) 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. T(2)-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. T(2) 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. T(2)-weighted MRI and DTI are useful indicators of functional outcome after perinatal HI.
authors.affiliation: Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, WI 53792, USA. cengiz@pediatrics.wisc.edu
authors.forename: Pelin
authors.initials: P
authors.lastname: Cengiz
authors.forename: Kutluay
authors.initials: K
authors.lastname: Uluc
authors.forename: Pinar
authors.initials: P
authors.lastname: Kendigelen
authors.forename: Erinc
authors.initials: E
authors.lastname: Akture
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Hutchinson
authors.forename: Chihwa
authors.initials: C
authors.lastname: Song
authors.forename: Louise
authors.initials: L
authors.lastname: Zhang
authors.forename: Jihae
authors.initials: J
authors.lastname: Lee
authors.forename: Greg E
authors.initials: GE
authors.lastname: Budoff
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Meyerand
authors.forename: Dandan
authors.initials: D
authors.lastname: Sun
authors.forename: Peter
authors.initials: P
authors.lastname: Ferrazzano
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000473:pathology* / Q000503:physiopathology*; D002648:Child; D003072:Cognition Disorders / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D006146:Guanidines / Q000378:metabolism; D006801:Humans; D020925:Hypoxia-Ischemia, Brain / Q000473:pathology* / Q000503:physiopathology*; D007231:Infant, Newborn; D007234:Infant, Premature; D007858:Learning / Q000502:physiology; D008279:Magnetic Resonance Imaging / Q000379:methods; D051379:Mice; D008810:Mice, Inbred C57BL; D009483:Neuropsychological Tests; D011897:Random Allocation; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors; D013450:Sulfones / Q000378:metabolism
chemical_list: D006146:Guanidines; D017923:Sodium-Hydrogen Exchangers; D013450:Sulfones; C069139:growth factor-activatable Na-H exchanger NHE-1; C093373:cariporide