A vitamin D(3) derivative (CB1093) induces nerve growth factor and prevents neurotrophic deficits in streptozotocin-diabetic rats.
OBJECTIVE
Streptozotocin-diabetic rats show impaired neurotrophic support by deficient nerve growth factor (NGF) in muscle and skin. We, therefore, examined a novel agent (CB1093; 1(S), 3(R)-Dihydroxy-20(R)-(1-ethoxy-5-ethyl-5-hydroxy-2-heptyn-1-yl)-9, 10-seco-pregna-5(Z),7(E),10(19)-triene), which induces expression of endogenous nerve growth factor.


METHODS
We gave CB1093 orally followed by measurements of mechanical nociception, nerve growth factor, neuropeptides (immunoassay) and nerve growth factor receptors (western blots).


RESULTS
In non-diabetic rats CB1093 caused dose-dependent increases in nerve growth factor production (140 % in soleus muscle and 190 % in sciatic nerve) and a mechanical hyperalgesia in the foot. There was also increased sciatic nerve expression of neuronal NGF target gene products, substance P (16 %) and calcitonin gene-related peptide (CGRP; 52 %). Depletions of nerve growth factor, substance P and CGRP in sciatic nerves of diabetic rats were prevented by CB1093, which also increased soleus nerve growth factor concentrations to 30 % over those seen in non-diabetic rats and increased its mRNA expression in skin. The CB1093 did not affect expression of nerve growth factor receptors (trkA and p75(NTR)) in dorsal root ganglia in control or diabetic rats, though the p75(NTR) expression was reduced by diabetes. The mechanical hyperalgesia seen in diabetic rats treated with vehicle was not exacerbated by CB1093.


CONCLUSIONS
These findings show that in animal models of diabetes it is possible to prevent depletions of nerve growth factor and the products of its neuronal target genes by oral treatment of a highly potent inducer of NGF gene expression. Pain is a possible side-effect, though this was a function of dose and was manifest more in controls than in diabetic rats. [Diabetologia (1999) 42: 1308-1313]
Riaz
S
S
Department of Pharmacology, Medical Sciences, Queen Mary and Westfield College, London, UK.
Malcangio
M
M
Miller
M
M
Tomlinson
D R
DR
D000818:Animals; D002117:Calcitriol / Q000031:analogs & derivatives* / Q000494:pharmacology; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism / Q000503:physiopathology*; D006614:Hindlimb; D006706:Homeostasis; D008297:Male; D018482:Muscle, Skeletal / Q000378:metabolism; D020932:Nerve Growth Factor / Q000235:genetics / Q000378:metabolism*; D009420:Nervous System / Q000503:physiopathology*; D009431:Neural Conduction / Q000187:drug effects; D009479:Neuropeptides / Q000378:metabolism; D009619:Nociceptors / Q000187:drug effects / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D020800:Receptor, Nerve Growth Factor / Q000378:metabolism; D020917:Receptor, trkA / Q000378:metabolism; D012584:Sciatic Nerve / Q000378:metabolism; D012867:Skin / Q000378:metabolism; D013997:Time Factors
C103436:CB 1093; D009479:Neuropeptides; D012333:RNA, Messenger; D020800:Receptor, Nerve Growth Factor; D020932:Nerve Growth Factor; D020917:Receptor, trkA; D002117:Calcitriol