Intrathecal gene delivery of glial cell line-derived neurotrophic factor ameliorated paraplegia in rats after spinal ischemia.
Paraplegia is a catastrophic complication of thoracic aortic surgery. At present, there is no effective mean to prevent the ischemia-induced spinal cord trauma. Gene delivery of neurotrophic factors may hold promises for prevention of spinal injury. In the present study, we evaluated the effect of glial cell line-derived neurotrophic factor (GDNF) gene delivery on prevention of the pathological changes due to spinal ischemia. Recombinant adenovirus vectors encoding GDNF (Ad-GDNF) and green fluorescent protein (Ad-GFP) were used for gene transfer studies. Treatment with cobalt chloride induced dose-dependent bcl-2 and synaptophysin downregulation in spinal neuronal cells, which could be effectively reversed by GDNF gene transfer. Intrathecal injection of Ad-GDNF led to maximal GDNF expression in spinal cord within 2-7 days. Thus, after intrathecal administration of adenovirus vectors for 3 days, Sprague-Dawley rats received transient aortic occlusion to induce spinal ischemia and were monitored for behavior deficits. The Ad-GDNF-treated rats showed significantly lower paraplegia rate (40%) than that of Ad-GFP- or saline-treated groups (75-85%; P<0.01). In addition, the Ad-GDNF-treated rats exhibited significantly improved locomotor function comparing with rats of control groups (P<0.001). Histological analysis revealed that GDNF gene delivery profoundly attenuated the infiltration of leukocytes in spinal cord after ischemic insults. Furthermore, GDNF gene delivery prominently attenuated the ischemia-induced neuronal loss in dorsal horn lamina VI-VIII and reduction in synaptophysin expression in spinal cords. In conclusion, GDNF gene transfer confers protection to the neuronal cells and synapses networks, thereby alleviated the paraplegia due to spinal ischemia.
Chou
An Kuo
AK
Department of Anesthesiology, Chang Gung Memorial Hospital, Kaohsiung 833, Taiwan; Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan. encore@adm.cgmh.org.tw
Yang
Lin Cheng
LC
Wu
Ping Ching
PC
Wong
Wen Tsang
WT
Liu
Guei Sheung
GS
Chen
Jing Tsang
JT
Howng
Shen-Long
SL
Tai
Ming-Hong
MH
D000256:Adenoviridae / Q000502:physiology; D000818:Animals; D001522:Behavior, Animal; D015153:Blotting, Western / Q000379:methods; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D003035:Cobalt / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D020233:Gait Disorders, Neurologic / Q000209:etiology / Q000628:therapy; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000502:physiology; D051100:Glial Cell Line-Derived Neurotrophic Factor; D007150:Immunohistochemistry / Q000379:methods; D007249:Inflammation / Q000209:etiology / Q000517:prevention & control; D008297:Male; D009414:Nerve Growth Factors / Q000096:biosynthesis / Q000235:genetics / Q000627:therapeutic use*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000821:virology; D010264:Paraplegia / Q000209:etiology / Q000628:therapy*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013116:Spinal Cord / Q000166:cytology; D020760:Spinal Cord Ischemia / Q000150:complications*; D016708:Synaptophysin / Q000378:metabolism; D013997:Time Factors
C495041:Gdnf protein, rat; D051100:Glial Cell Line-Derived Neurotrophic Factor; D009414:Nerve Growth Factors; D019253:Proto-Oncogene Proteins c-bcl-2; D016708:Synaptophysin; D003035:Cobalt; C018021:cobaltous chloride