GDNF rescues nonpeptidergic unmyelinated primary afferents in streptozotocin-treated diabetic mice.
Sensory deficits induced by diabetes commonly affect small unmyelinated peptidergic and nonpeptidergic sensory neurons. The peptidergic population responds to nerve growth factor (NGF), while the nonpeptidergic DRG neurons postnatally switch their dependency from NGF to glial cell line-derived neurotrophic factor (GDNF). Recent studies have demonstrated that deficient NGF support of peptidergic nociceptors is involved in problems with small-fiber diabetic neuropathy. To determine if nonpeptidergic GDNF-responsive neurons are similarly affected by hyperglycemia, diabetes was induced in mice using streptozotocin (STZ). Four weeks following diabetes induction, staining of axon terminals of nonpeptidergic unmyelinated neurons labeled with the isolectin IB4 or enzyme activity for thiamine monophosphatase (TMP) was reduced in lamina IIi of the lumbar dorsal horn, particularly in the medial region which receives distal sciatic afferents. In contrast, NGF-responsive CGRP-immunoreactive (ir) axons showed no or only a slight decrease in spinal terminations. Insulin treatment in diabetic mice failed to improve deficits in IB4/TMP central afferents. To test whether GDNF or NGF could restore spinal deficits in nonpeptidergic afferents, STZ-treated mice were treated intrathecally for 2 weeks with NGF or GDNF. NGF administration enhanced CGRP-ir staining but failed to improve IB4/TMP projections. GDNF treatment had no effect on CGRP-ir projections but restored TMP labeling in lamina IIi. Our results demonstrate that nonpeptidergic unmyelinated sensory neurons are vulnerable to diabetes and that GDNF administration can selectively reverse deficits caused by diabetes in the IB4/TMP subpopulation.
Akkina
S K
SK
Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, Kansas 66160, USA.
Patterson
C L
CL
Wright
D E
DE
D000818:Animals; D001786:Blood Glucose / Q000187:drug effects; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000150:complications* / Q000473:pathology; D003929:Diabetic Neuropathies / Q000188:drug therapy* / Q000473:pathology; D005727:Ganglia, Spinal / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051100:Glial Cell Line-Derived Neurotrophic Factor; D007278:Injections, Spinal; D007328:Insulin / Q000494:pharmacology; D037102:Lectins / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009186:Myelin Sheath / Q000378:metabolism*; D020932:Nerve Growth Factor / Q000008:administration & dosage; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins / Q000008:administration & dosage*; D009475:Neurons, Afferent / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism; D037121:Plant Lectins; D017729:Presynaptic Terminals / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D013311:Streptozocin
D001786:Blood Glucose; C495040:Gdnf protein, mouse; D051100:Glial Cell Line-Derived Neurotrophic Factor; C045475:Griffonia simplicifolia lectins; D007328:Insulin; D037102:Lectins; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D037121:Plant Lectins; D013311:Streptozocin; D020932:Nerve Growth Factor; C022734:thiamine monophosphatase; D010744:Phosphoric Monoester Hydrolases; D015740:Calcitonin Gene-Related Peptide