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The role of endogenous nerve growth factor in human diabetic neuropathy

Nature Medicine volume 2, pages 703707 (1996) | Download Citation

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Abstract

Nerve growth factor (NCF) is trophic to sensory and sympathetic fibers1–3. In animal models, NGF is depleted in diabetic nerves4 and NGF deprivation produces hypoalgesia5. Exogenous NGF can reverse some of the pathological changes in diabetic nerves1,6 and NGF excess leads to hyperalgesia5. We have quantified sensory and autonomic function in early diabetic polyneuropathy and correlated changes with levels of NGF and neuropeptides in affected skin. We describe an early length–dependent dysfunction of sensory small–diameter fibers, prior to dysfunction of sympathetic fibers, with depletion of skin NGF and the sensory neuropeptide substance P. We describe a significant correlation between NGF depletion and decreased skin axon–reflex vasodilation, mediated by small sensory fibers partly via substance P release3. Immunostaining shows depletion of NGF in keratinocytes in diabetic skin. We propose that a decrease in endogenous skin–derived NGF influences the presentation of diabetic polyneuropathy, although metabolic or vascular abnormalites may be the cause of the neuropathy7,8. As loss of nociception and axon–reflex vasodilation contribute to diabetic foot ulceration9, early and prolonged NGF treatment at an appropriate dose may provide rational prophylaxis for this condition.

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References

  1. 1.

    , , & NGF: Actions in the peripheral and central nervous systems, in Neurotrophic Factors (eds. Loughlin, S.E. & Fallen, J.H.) 209–256 (Academic Press, San Diego, California, 1993).

  2. 2.

    & Nerve growth factor regulates expression of neuropeptide genes in adult sensory neurones. Nature 337, 362–364 (1989).

  3. 3.

    et al. A new autonomic and sensory neuropathy with loss of adrener-gic sympathetic function and sensory neuropeptides. Lancet 337, 1353–1355 (1991).

  4. 4.

    et al. Diabetes mellitus-associated decrease in nerve growth factor levels is reversed by allogeneic pancreatic islet transplantation. Neurosci. Lett. 125, 1–4 (1991).

  5. 5.

    & Nerve Growth Factor and nociception. Trends Neurosci. 16, 353–359 (1993).

  6. 6.

    , , , & Nerve growth factor administration protects against experimental diabetic sensory neuropathy. Brain Res. 634, 7–12 (1994).

  7. 7.

    Nerve growth factor regulates nociception in human health and disease. Br. J. Anaesth. 75, 201–208 (1995).

  8. 8.

    & Diabetic and hypoglycemic neuropathy, in Peripheral Neuropathy. 3rd edn. (eds. Dyck, P.J., Thomas, P.K., Griffin, J.W., Low, P.A. & Poduslo, J.F.) 1219–1250 (WB Saunders & Co, Philadelphia/London, 1993).

  9. 9.

    & Impaired neurogenic vascular response in patients with diabetes and neuropathic foot lesions. N. Engl. J. Med. 318, 1306–1309 (1988).

  10. 10.

    , , & NGF regulates adult rat dorsal root ganglion neuron responses to the excitotoxin capsaicin. Neuron 1, 937–981 (1988).

  11. 11.

    , , , & Axonal transport of endogenous nerve growth factor (NGF) and NGF receptor in experimental diabetic neuropathy. Experimental Neural. 130, 24–30 (1994).

  12. 12.

    , , & Deficits in sciatic nerve neuropeptide content coincide with a reduction in target tissue nerve growth factor messenger mRNA in streptozotocin-diabetic rats: effects of insulin treatment. Neuroscience 62, 337–344 (1994).

  13. 13.

    , , , & Retrograde transport of 1251-nerve growth factor in rat Heal mesenteric nerves. Effect of streptozocin diabetes. Diabetes 34, 1230–1240 (1985).

  14. 14.

    et al. Early increase precedes a depletion of VIP and PGP9.5 in the skin of insulin-dependent diabetics — correlation of quantitative immunohis-tochemistry and clinical assessment of peripheral neuropathy. J. Pathol. 169, 269–277 (1993).

  15. 15.

    et al. Immunohistochemical measurements of nerves and neuropeptides in diabetic skin: relationship to tests of neurological function. Diabetologia 35, 889–897 (1992).

  16. 16.

    et al. Nerve fibre studies in skin biopsies in peripheral neuropathies. I. Immunohistochemical analysis of neuropeptides in diabetes mellitus. J. Neural. Sci. 93, 289–296 (1989).

  17. 17.

    et al. Water content, vasoactive intestinal polypeptide and substance P in Intact and crushed sciatic nerves of normal and streptozotocin-diabetic rats. J. Neural. Sci. 83, 167–177 (1988).

  18. 18.

    et al. Targeted mutation of the gene encoding the low affinity NGF receptor p75 leads to deficits in the peripheral sensory nervous system. Cell 69, 737–49 (1992).

  19. 19.

    et al. Depletion of nerve growth factor in leprosy. Lancet 344, 129–130 (1994).

  20. 20.

    , & Endogenous NGF and nerve impulses regulate the collateral sprouting of sensory axons in the skin of the adult rat. J. Neurosci. 12, 1454–1466 (1992).

  21. 21.

    , & Estrogen differentially regulates estrogen and NGF receptor mRNAs in adult sensory neurons. J. Neurosci. 14, 459–71 (1994).

  22. 22.

    , & Increased NGF mRNA expression in denervated rat skin. Neuroreport 4, 351–4 (1993).

  23. 23.

    , , , & An investigation of antibodies to nerve growth factor in diabetic autonomic neuropathy. Diab. Med. 11, 378–83 (1994).

  24. 24.

    et al. Nerve growth factor in cultured human skin cells: Effect of gestation and viral transformation. Neurosci. Lett. 184, 157–60 (1995).

  25. 25.

    , & Increased corneocyte surface area in diabetic skin. Japanese J. Dermatol. 10, 129–134 (1991).

  26. 26.

    et al. The effect of systemically administered recombinant human nerve growth factor in healthy human subjects. Ann. Neurol. 36, 244–246 (1994).

  27. 27.

    , & Assessment of cutaneous sensory and autonomic reflexes in rheumatoid arthritis. Ann. Rheumatic Dis. 54, 251–255 (1995).

  28. 28.

    , , & Evaluation of thermal and vibration sensation in diabetic neuropathy. Diabetologia 28, 131–137 (1985).

  29. 29.

    , & Testing sensibility, including touch-pressure, two point discrimination point localisation and vibration. J. Hand Therap. 6, 114–123 (1993).

  30. 30.

    , , & Sympathetic activity influences the vascular axon reflex in skin. Acta Physiol. Scand. 139, 77–84 (1990).

  31. 31.

    et al. Regional changes of ciliary neurotrophic factor and nerve growth factor immunoreactivity in spinal cord and cerebral cortex in human motoneurone disease. Nature Med. 2, 168–72 (1995).

  32. 32.

    et al. A VIP-containing system in human lumbosacral spinal cord. Nature 305, 143–45 (1983).

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Affiliations

  1. Department of Neurology London Hospital Medical College, Royal London Hospital, Whitechapel, London E1 1BB,

    • P. Anand
    •  & G. Warner
  2. Blond Mclndoe Centre, Queen Victoria Hospital, East Grinstead, RH19 3DZ, UK

    • G. Terenghi
  3. Department of Medicine, London Hospital Medical College, Royal London Hospital, Whitechapel, London E1 1BB, UK

    • P. Kopelman
  4. Department of Bio Analytical Technology, Genentech, Inc., San Francisco, California 94080, USA

    • R.E. Williams-Chestnut
    •  & D.V. Sinicropi

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Correspondence to P. Anand.

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https://doi.org/10.1038/nm0696-703