Therapeutic efficacy of sonic hedgehog protein in experimental diabetic neuropathy.
Hedgehog proteins modulate development and patterning of the embryonic nervous system. As expression of desert hedgehog and the hedgehog receptor, patched-1, persist in the postnatal and adult peripheral nerves, the hedgehog pathway may have a role in maturation and maintenance of the peripheral nervous system in normal and disease states. We measured desert hedgehog expression in the peripheral nerve of maturing diabetic rats and found that diabetes caused a significant reduction in desert hedgehog mRNA. Treating diabetic rats with a sonic hedgehog-IgG fusion protein fully restored motor- and sensory-nerve conduction velocities and maintained the axonal caliber of large myelinated fibers. Diabetes-induced deficits in retrograde transport of nerve growth factor and sciatic-nerve levels of calcitonin gene-related product and neuropeptide Y were also ameliorated by treatment with the sonic hedgehog-IgG fusion protein, as was thermal hypoalgesia in the paw. These studies implicate disruption of normal hedgehog function in the etiology of diabetes-induced peripheral-nerve dysfunction and indicate that delivery of exogenous hedgehog proteins may have therapeutic potential for the treatment of diabetic neuropathy.
Calcutt
Nigel A
NA
Department of Pathology, University of California at San Diego, La Jolla, California 92093-0612, USA. ncalcutt@ucsd.edu
Allendoerfer
Karen L
KL
Mizisin
Andrew P
AP
Middlemas
Alicia
A
Freshwater
Jason D
JD
Burgers
Monica
M
Ranciato
Rigel
R
Delcroix
Jean-Dominique
JD
Taylor
Frederick R
FR
Shapiro
Renee
R
Strauch
Kathy
K
Dudek
Henryk
H
Engber
Thomas M
TM
Galdes
Alphonse
A
Rubin
Lee L
LL
Tomlinson
David R
DR
D000818:Animals; D003929:Diabetic Neuropathies / Q000188:drug therapy* / Q000235:genetics / Q000503:physiopathology; D053823:Hedgehog Proteins; D006801:Humans; D007074:Immunoglobulin G / Q000235:genetics / Q000627:therapeutic use; D008297:Male; D009431:Neural Conduction / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000627:therapeutic use; D012584:Sciatic Nerve / Q000187:drug effects / Q000503:physiopathology; D015534:Trans-Activators / Q000235:genetics / Q000627:therapeutic use*
D053823:Hedgehog Proteins; D007074:Immunoglobulin G; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; C509239:SHH protein, human; D015534:Trans-Activators