Beneficial effects of PKF275-055, a novel, selective, orally bioavailable, long-acting dipeptidyl peptidase IV inhibitor in streptozotocin-induced diabetic peripheral neuropathy.

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.

• Authors: R Bianchi, I Cervellini, C Porretta-Serapiglia, N Oggioni, B Burkey, P Ghezzi, G Cavaletti, G Lauria
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 340 Issue 1 Pg. 64-72 (Jan 2012) ISSN: 1521-0103 [Electronic] United States
• PMID: 21984837 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 1-((2-adamantyl)amino)acetyl-2-cyano-(S)-pyrrolidine, monohydrochloride
• Dipeptidyl-Peptidase IV Inhibitors
• Nitriles
• Pyrrolidines
• Glucagon-Like Peptide 1
• Sodium-Potassium-Exchanging ATPase
• Vildagliptin
• Adamantane

Topics

• Adamantane (analogs & derivatives, chemistry, pharmacology)
• Animals
• Behavior, Animal (drug effects)
• Body Weight (drug effects)
• Diabetes Mellitus, Experimental (complications)
• Diabetic Neuropathies (drug therapy)
• Dipeptidyl-Peptidase IV Inhibitors (pharmacology)
• Disease Progression
• Dose-Response Relationship, Drug
• Drinking (drug effects)
• Eating (drug effects)
• Glucagon-Like Peptide 1 (metabolism)
• Glucose Tolerance Test
• Male
• Neural Conduction (drug effects)
• Nitriles (chemistry, pharmacology)
• Pain Threshold (drug effects)
• Peripheral Nervous System Diseases (drug therapy)
• Pyrrolidines (chemistry, pharmacology)
• Rats
• Rats, Sprague-Dawley
• Sodium-Potassium-Exchanging ATPase (metabolism)
• Vildagliptin