Retrograde delivery of adenovirus carrying neurotrophic factor gene suppresses apoptosis of neurons and oligodendrocytes in hyperostotic mouse (twy/twy) with chronic mechanical cord compression

Keno Uchida
Department of Orthopaedics and Rehabilitation Medicine Faculty of Medical Sciences, University of Fukui Eiheiji, Fukui 910-1193, Japan

Abstract:

Objectives:
To investigate the neuroprotective effects of targeted retrograde　gene delivery in the chronic mechanical compressed spinal cord.

Methods:
We investigated the efficacy of retrograde gene delivery via sternomastoid muscles of adenoviral vector (AdV) carrying brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) gene into 16-week-old twy (twy/twy) mouse spinal cord anterior horn neurons with chronic and progressive mechanical compression at C1-C2 level. Four weeks after injection, the compressed cervical spinal cord was examinedhistologically, immunohistologically and by immunoblot analysis.

Results:
Four weeks after injection, the retrograde delivery of LacZ marker gene was identified in both cervical spinal neurons and some glial cells including oligodendrocytes in the white matter of twy/twy mice. AdV-BDNF resulted in a significant decrease in the number of TUNEL-positive apoptotic cells mediated by downregulation of the casepase-3 apoptotic pathway including p75NTR, and overexpression of growth associated proteins (GAP)-43, RT97, and NG2 in chronically compressed spinal cord, compared with the AdV-LacZ injection. AdV-NT-3 gene transfer increased neurite length of anterior horn WGA-HRP-labeled neurons.

Conclusion:
Targeted retrograde neurotrophic factor gene delivery could suppress apoptosis of neurons and oligodendrocytes, and has beneficial effects including repair of chronically compressed spinal cord.