Induction of striatal neurogenesis enhances functional recovery in an adult animal model of neonatal hypoxic-ischemic brain injury.
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).
Im
S H
SH
Department and Research Institute of Rehabilitation Medicine, Yonsei University College of Medicine, Seoul, South Korea.
Yu
J H
JH
Park
E S
ES
Lee
J E
JE
Kim
H O
HO
Park
K I
KI
Kim
G W
GW
Park
C I
CI
Cho
S-R
SR
D000818:Animals; D001259:Ataxia / Q000188:drug therapy / Q000209:etiology / Q000503:physiopathology; D001925:Brain Damage, Chronic / Q000209:etiology / Q000517:prevention & control*; D019208:Brain-Derived Neurotrophic Factor / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D002339:Carotid Arteries; D002547:Cerebral Palsy; D003342:Corpus Striatum / Q000187:drug effects / Q000503:physiopathology*; D003561:Cytarabine / Q000494:pharmacology; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D004815:Epidermal Growth Factor / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D005552:Forelimb / Q000503:physiopathology; D006429:Hemiplegia / Q000188:drug therapy / Q000209:etiology / Q000503:physiopathology; D000860:Hypoxia / Q000150:complications; D020925:Hypoxia-Ischemia, Brain / Q000188:drug therapy* / Q000503:physiopathology; D057967:Infusions, Intraventricular; D008026:Ligation; D051379:Mice; D008813:Mice, Inbred ICR; D055495:Neurogenesis / Q000187:drug effects*; D011897:Random Allocation; D020127:Recovery of Function
D019208:Brain-Derived Neurotrophic Factor; D003561:Cytarabine; D004815:Epidermal Growth Factor