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Sildenafil Ameliorates Long Term Peripheral Neuropathy in Type II Diabetic Mice
Diabetic peripheral neuropathy is a common complication of long-standing diabetes mellitus. To mimic clinical trials in which patients with diabetes enrolled have advanced peripheral neuropathy, we investigated the effect of sildenafil, a specific inhibitor of phosphodiesterase type 5 enzyme, on lon...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4331563/ https://www.ncbi.nlm.nih.gov/pubmed/25689401 http://dx.doi.org/10.1371/journal.pone.0118134 |
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author | Wang, Lei Chopp, Michael Szalad, Alexandra Jia, LongFei Lu, XueRong Lu, Mei Zhang, Li Zhang, Yi Zhang, RuiLan Zhang, Zheng Gang |
author_facet | Wang, Lei Chopp, Michael Szalad, Alexandra Jia, LongFei Lu, XueRong Lu, Mei Zhang, Li Zhang, Yi Zhang, RuiLan Zhang, Zheng Gang |
author_sort | Wang, Lei |
collection | PubMed |
description | Diabetic peripheral neuropathy is a common complication of long-standing diabetes mellitus. To mimic clinical trials in which patients with diabetes enrolled have advanced peripheral neuropathy, we investigated the effect of sildenafil, a specific inhibitor of phosphodiesterase type 5 enzyme, on long term peripheral neuropathy in middle aged male mice with type II diabetes. Treatment of diabetic mice (BKS.Cg-m+/+Lepr(db)/J, db/db) at age 36 weeks with sildenafil significantly increased functional blood vessels and regional blood flow in the sciatic nerve, concurrently with augmentation of intra-epidermal nerve fiber density in the skin and myelinated axons in the sciatic nerve. Functional analysis showed that the sildenafil treatment considerably improved motor and sensory conduction velocities in the sciatic nerve and peripheral thermal stimulus sensitivity compared with the saline treatment. In vitro studies showed that mouse dermal endothelial cells (MDE) cultured under high glucose levels exhibited significant down regulation of angiopoietin 1 (Ang1) expression and reduction of capillary-like tube formation, which were completely reversed by sildenafil. In addition, incubation of dorsal root ganglia (DRG) neurons with conditioned medium harvested from MDE under high glucose levels suppressed neurite outgrowth, where as conditional medium harvested from MDE treated with sildenafil under high glucose levels did not inhibit neurite outgrowth of DRG neurons. Moreover, blockage of the Ang1 receptor, Tie2, with a neutralized antibody against Tie2 abolished the beneficial effect of sildenafil on tube formation and neurite outgrowth. Collectively, our data indicate that sildenafil has a therapeutic effect on long term peripheral neuropathy of middle aged diabetic mice and that improvement of neurovascular dysfunction by sildenafil likely contributes to the amelioration of nerve function. The Ang1/Tie2 signaling pathway may play an important role in these restorative processes. |
format | Online Article Text |
id | pubmed-4331563 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-43315632015-02-24 Sildenafil Ameliorates Long Term Peripheral Neuropathy in Type II Diabetic Mice Wang, Lei Chopp, Michael Szalad, Alexandra Jia, LongFei Lu, XueRong Lu, Mei Zhang, Li Zhang, Yi Zhang, RuiLan Zhang, Zheng Gang PLoS One Research Article Diabetic peripheral neuropathy is a common complication of long-standing diabetes mellitus. To mimic clinical trials in which patients with diabetes enrolled have advanced peripheral neuropathy, we investigated the effect of sildenafil, a specific inhibitor of phosphodiesterase type 5 enzyme, on long term peripheral neuropathy in middle aged male mice with type II diabetes. Treatment of diabetic mice (BKS.Cg-m+/+Lepr(db)/J, db/db) at age 36 weeks with sildenafil significantly increased functional blood vessels and regional blood flow in the sciatic nerve, concurrently with augmentation of intra-epidermal nerve fiber density in the skin and myelinated axons in the sciatic nerve. Functional analysis showed that the sildenafil treatment considerably improved motor and sensory conduction velocities in the sciatic nerve and peripheral thermal stimulus sensitivity compared with the saline treatment. In vitro studies showed that mouse dermal endothelial cells (MDE) cultured under high glucose levels exhibited significant down regulation of angiopoietin 1 (Ang1) expression and reduction of capillary-like tube formation, which were completely reversed by sildenafil. In addition, incubation of dorsal root ganglia (DRG) neurons with conditioned medium harvested from MDE under high glucose levels suppressed neurite outgrowth, where as conditional medium harvested from MDE treated with sildenafil under high glucose levels did not inhibit neurite outgrowth of DRG neurons. Moreover, blockage of the Ang1 receptor, Tie2, with a neutralized antibody against Tie2 abolished the beneficial effect of sildenafil on tube formation and neurite outgrowth. Collectively, our data indicate that sildenafil has a therapeutic effect on long term peripheral neuropathy of middle aged diabetic mice and that improvement of neurovascular dysfunction by sildenafil likely contributes to the amelioration of nerve function. The Ang1/Tie2 signaling pathway may play an important role in these restorative processes. Public Library of Science 2015-02-17 /pmc/articles/PMC4331563/ /pubmed/25689401 http://dx.doi.org/10.1371/journal.pone.0118134 Text en © 2015 Wang et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Wang, Lei Chopp, Michael Szalad, Alexandra Jia, LongFei Lu, XueRong Lu, Mei Zhang, Li Zhang, Yi Zhang, RuiLan Zhang, Zheng Gang Sildenafil Ameliorates Long Term Peripheral Neuropathy in Type II Diabetic Mice |
title | Sildenafil Ameliorates Long Term Peripheral Neuropathy in Type II Diabetic Mice |
title_full | Sildenafil Ameliorates Long Term Peripheral Neuropathy in Type II Diabetic Mice |
title_fullStr | Sildenafil Ameliorates Long Term Peripheral Neuropathy in Type II Diabetic Mice |
title_full_unstemmed | Sildenafil Ameliorates Long Term Peripheral Neuropathy in Type II Diabetic Mice |
title_short | Sildenafil Ameliorates Long Term Peripheral Neuropathy in Type II Diabetic Mice |
title_sort | sildenafil ameliorates long term peripheral neuropathy in type ii diabetic mice |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4331563/ https://www.ncbi.nlm.nih.gov/pubmed/25689401 http://dx.doi.org/10.1371/journal.pone.0118134 |
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