The majority of individuals with .long-term diabetes become afflicted with diabetic peripheral neuropathy (DPN), an often painful and debilitating secondary complication of the disease. Symptomatic treatments, which do not address the underlying nerve damage in diabetes, are currently the only therapeutic options for DPN, aside from rigorous control of blood glucose, which only occasionally reduces the incidence and severity of DPN. Given the progressive nature of disorder, and the failure of the classical neurotrophins in clinical trials for DPN, it is important to develop new therapeutics that can counteract the nerve damage in diabetes. / Pancreas-derived peptides that stimulate islet regeneration have gained increasing interest for use in DPN, in part due to the unique similarities that exist between pancreatic and neural tissues. We studied the effects of one such peptide, the Islet Neogenesis Associated Protein (INGAP) peptide, on axonal regrowth in the peripheral nervous system (PNS) in adult C57BLJ6 mice. Using dorsal root ganglia (DRG) explant cultures as in vitro model of axotomy, we found that INGAP peptide enhances axonal regrowth in a time- and concentration-dependent manner that involves cyclic AMP-dependent activation of protein kinase A (PKA) and stimulation of phosphatidylinositol-3 kinase (PI3K). The neuritogenic effects of INGAP peptide were reduced by blocking antibodies against a number of growth factors that are secreted by Schwann cells including nerve growth factor (NGF), insulin-like growth factor-I (IGF-I) and transforming growth factor-beta (TGF-(3), suggesting an indirect action of INGAP peptide on outgrowth from DRG neurons, achieved via a primary action on Schwann cells. / To further assess the potential usefulness of INGAP peptide in DPN, we used streptozotocin-induced type 1 diabetic mice and found that after two weeks of INGAP peptide administration, begun twelve weeks after the STZ treatment, sensory dysfunction (reduced sensitivity to heat stimulation) was corrected without inducing the hyperalgesia associated with direct administration of NGF. These effects were accompanied by increases in the levels of a number of structural proteins and transcription factors associated with nerve growth. Significantly, the beneficial effects of INGAP peptide on the PNS in vivo occurred independently of its normalizing effects on hyperglycemia. Finally, we found that INGAP peptide enhanced the mitochondrial inner transmembrane potential (DeltaPsim), and that the mitochondrial effects were largely mediated by PKA. / Taken together, these studies demonstrate that INGAP peptide enhances sensory axonal regrowth independently of islet neogenesis and the consequent secretion of insulin, and that it may be of benefit in the treatment of peripheral neuropathy associated with diabetes and possibly other clinical conditions.
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:QMM.103186 |
| Date | January 2006 |
| Creators | Tam, Joseph. |
| Publisher | McGill University |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Format | application/pdf |
| Coverage | Doctor of Philosophy (Department of Pharmacology & Therapeutics.) |
| Rights | © Joseph Tam, 2006 |
| Relation | alephsysno: 002585532, proquestno: AAINR32390, Theses scanned by UMI/ProQuest. |
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