Restorative effects of neurotrophin treatment on diabetes-induced cutaneous axon loss in mice.
Chronic hyperglycemia in diabetes causes a variety of somatosensory deficits, including reduced cutaneous innervation of distal extremities. Deficient neurotrophin support has been proposed to contribute to the development of diabetic neuropathy. Here, studies were carried out in streptozotocin (STZ)-treated mice to determine whether (1) cutaneous innervation deficits develop in response to hyperglycemia, (2) neurotrophin production is altered in the skin, and (3) neurotrophin treatment improves cutaneous innervation deficits. Cutaneous innervation was quantified in the hindlimb skin using antibodies that label nerve growth factor- (NGF) responsive (CGRP), glial cell line-derived neurotrophic factor (GDNF)/neurturin (NTN) -responsive (P2X(3)), or all cutaneous axons (PGP 9.5). Diabetic mice displayed severely reduced cutaneous innervation for all three antibodies in both flank and footpad skin regions, similar to reports of cutaneous innervation loss in human diabetic patients. Qualitative assessment of mRNAs for NGF, GDNF, and NTN demonstrated that these mRNAs were expressed in hindlimb flank and footpad skin from diabetic mice. Next, diabetic mice were then treated intrathecally for 2 weeks with NGF, GDNF, or NTN. NGF treatment failed to improve cutaneous innervation, but stimulated axon branching. In comparison, GDNF and NTN treatment increased cutaneous innervation and axon branching. Our results reveal that similar to human diabetic patients, STZ-induced diabetes significantly reduces hindlimb cutaneous innervation in mice. Importantly, intrathecal treatment using GDNF or NTN strongly stimulated axon growth and branching, suggesting that administration of these trophic factors can improve cutaneous innervation deficits caused by diabetes.
Christianson
Julie A
JA
Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City 66160, USA.
Riekhof
John T
JT
Wright
Douglas E
DE
D000818:Animals; D001369:Axons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D015740:Calcitonin Gene-Related Peptide / Q000096:biosynthesis; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000150:complications* / Q000473:pathology; D003929:Diabetic Neuropathies / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D018450:Disease Progression; D051100:Glial Cell Line-Derived Neurotrophic Factor; D007278:Injections, Spinal; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020932:Nerve Growth Factor / Q000235:genetics / Q000627:therapeutic use; D009414:Nerve Growth Factors / Q000235:genetics / Q000627:therapeutic use*; D009416:Nerve Regeneration / Q000187:drug effects; D051101:Neurturin; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D018048:Receptors, Purinergic P2 / Q000096:biosynthesis; D058477:Receptors, Purinergic P2X3; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012867:Skin / Q000737:chemistry / Q000294:innervation* / Q000473:pathology; D013311:Streptozocin; D013869:Thiolester Hydrolases / Q000096:biosynthesis; D043222:Ubiquitin Thiolesterase
C495040:Gdnf protein, mouse; D051100:Glial Cell Line-Derived Neurotrophic Factor; D009414:Nerve Growth Factors; D051101:Neurturin; C495056:Nrtn protein, mouse; C546407:P2RX3 protein, human; C546409:P2rx3 protein, mouse; D012333:RNA, Messenger; D018048:Receptors, Purinergic P2; D058477:Receptors, Purinergic P2X3; D013311:Streptozocin; D020932:Nerve Growth Factor; D013869:Thiolester Hydrolases; D043222:Ubiquitin Thiolesterase; D015740:Calcitonin Gene-Related Peptide