Endogenous levels of nerve growth factor (NGF) are altered in experimental diabetes mellitus: a possible role for NGF in the pathogenesis of diabetic neuropathy.
Sympathetic and neural-crest derived sensory neurons consisting of unmyelinated and small myelinated fibers are known to be affected at an early stage in diabetes mellitus (DM). Since these peripheral neurons need nerve growth factor (NGF) for their development and maintenance of function in adulthood, changes in endogenous NGF levels could be of relevance for the pathogenesis of diabetic neuropathy (DNP). Using an improved two-site enzyme immunoassay for NGF, we have investigated whether endogenous NGF levels are altered in Sprague-Dawley rats with DM induced by a single injection of streptozotocin (STZ). STZ-treated rats are known to develop in many respects equivalents to neuropathic complications observed in human DM. We found in some sympathetically innervated target organs decreased NGF contents by maximally 56%: transiently in the iris 2 weeks and in the ventricle 12-24 weeks after DM induction and permanently in the submandibular gland already 3 days after DM induction. Several weeks after onset of DM, NGF content was increased by maximally 145-300% in most peripheral targets investigated, such as in iris, cardiac atrium and ventricle, spleen, prostate gland, and vas deferens. This is suggestive for an impaired NGF removal by NGF-sensitive neurons in diabetic rats. Moreover, NGF levels were decreased to minimally 42.6 +/- 4% of control in the NGF-transporting sciatic nerve. NGF levels began to decrease not before 3 weeks after DM induction and remained decreased with 54.0 +/- 5% of control even after 6 months duration of DM. About the same time (i.e., 2 weeks after induction of DM) NGF levels began to decrease in the superior cervical ganglion (where the sympathetic perikarya are located) to minimally 53.2 +/- 4% of control 12 weeks after DM induction. No altered NGF levels were observed during a 3-month duration of DM in the terminal ileum and sensory trigeminal ganglion. Since NGF exerts its neurotrophic action in the perikarya after its retrograde transport from the NGF-producing periphery, our results are consistent with the hypothesis that an alteration in NGF levels may play a role in the pathogenesis of DNP as far as sympathetic neurons are concerned. Thus, our results suggest that DM influences the production and/or transport of endogenous NGF and consequently, that a deprivation of this neurotrophic factor may account for some of the functional deficits known to occur in DNP, such as impaired catecholaminergic transmitter synthesis. This hypothesis possibly opens the way for new concepts in the therapy of DNP.
Hellweg
R
R
Max-Planck-Institute for Psychiatry, Clinical Institute, München, Federal Republic of Germany.
Hartung
H D
HD
D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000378:metabolism*; D003929:Diabetic Neuropathies / Q000503:physiopathology*; D005728:Ganglia, Sympathetic / Q000378:metabolism*; D006325:Heart Atria / Q000294:innervation / Q000378:metabolism*; D008297:Male; D009414:Nerve Growth Factors / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D012584:Sciatic Nerve / Q000378:metabolism*; D013311:Streptozocin; D013363:Submandibular Gland / Q000294:innervation / Q000378:metabolism*
D009414:Nerve Growth Factors; D013311:Streptozocin