title: Hypoxia-ischemia induces hypo-phosphorylation of collapsin response mediator protein 2 in a neonatal rat model of periventricular leukomalacia.
abstract: Collapsin response mediator protein2 (CRMP2) is a brain-specific protein involved in neuronal polarity and axonal guidance, and phosphorylation of CRMP2 regulates the function and the activity. CRMP2 has shown to be implicated in several neurodegenerative diseases (Alzheimer's disease, epilepsy and ischemia) and this study was designed to assess the role of CRMP2 in periventricular leukomalacia (PVL). We developed a PVL model using 3-day-old rats to investigate the expression and phosphorylation of CRMP2 in the newborn brain. Hypoxia-ischemia was applied by unilateral carotid ligation followed by exposure to 5% oxygen for 30min. Pathological changes were evaluated from 0h to 21d post-HI, and white matter damage including severe necrosis, white matter rarefaction and lateral ventricle dilatation were found. In the PVL model astrogliosis and axonal damage were detected in the injured white matter by immunohistochemistry at 48-168h post-HI, and delayed myelination was verified by Western blotting after 21-day post-HI. We confirmed that this model showed neuropathological features of PVL. Next, significant changes of CRMP2 were observed in the brain of the PVL model. Western blotting and immunohistochemistry showed that cleavage and hypo-phosphorylation of CRMP2 occurred after 48h post-HI in the PVL brain. Our results suggest that cleaved CRMP2 could represent hypo-phosphorylated-CRMP2 and HI could induce activation of CRMP2 in the PVL brain. The activated CRMP2 may play an important role in neuronal plasticity in PVL. Our findings suggest that future treatment strategies of PVL should target the phosphorylation mechanism of CRMP2.
authors.affiliation: Department of Reproductive and Developmental Medicine, Akita University School of Medicine, Akita, Japan. yk_sato@hotmail.co.jp
authors.forename: Yoko
authors.initials: Y
authors.lastname: Sato
authors.forename: Wako
authors.initials: W
authors.lastname: Ishida-Nakajima
authors.forename: Masanari
authors.initials: M
authors.lastname: Kawamura
authors.forename: Shinobu
authors.initials: S
authors.lastname: Miura
authors.forename: Rena
authors.initials: R
authors.lastname: Oguma
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Arai
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Takahashi
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000502:physiology; D005260:Female; D006801:Humans; D020925:Hypoxia-Ischemia, Brain / Q000378:metabolism* / Q000503:physiopathology; D007231:Infant, Newborn; D036341:Intercellular Signaling Peptides and Proteins; D007969:Leukomalacia, Periventricular / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D009419:Nerve Tissue Proteins / Q000378:metabolism* / Q000502:physiology; D009473:Neuronal Plasticity / Q000502:physiology; D010766:Phosphorylation / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; C095114:collapsin response mediator protein-2