INGAP peptide improves nerve function and enhances regeneration in streptozotocin-induced diabetic C57BL/6 mice.
INGAP peptide comprises the core active sequence of Islet Neogenesis Associated Protein (INGAP), a pancreatic cytokine that can induce new islet formation and restore euglycemia in diabetic rodents. The ability of INGAP peptide in vitro to enhance nerve growth from sensory ganglia suggests its potential utility in peripheral nerve disorders. In this study, INGAP peptide was administered alone or in combination with insulin to streptozotocin-induced diabetic mice exhibiting signs of peripheral neuropathy. Following a 2-wk treatment period, thermal hypoalgesia in diabetic mice was significantly improved in groups that received INGAP peptide, without development of hyperalgesia. Explanted dorsal root ganglia (DRG) from these groups showed enhanced nerve outgrowth and evidence of increased mitochondrial activity. Western blotting experiments revealed attenuation of neurofilament hyperphosphorylation, up-regulation of beta-tubulin and actin, and increased phosphorylation of the transcription factor STAT3 in DRG. These findings suggest that INGAP peptide can activate some of the signaling pathways implicated in nerve regeneration in sensory ganglia, thereby providing a means of improvement of nociceptive dysfunction in the peripheral nervous system.
Tam
Joseph
J
Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada.
Rosenberg
Lawrence
L
Maysinger
Dusica
D
D000818:Animals; D016207:Cytokines / Q000627:therapeutic use*; D003921:Diabetes Mellitus, Experimental / Q000628:therapy*; D003929:Diabetic Neuropathies / Q000378:metabolism / Q000503:physiopathology / Q000628:therapy*; D005727:Ganglia, Spinal / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism; D009416:Nerve Regeneration / Q000187:drug effects*; D016900:Neurofilament Proteins / Q000378:metabolism; D017288:Pain Threshold; D000073718:Pancreatitis-Associated Proteins; D010446:Peptide Fragments / Q000627:therapeutic use*; D015398:Signal Transduction / Q000187:drug effects
D016207:Cytokines; C500438:INGAP peptide; D016900:Neurofilament Proteins; D000073718:Pancreatitis-Associated Proteins; D010446:Peptide Fragments; C000612141:REG3A protein, human