PMID- 22648027
OWN - NLM
STAT- MEDLINE
DCOM- 20130524
LR  - 20121214
IS  - 1528-1159 (Electronic)
IS  - 0362-2436 (Linking)
VI  - 37
IP  - 26
DP  - 2012 Dec 15
TI  - The retrograde delivery of adenovirus vector carrying the gene for brain-derived 
      neurotrophic factor protects neurons and oligodendrocytes from apoptosis in the 
      chronically compressed spinal cord of twy/twy mice.
PG  - 2125-35
LID - 10.1097/BRS.0b013e3182600ef7 [doi]
AB  - STUDY DESIGN: The twy/twy mouse undergoes spontaneous chronic mechanical 
      compression of the spinal cord; this in vivo model system was used to examine the 
      effects of retrograde adenovirus (adenoviral vector [AdV])-mediated brain-derived 
      neurotrophic factor (BDNF) gene delivery to spinal neural cells. OBJECTIVE: To 
      investigate the targeting and potential neuroprotective effect of retrograde 
      AdV-mediated BDNF gene transfection in the chronically compressed spinal cord in 
      terms of prevention of apoptosis of neurons and oligodendrocytes. SUMMARY OF 
      BACKGROUND DATA: Several studies have investigated the neuroprotective effects of 
      neurotrophins, including BDNF, in spinal cord injury. However, no report has 
      described the effects of retrograde neurotrophic factor gene delivery in 
      compressed spinal cords, including gene targeting and the potential to prevent 
      neural cell apoptosis. METHODS: AdV-BDNF or AdV-LacZ (as a control gene) was 
      injected into the bilateral sternomastoid muscles of 18-week old twy/twy mice for 
      retrograde gene delivery via the spinal accessory motor neurons. Heterozygous 
      Institute of Cancer Research mice (+/twy), which do not undergo spontaneous 
      spinal compression, were used as a control for the effects of such compression on 
      gene delivery. The localization and cell specificity of beta-galactosidase 
      expression (produced by LacZ gene transfection) and BDNF expression in the spinal 
      cord were examined by coimmunofluorescence staining for neural cell markers 
      (NeuN, neurons; reactive immunology protein, oligodendrocytes; glial fibrillary 
      acidic protein, astrocytes; OX-42, microglia) 4 weeks after gene injection. The 
      possible neuroprotection afforded by retrograde AdV-BDNF gene delivery versus 
      AdV-LacZ-transfected control mice was assessed by scoring the prevalence of 
      apoptotic cells (terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick 
      end labeling-positive cells) and immunoreactivity to active caspases -3, -8, and 
      -9, p75, neurofilament 200 kD (NF), and for the oligodendroglial progenitor 
      marker, NG2. RESULTS.: Four weeks after injection, the retrograde delivery of the 
      LacZ marker gene was identified in cervical spinal neurons and some glial cells, 
      including oligodendrocytes in the white matter of the spinal cord, in both the 
      twy/twy mouse and the heterozygous Institute of Cancer Research mouse (+/twy). In 
      the compressed spinal cord of twy/twy mouse, AdV-BDNF gene transfection resulted 
      in a significant decrease in the number of terminal deoxynucleotidyl 
      transferase-mediated dUTP-biotin nick end labeling-positive cells present in the 
      spinal cord and a downregulation in the caspase apoptotic pathway compared with 
      AdV-LacZ (control) gene transfection. There was a marked and significant increase 
      in the areas of the spinal cord of AdV-BDNF-injected mice that were NF- and 
      NG2-immunopositive compared with AdV-LacZ-injected mice, indicating the increased 
      presence of neurons and oligodendrocytes in response to BDNF transfection. 
      CONCLUSION: Our results demonstrate that targeted retrograde BDNF gene delivery 
      suppresses apoptosis in neurons and oligodendrocytes in the chronically 
      compressed spinal cord of twy/twy mouse. Further work is required to establish 
      whether this method of gene delivery may provide neuroprotective effects in other 
      situations of compressive spinal cord injury.
FAU - Uchida, Kenzo
AU  - Uchida K
AD  - Department of Orthopaedics and Rehabilitation Medicine, Fukui University Faculty 
      of Medical Sciences, Fukui, Japan. kuchida@u-fukui.ac.jp
FAU - Nakajima, Hideaki
AU  - Nakajima H
FAU - Hirai, Takayuki
AU  - Hirai T
FAU - Yayama, Takafumi
AU  - Yayama T
FAU - Chen, Kebing
AU  - Chen K
FAU - Guerrero, Alexander Rodriguez
AU  - Guerrero AR
FAU - Johnson, William Eustace
AU  - Johnson WE
FAU - Baba, Hisatoshi
AU  - Baba H
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Spine (Phila Pa 1976)
JT  - Spine
JID - 7610646
RN  - 0 (Brain-Derived Neurotrophic Factor)
SB  - IM
MH  - Adenoviridae
MH  - Animals
MH  - Apoptosis/*genetics
MH  - Brain-Derived Neurotrophic Factor/*genetics/metabolism
MH  - Disease Models, Animal
MH  - Genetic Therapy/*methods
MH  - Genetic Vectors
MH  - Hyperostosis/genetics/metabolism/pathology
MH  - Mice
MH  - Neurons/metabolism/*pathology
MH  - Oligodendroglia/metabolism/*pathology
MH  - Spinal Cord/metabolism/pathology
MH  - Spinal Cord Compression/genetics/pathology/*therapy
EDAT- 2012/06/01 06:00
MHDA- 2013/05/28 06:00
CRDT- 2012/06/01 06:00
PHST- 2012/06/01 06:00 [entrez]
PHST- 2012/06/01 06:00 [pubmed]
PHST- 2013/05/28 06:00 [medline]
AID - 10.1097/BRS.0b013e3182600ef7 [doi]
PST - ppublish
SO  - Spine (Phila Pa 1976). 2012 Dec 15;37(26):2125-35. doi: 
      10.1097/BRS.0b013e3182600ef7.