Gene transfer of insulin-like growth factor-I providing neuroprotection after spinal cord injury in rats.
OBJECTIVE
Insulin-like growth factor-I (IGF-I) has been shown to be a potent neurotrophic factor that promotes the growth of projection neurons, dendritic arborization, and synaptogenesis. Its neuroprotective roles may be coordinated by activation of Akt, inhibition of glycogen synthase kinase-3beta (GSK-3beta), and thus inhibition of tau phosphorylation. The authors investigated the role and mechanism of IGF-I gene transfer after spinal cord injury (SCI).


METHODS
Studies were performed in 40 male Sprague-Dawley rats after spinal cord hemisection. The authors conducted hydrodynamics-based gene transfection in which an IGF-I plasmid was rapidly injected into the rat's tail vein 30 minutes after SCI. The animals were randomly divided into four groups: Group I, sham operated; Group II, SCI treated with pCMV-IGF-I gene; Group III, SCI treated with vehicle pCMV-LacZ gene; and Group IV, SCI only. The results showed that IGF-I gene transfer promoted motor recovery, antiinflammatory responses, and antiapoptotic effects after SCI. Using techniques of Western blotting and immunohistochemistry, the authors assessed the mechanism of IGF-I gene transfer after SCI in terms of activation of Akt, inhibition of GSK-3beta, attenuation of p35, and inhibition of tau phosphorylation. Moreover, they found that IGF-I gene transfer could block caspase-9 cleavage, increase Bcl-2 formation, and thus inhibit apoptosis after SCI.


CONCLUSIONS
The intravenous administration of IGF-I after SCI activated Akt, attenuated GSK-3beta, inhibited p35 activation, diminished tau hyperphosphorylation, ended microglia and astrocyte activation, inhibited neuron loss, and significantly improved neurological dysfunction. Furthermore, IGF-I attenuated caspase-9 cleavage, increased Bcl2, and thus inhibited apoptosis after SCI.
Hung
Kuo-Sheng
KS
Department of Neurosurgery, Graduate Institute of Injury Prevention and Control, Taipei Medical University, Wan Fang Medical Center, Taipei, Taiwan.
Tsai
Shin-Han
SH
Lee
Tao-Chen
TC
Lin
Jia-Wei
JW
Chang
Cheng-Kuei
CK
Chiu
Wen-Ta
WT
D000818:Animals; D001253:Astrocytes / Q000187:drug effects; D015153:Blotting, Western; D053453:Caspase 9 / Q000187:drug effects; D003712:Dendrites / Q000187:drug effects / Q000473:pathology; D004195:Disease Models, Animal; D018014:Gene Transfer Techniques / Q000295:instrumentation*; D019254:Genes, bcl-2 / Q000235:genetics; D016158:Genes, p53 / Q000235:genetics; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors; D000071679:Glycogen Synthase Kinase 3 beta; D007334:Insulin-Like Growth Factor I / Q000235:genetics* / Q000494:pharmacology / Q000627:therapeutic use*; D007763:Lac Operon / Q000235:genetics; D008297:Male; D017628:Microglia / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D010766:Phosphorylation / Q000187:drug effects; D010957:Plasmids / Q000235:genetics; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D013119:Spinal Cord Injuries / Q000235:genetics* / Q000473:pathology / Q000628:therapy*; D013569:Synapses / Q000187:drug effects / Q000473:pathology; D016875:tau Proteins / Q000235:genetics
D018696:Neuroprotective Agents; D016875:tau Proteins; D007334:Insulin-Like Growth Factor I; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D038362:Glycogen Synthase Kinase 3; D053453:Caspase 9