title: Sildenafil ameliorates long term peripheral neuropathy in type II diabetic mice.
abstract: 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+/+Leprdb/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.
authors.affiliation: Department of Neurology, Henry Ford Hospital, 2799 W. Grand Boulevard, Detroit, Michigan, 48202, United States of America.
authors.forename: Lei
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Neurology, Henry Ford Hospital, 2799 W. Grand Boulevard, Detroit, Michigan, 48202, United States of America; Department of Physics, Oakland University, Rochester, Michigan, 48309, United States of America.
authors.forename: Michael
authors.initials: M
authors.lastname: Chopp
authors.affiliation: Department of Neurology, Henry Ford Hospital, 2799 W. Grand Boulevard, Detroit, Michigan, 48202, United States of America.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Szalad
authors.affiliation: Department of Neurology, Henry Ford Hospital, 2799 W. Grand Boulevard, Detroit, Michigan, 48202, United States of America.
authors.forename: LongFei
authors.initials: L
authors.lastname: Jia
authors.affiliation: Department of Neurology, Henry Ford Hospital, 2799 W. Grand Boulevard, Detroit, Michigan, 48202, United States of America.
authors.forename: XueRong
authors.initials: X
authors.lastname: Lu
authors.affiliation: Department of Neurology, Henry Ford Hospital, 2799 W. Grand Boulevard, Detroit, Michigan, 48202, United States of America.
authors.forename: Mei
authors.initials: M
authors.lastname: Lu
authors.affiliation: Department of Neurology, Henry Ford Hospital, 2799 W. Grand Boulevard, Detroit, Michigan, 48202, United States of America.
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Neurology, Henry Ford Hospital, 2799 W. Grand Boulevard, Detroit, Michigan, 48202, United States of America.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Neurology, Henry Ford Hospital, 2799 W. Grand Boulevard, Detroit, Michigan, 48202, United States of America.
authors.forename: RuiLan
authors.initials: R
authors.lastname: Zhang
authors.affiliation: Department of Neurology, Henry Ford Hospital, 2799 W. Grand Boulevard, Detroit, Michigan, 48202, United States of America.
authors.forename: Zheng Gang
authors.initials: ZG
authors.lastname: Zhang
mesh_terms: D042683:Angiopoietin-1 / Q000378:metabolism; D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000150:complications*; D003924:Diabetes Mellitus, Type 2 / Q000150:complications*; D008297:Male; D051379:Mice; D010523:Peripheral Nervous System Diseases / Q000150:complications* / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D042787:Receptor, TIE-2 / Q000378:metabolism; D020127:Recovery of Function / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D000068677:Sildenafil Citrate / Q000494:pharmacology* / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D042683:Angiopoietin-1; D000068677:Sildenafil Citrate; D042787:Receptor, TIE-2; C079086:Tek protein, mouse