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Induction of striatal neurogenesis enhances functional recovery in an adult animal model of neonatal hypoxic-ischemic brain injury

Authors
 S.H. Im  ;  J.H. Yu  ;  E.S. Park  ;  J.E. Lee  ;  H.O. Kim  ;  K.I. Park  ;  G.W. Kim  ;  C.I. Park  ;  S.-R. Cho 
Citation
 NEUROSCIENCE, Vol.169(1) : 259-268, 2010 
Journal Title
 NEUROSCIENCE 
ISSN
 0306-4522 
Issue Date
2010
MeSH
Animals ; Ataxia/drug therapy ; Ataxia/etiology ; Ataxia/physiopathology ; Brain Damage, Chronic/etiology ; Brain Damage, Chronic/prevention & control* ; Brain-Derived Neurotrophic Factor/administration & dosage ; Brain-Derived Neurotrophic Factor/pharmacology ; Brain-Derived Neurotrophic Factor/therapeutic use* ; Carotid Arteries ; Cerebral Palsy ; Corpus Striatum/drug effects ; Corpus Striatum/physiopathology* ; Cytarabine/pharmacology ; Disease Models, Animal ; Drug Evaluation, Preclinical ; Epidermal Growth Factor/administration & dosage ; Epidermal Growth Factor/pharmacology ; Epidermal Growth Factor/therapeutic use ; Forelimb/physiopathology ; Hemiplegia/drug therapy ; Hemiplegia/etiology ; Hemiplegia/physiopathology ; Hypoxia/complications ; Hypoxia-Ischemia, Brain/drug therapy* ; Hypoxia-Ischemia, Brain/physiopathology ; Infusions, Intraventricular ; Ligation ; Mice ; Mice, Inbred ICR ; Neurogenesis/drug effects* ; Random Allocation ; Recovery of Function
Keywords
brain-derived neurotrophic factor ; epidermal growth factor ; intraventricular infusion ; neurogenesis ; cerebral palsy
Abstract
While intraventricular administration of epidermal growth factor (EGF) expands the proliferation of neural stem/progenitor cells in the subventricular zone (SVZ), overexpression of brain-derived neurotrophic factor (BDNF) is particularly effective in enhancing striatal neurogenesis. We assessed the induction of striatal neurogenesis and consequent functional recovery after chronic infusion of BDNF and EGF in an adult animal model of neonatal hypoxic-ischemic (HI) brain injury. Permanent brain damage was induced in CD-1 (ICR) mice (P7) by applying the ligation of unilateral carotid artery and hypoxic condition. At 6 weeks of age, the mice were randomly assigned to groups receiving a continuous 2-week infusion of one of the following treatments into the ventricle: BDNF, EGF, BDNF/EGF, or phosphate buffered saline (PBS). Two weeks after treatment, immunohistochemical analysis revealed an increase in the number of BrdU(+) cells in the SVZ and striata of BDNF/EGF-treated mice. The number of new neurons co-stained with BrdU and betaIII-tubulin was also significantly increased in the neostriata of BDNF/EGF-treated mice, compared with PBS group. In addition, the newly generated cells were expressed as migrating neuroblasts labeled with PSA-NCAM or doublecortin in the SVZ and the ventricular side of neostriata. The new striatal neurons were also differentiated as mature neurons co-labeled with BrdU(+)/NeuN(+). When evaluated post-surgical 8 weeks, BDNF/EGF-treated mice exhibited significantly longer rotarod latencies at constant speed (48 rpm) and under accelerating condition (4-80 rpm), relative to PBS and untreated controls. In the forelimb-use asymmetry test, BDNF/EGF-treated mice showed significant improvement in the use of the contralateral forelimb. In contrast, this BDNF/EGF-associated functional recovery was abolished in mice receiving a co-infusion of 2% cytosine-b-d-arabinofuranoside (Ara-C), a mitotic inhibitor. Induction of striatal neurogenesis by the intraventricular administration of BDNF and EGF promoted functional recovery in an adult animal model of neonatal HI brain injury. The effect of Ara-C to completely block functional recovery indicates that the effect may be the result of newly generated neurons. Therefore, this treatment may offer a promising strategy for the restoration of motor function for adults with cerebral palsy (CP).
Full Text
http://www.sciencedirect.com/science/article/pii/S0306452210005816
DOI
10.1016/j.neuroscience.2010.04.038
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Neurology (신경과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Pediatrics (소아청소년과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Laboratory Medicine (진단검사의학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Anatomy (해부학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Yonsei Biomedical Research Center (연세의생명연구원) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Rehabilitation Medicine (재활의학교실) > 1. Journal Papers
Yonsei Authors
Kim, Gyung Whan(김경환) ORCID logo https://orcid.org/0000-0001-7053-4372
Kim, Hyun Ok(김현옥) ORCID logo https://orcid.org/0000-0002-4964-1963
Park, Kook In(박국인) ORCID logo https://orcid.org/0000-0001-8499-9293
Park, Eun Sook(박은숙) ORCID logo https://orcid.org/0000-0002-9144-3063
Park, Chang Il(박창일)
Yu, Ji Hea(유지혜)
Lee, Jong Eun(이종은) ORCID logo https://orcid.org/0000-0001-6203-7413
Im, Sang Hee(임상희) ORCID logo https://orcid.org/0000-0001-5128-5526
Cho, Sung-Rae(조성래) ORCID logo https://orcid.org/0000-0003-1429-2684
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/101108
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