Peripheral gene transfer of glial cell-derived neurotrophic factor ameliorates neuropathic deficits in diabetic rats.
Deprivation of neurotrophic factors contributes to the pathogenesis of diabetic neuropathy. However, the role of glial cell-derived neurotrophic factor (GDNF) in the pathogenesis of diabetic neuropathy remains unclear. The present study evaluated the pathogenic role of GDNF deficiency and the therapeutic potential of GDNF gene transfer for diabetic neuropathy. After injection of streptozotocin (STZ) for 2 weeks, diabetic rats displayed significant alteration in electrophysiological parameters, which was associated with structural changes and defective myelination in the sciatic nerves. The early diabetic neuropathy was accompanied by attenuation of the GDNF/GFRalpha1/Akt signaling cascade and depletion of sensory neuropeptides in the peripheral nerves. After detection of neuropathy, intramuscular GDNF gene transfer reversed the deficiency of GDNF/Akt signaling in the sciatic nerve and improved the neurological functions of diabetic rats. Moreover, GDNF gene delivery alleviated the axonal demyelination and restored the sensory neuropeptide levels in the sciatic nerve of diabetic rats. In summary, peripheral GDNF gene delivery ameliorates the diabetes-induced downregulation of the GDNF signaling complex in the peripheral nervous system and holds promises for treatment of diabetic neuropathy.
Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan.
Guei-Sheung
GS
Liu
Jhih-Yin
JY
Shi
Chiou-Lian
CL
Lai
Yi-Ren
YR
Hong
Shyi-Jang
SJ
Shin
Hung-Tu
HT
Huang
Hing-Chung
HC
Lam
Zhi-Hong
ZH
Wen
Kuei-Sen
KS
Hsu
Chih-Hao
CH
Chen
Shen-Long
SL
Howng
Ming-Hong
MH
Tai
D000818:Animals; D001369:Axons / Q000473:pathology / Q000648:ultrastructure; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism; D003929:Diabetic Neuropathies / Q000150:complications / Q000235:genetics / Q000473:pathology* / Q000628:therapy*; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000008:administration & dosage / Q000172:deficiency / Q000235:genetics* / Q000627:therapeutic use*; D006943:Hyperglycemia / Q000150:complications / Q000473:pathology; D007273:Injections, Intramuscular; D009186:Myelin Sheath / Q000473:pathology / Q000648:ultrastructure; D051381:Rats; D012584:Sciatic Nerve / Q000378:metabolism* / Q000648:ultrastructure; D015398:Signal Transduction; D013311:Streptozocin; D013373:Substance P / Q000378:metabolism
D051100:Glial Cell Line-Derived Neurotrophic Factor; D013373:Substance P; D013311:Streptozocin; D015740:Calcitonin Gene-Related Peptide