Abstract
1-[(2-adamantyl)amino]acetyl-2-cyano-(S)-pyrrolidine, monohydrochloride (PKF275–055), a vildagliptin analog, is a novel, selective, potent, orally bioavailable, and long-acting dipeptidyl peptidase IV inhibitor. We studied the effect of PKF275-055 administration on the prevention, protection, and treatment of diabetic neuropathy in the streptozotocin-induced diabetic rat. PKF275-055 improved body and muscle weight. Oral glucose tolerance tests showed a marked improvement in glucose metabolism under all treatment schedules. When tested in prevention and protection experiments, PKF275-055 completely averted the decrease of Na+/K+-ATPase activity and partially counteracted the nerve conduction velocity (NCV) deficit observed in untreated diabetic rats but had no effects on abnormal mechanical and thermal sensitivity. When used in a therapeutic setting, PKF275-055 induced a significant correction in the alteration in Na+,K+-ATPase activity and NCV present in untreated diabetics. Diabetic rats developed mechanical hyperalgesia within 2 weeks after streptozotocin injection and exhibited significantly longer thermal response latencies. It is noteworthy that PKF275-055 treatment restored mechanical sensitivity thresholds by approximately 50% (p < 0.01) and progressively improved the alteration in thermal responsiveness. In conclusion, PKF275-055 showed an anabolic effect, improved oral glucose tolerance, and counteracted the alterations in Na+,K+-ATPase activity, NCV, and nociceptive thresholds in diabetic rats. The present data support a potential therapeutic effect of PKF275-055 in the treatment of rodent diabetic neuropathy.
Footnotes
This work was supported by Novartis (Italy).
R.B., I.C., C.P-S, and P.G. previously worked at “Mario Negri” Institute for Pharmacological Research, Milan, Italy.
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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ABBREVIATIONS:
- DPN
- diabetic peripheral neuropathy
- AUC
- areas under the curve
- DPP IV
- dipeptidyl-peptidase IV
- EDL
- extensor digitorum longus
- GLP-1
- glucagon-like peptide-1
- GLP-1R
- GLP-1 receptor
- IENF
- intraepidermal nerve fiber
- NCV
- nerve conduction velocity
- OGTT
- oral glucose tolerance test
- STZ
- streptozotocin
- ANOVA
- analysis of variance
- CTRL
- control
- PKF275–055
- 1-[(2-adamantyl)amino]acetyl-2-cyano-(S)-pyrrolidine, monohydrochloride.
- Received March 16, 2011.
- Accepted October 6, 2011.
- Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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