Peripheral neuropathy is one of the major complications of diabetes. There is a compelling need to develop effective therapeutic approaches specifically designed to improve neurological function in the damaged peripheral nervous system after diabetes. Cyclic guanosine-monophosphate (GMP) is involved in the regulation of many neural functions. The phosphodiesterase-5 (PDE5) enzyme is highly specific for hydrolysis of cGMP. The role of PDE5 in diabetic peripheral neuropathy has not been fully investigated. In a novel set of experiments, our data show that hyperglycemia upregulates PDE5 expression and suppression of PDE5 by sildenafil, a specific inhibitor of PDE5, increases cGMP levels and significantly improves neurological outcome in diabetic mice, indicating that sildenafil may have a beneficial effect on the clinical treatment of diabetic peripheral neuropathy In this application, we therefore seek to investigate the mechanisms underlying the therapeutic effects of inhibition of PDE5 by sildenafil on the treatment of diabetic peripheral neuropathy. We propose that sildenafil and tadalafil by suppressing PDE5 activity ameliorates diabetic peripheral neuropathy. Our hypotheses are: 1. Treatment with PDE5 inhibitors, sildenafil and tadalafil, improves neurological function of peripheral neuropathy in diabetic mice. 2. Sildenafil by suppressing PDE5 increases cGMP levels in diabetic Schwann cells and dorsal root ganglia (DRG) neurons, leading to activation of the cGMP/cGMP-dependent protein kinase (PKG) signaling pathway that mediates sildenafil-enhanced axonal outgrowth and myelination. 3. NGF and BDNF upregulated by sildenafil-activated cGMP/PKG signaling pathway mediate axonal outgrowth and myelination. The proposed experiments have been designed to test these hypotheses. To investigate the effect of PDE5 inhibitors on neurological outcome, type II diabetic mice which develop severe peripheral neuropathy will be treated with sildenafil and tadalafil. To investigate the molecular mechanisms that mediate sildenafil-enhanced axonal outgrowth and myelination in diabetic mice, the effect of sildenafil on expression of PDE5, cGMP, and activation of cGMP/PKG signaling pathways will be examined. Using pharmacological analogs, inhibitors and transgenic mice, we will investigate the cause-effect of the cGMP/PKG signaling pathway and NGF and BDNF on regulating sildenafil-enhanced axonal outgrowth and myelination. These studies are innovative and will provide new insight into mechanisms underlying the neurological dysfunction of diabetic peripheral neuropathy and lead to the development of a new treatment using PDE5 inhibitors. Relevance Statement: Peripheral neuropathy often stemming from diabetes is a major disability affecting millions of Americans. In this proposal, I seek to develop a novel treatment for peripheral neuropathy using PDE5 inhibitors, sildenafil and tadalafil. These drugs, clinically employed for the treatment of erectil dysfunction, are shown to be highly effective in substantially reducing neurological dysfunction caused by diabetes. The molecular mechanism by which sildenafil is therapeutically effective is elucidated.

Public Health Relevance

In this application, we propose to investigate whether PDE5 inhibitors-enhanced axonal outgrowth and myelination contribute to improvement of peripheral nerve recovery in experimental diabetic mice, which may provide a novel restorative therapy for diabetic peripheral neuropathy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS075084-01A1
Application #
8371423
Study Section
Molecular Neuropharmacology and Signaling Study Section (MNPS)
Program Officer
Gwinn, Katrina
Project Start
2012-05-15
Project End
2016-04-30
Budget Start
2012-05-15
Budget End
2013-04-30
Support Year
1
Fiscal Year
2012
Total Cost
$320,469
Indirect Cost
$101,719
Name
Henry Ford Health System
Department
Type
DUNS #
073134603
City
Detroit
State
MI
Country
United States
Zip Code
48202
Jia, Longfei; Chopp, Michael; Wang, Lei et al. (2018) MiR-34a Regulates Axonal Growth of Dorsal Root Ganglia Neurons by Targeting FOXP2 and VAT1 in Postnatal and Adult Mouse. Mol Neurobiol 55:9089-9099
Wang, Lei; Chopp, Michael; Lu, XueRong et al. (2018) miR-146a Mediates Thymosin ?4 Induced Neurovascular Remodeling of Diabetic Peripheral Neuropathy in Type-II Diabetic Mice. Brain Res :
Jia, Longfei; Chopp, Michael; Wang, Lei et al. (2018) Exosomes derived from high-glucose-stimulated Schwann cells promote development of diabetic peripheral neuropathy. FASEB J :fj201800597R
Wang, Lei; Chopp, Michael; Szalad, Alexandra et al. (2018) Angiopoietin-1/Tie2 signaling pathway contributes to the therapeutic effect of thymosin ?4 on diabetic peripheral neuropathy. Neurosci Res :
Jia, Longfei; Wang, Lei; Chopp, Michael et al. (2018) MiR-29c/PRKCI Regulates Axonal Growth of Dorsal Root Ganglia Neurons Under Hyperglycemia. Mol Neurobiol 55:851-858
Wang, Lei; Chopp, Michael; Zhang, Zheng Gang (2017) PDE5 inhibitors promote recovery of peripheral neuropathy in diabetic mice. Neural Regen Res 12:218-219
Wang, Lei; Chopp, Michael; Szalad, Alexandra et al. (2016) Tadalafil Promotes the Recovery of Peripheral Neuropathy in Type II Diabetic Mice. PLoS One 11:e0159665
Jia, Longfei; Wang, Lei; Chopp, Michael et al. (2016) MicroRNA 146a locally mediates distal axonal growth of dorsal root ganglia neurons under high glucose and sildenafil conditions. Neuroscience 329:43-53
Wang, Lei; Chopp, Michael; Szalad, Alexandra et al. (2015) Sildenafil ameliorates long term peripheral neuropathy in type II diabetic mice. PLoS One 10:e0118134
Wang, Lei; Chopp, Michael; Jia, Longfei et al. (2015) Therapeutic Benefit of Extended Thymosin ?4 Treatment Is Independent of Blood Glucose Level in Mice with Diabetic Peripheral Neuropathy. J Diabetes Res 2015:173656

Showing the most recent 10 out of 12 publications