Article

Nerve growth factor/p38 signaling increases intraepidermal nerve fiber densities in painful neuropathy of type 2 diabetes

Department of Neurology, University of Michigan Medical Center, Ann Arbor, Michigan 48109, USA.
Neurobiology of Disease (Impact Factor: 5.2). 08/2011; 45(1):280-7. DOI: 10.1016/j.nbd.2011.08.011
Source: PubMed

ABSTRACT Painful diabetic neuropathy (PDN) is a common, yet devastating complication of type 2 diabetes. At this time, there is no objective test for diagnosing PDN. In the current study, we measured the peptidergic intraepidermal nerve fiber densities (IENFD) from hind paws of the db/db mouse, an animal model for type 2 diabetes, during the period of mechanical allodynia from 6 to 12 weeks of age. Intraepidermal nerve fibers (IENF) of the hind footpads were identified by protein gene product (PGP) 9.5 immunohistochemistry. The peptidergic IENF were determined by double immunofluorescence using anti-PGP9.5 and antibodies against tropomyosin-receptor-kinase (Trk) A. We observed a significant increase in PGP9.5-positive IENFD at 8 and 10 weeks of age. Similarly, Trk A-positive peptidergic IENF, which also express substance P and calcitonin gene related peptide in db/db mice, were observed to be elevated from 1.5 to 2 fold over controls. This upregulation ended at 16 weeks of age, in accordance with the reduction of mechanical allodynia. Anti-NGF treatment significantly inhibited the upregulation of peptidergic IENFD during the period of mechanical allodynia, suggesting that increased neurotrophism may mediate this phenomenon. In addition, SB203580, an inhibitor of p38, blocked the increase in peptidergic IENFD in db/db mice. The current results suggest that peptidergic IENFD could be a potential diagnostic indicator for PDN in type 2 diabetes. Furthermore, the inhibition of NGF-p38 signaling could be a potential therapeutic strategy for treating this painful condition.

Download full-text

Full-text

Available from: Brandon M Yanik, Jul 29, 2015
0 Followers
 · 
117 Views
  • Source
    • "For example, variability in NGF levels is associated with atherosclerosis and hence cardiovascular disease and also metabolic disorders such as diabetes and obesity [29] [30]. Specifically, NGF levels are decreased in atherosclerotic coronary vascular tissue and a decrease in plasma NGF could be detected in metabolic syndrome patients [31]. NGF deficits are the main cause of these diseases mentioned above, so, to some extent, supply of NGF to the target region may reverse the pathology of the diseases or alleviate the symptoms. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Neuroprotective therapies which focus on factors leading to retinal ganglion cells (RGCs) degeneration have been drawing more and more attention. The beneficial effects of nerve growth factor (NGF) on the glaucoma have been recently suggested, but its effects on eye tissue are complex and controversial in various studies. Recent clinical trials of systemically and topically administrated NGF demonstrate that NGF is effective in treating several ocular diseases, including glaucoma. NGF has two receptors named high affinity NGF tyrosine kinase receptor TrkA and low affinity receptor p75NTR. Both receptors exist in cells in retina like RGC (expressing TrkA) and glia cells (expressing p75NTR). NGF functions by binding to TrkA or p75NTR alone or both together. The binding of NGF to TrkA alone in RGC promotes RGC's survival and proliferation through activation of TrkA and several prosurvival pathways. In contrast, the binding of NGF to p75NTR leads to apoptosis although it also promotes survival in some cases. Binding of NGF to both TrkA and p75NTR at the same time leads to survival in which p75NTR functions as a TrkA helping receptor. This review discusses the current understanding of the NGF signaling in retina and the therapeutic implications in the treatment of glaucoma.
    BioMed Research International 08/2014; 2014:759473. DOI:10.1155/2014/759473 · 2.71 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Peripheral neuropathies are common neurological diseases, and various animal models have been developed to study disease pathogenesis and test potential therapeutic drugs. Three commonly studied disease models with huge public health impact are diabetic peripheral neuropathy, chemotherapy-induced peripheral neuropathy, and human immunodeficiency virus-associated sensory neuropathies. A common theme in these animal models is the comprehensive use of pathological, electrophysiological, and behavioral outcome measures that mimic the human disease. In recent years, the focus has shifted to the use of outcome measures that are also available in clinical use and can be done in a blinded and quantitative manner. One such evaluation tool is the evaluation of epidermal innervation with a simple skin biopsy. Future clinical trials will be needed to validate the translational usefulness of this outcome measure and validation against accepted outcome measures that rely on clinical symptoms or examination findings in patients.
    Journal of the American Society for Experimental NeuroTherapeutics 03/2012; 9(2):262-9. DOI:10.1007/s13311-012-0116-y · 3.88 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Dyslipidemia has been identified as an important pathogenic risk factor for diabetic neuropathy, but current animal models do not adequately reproduce the lipid profile observed in human diabetics (increased triglycerides with an elevated LDL-cholesterol and reduced HDL-cholesterol). High fat feeding of mice produces hyperlipidemia, but mice are resistant to increases in the LDL to HDL ratio, reducing the potential for peripheral lipid deposits to impact neuropathy, as is postulated to occur in human subjects. Genetic manipulations provide an alternative approach to reproducing a neuropathic plasma lipid profile. Based on findings from the atherosclerosis literature, we began with knockout of ApoE. Since knockout of ApoE alone only partially mimics the human diabetic lipid profile, we examined the impact of its combination with a well-characterized model of type 2 diabetes exhibiting neuropathy, the db/db mouse. We added further gene manipulations to increase hyperlipidemia by using mice with both ApoE and ApoB48 knockout on the ob/+ (leptin mutation) mice. In all of these models, we found that either the db/db or ob/ob genotypes had increased body weight, hyperlipidemia, hyperglycemia, and evidence of neuropathy compared with the control groups (db/+ or ob/+, respectively). We found that ApoE knockout combined with leptin receptor knockout produced a lipid profile most closely modeling human dyslipidemia that promotes neuropathy. ApoE knockout combined with additional ApoB48 and leptin knockout produced similar changes of smaller magnitude, but, notably, an increase in HDL-cholesterol. Our data suggest that the overall effects of ApoE knockout, either directly upon nerve structure and function or indirectly on lipid metabolism, are insufficient to significantly alter the course of diabetic neuropathy. Although these models ultimately do not deliver optimal lipid profiles for translational diabetic neuropathy research, they do present glycemic and lipid profile properties of value for future therapeutic investigations.
    Experimental Neurology 10/2012; 239. DOI:10.1016/j.expneurol.2012.10.002 · 4.62 Impact Factor
Show more