NIH Research Festival
At least 50% of diabetic patients develop nerve dysfunction in the skin, leading to severe burning or shooting pain called small fiber neuropathy. In addition to functional abnormalities, patients with small fiber neuropathy develop degeneration of axon terminals and vascular abnormalities in the skin. Although the symptoms of diabetic small fiber neuropathy are well characterized, the mechanism of etiology and therapeutic strategies remain elusive. We have developed an in vivo live calcium imaging of sensory nerves in the ear skin of the diet-induced obesity (DIO) mice to visualize pain reactions in response to capsaicin stimulation. The DIO skin at 22 weeks-of-age shows abnormal sensory hypersensitivity characterized as a pain reaction, while exhibiting no severe sensory axon terminal degeneration or vascular abnormalities. At 30 weeks-of-age, the DIO skin shows a significant reduction of sensory axon terminals, indicating that sensory axons undergo severe degeneration, as well as an increased expression of the vascular leakage marker PLVAP in capillary endothelial cells. These results suggest that sensory nerve hypersensitivity develops prior to sensory degeneration and vascular abnormalities in the DIO skin. At mechanistic level, the enhanced expression of nerve growth factor (NGF) is observed in the DIO skin. Short-term treatment of the DIO skin with anti-NGF neutralized antibody or Wortmannin as a selective inhibitor of phosphatidylinositol 3-kinase (PI3K) results in suppression of hypersensitivity. Taken together, a modulation of local NGF-TrkA-PI3K signaling could be an effective therapeutic strategy for diabetic small fiber neuropathy.
Scientific Focus Area: Neuroscience
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