Effect of IGF-I and neurotrophin-3 on gracile neuroaxonal dystrophy in diabetic and aging rats.
Neuroaxonal dystrophy (NAD), a distinctive axonopathy characterized by dramatic swelling of preterminal axons and nerve terminals by the accumulation of a variety of subcellular organelles, develops in the central projections of sensory neurons to medullary gracile nuclei in aged animals and man, and in a number of diseases and experimental conditions. Although its pathogenesis is unknown, proposed mechanisms include abnormalities of axonal regeneration, collateral sprouting and synaptic plasticity which may reflect alteration in neurotrophic support. In the current study, we have demonstrated quantitatively that aging causes the expected marked increase in the frequency of gracile NAD; however, substantial numbers of dystrophic axons develop between 6 and 10 months of age, earlier than expected. Although diabetes has been reported to increase the frequency of NAD in the central processes of sensory neurons in the gracile fasciculus of genetically diabetic BB rats, we have found that 8-10 months of streptozotocin-induced diabetes results in fewer dystrophic axons in the gracile nucleus than in age-matched controls. Administration of neurotrophin-3 (NT-3) and insulin-like growth factor-I (IGF-I), which have been shown to affect synaptic plasticity (implicated in the pathogenesis of NAD), for the last two months before sacrifice did not affect the frequency of gracile NAD in controls or diabetics. The sensory terminals in the gracile nuclei provide a simple, well-characterized experimental system in which questions of pathogenesis and prevention of neuroaxonal dystrophy can be addressed.
Schmidt
R E
RE
Department of Pathology, Divisions of Neuropathology and Laboratory Medicine. Washington University School of Medicine, St Louis, MO 63110, USA. reschmidt@pathology.wustl.edu
Dorsey
D A
DA
Beaudet
L N
LN
Plurad
S B
SB
Parvin
C A
CA
Ohara
S
S
D000375:Aging / Q000502:physiology*; D000818:Animals; D001927:Brain Diseases / Q000209:etiology*; D003921:Diabetes Mellitus, Experimental / Q000150:complications*; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D008297:Male; D008526:Medulla Oblongata / Q000473:pathology / Q000648:ultrastructure; D019150:Neuroaxonal Dystrophies / Q000209:etiology* / Q000473:pathology; D020933:Neurotrophin 3 / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012016:Reference Values
D020933:Neurotrophin 3; D007334:Insulin-Like Growth Factor I