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

Journal article

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: Bianchi, R; Cervellini, I; Porretta-Serapiglia, C; Oggioni, N; Burkey, B

• Journal: Journal of pharmacology and experimental therapeutics
• Volume: 340
• Issue: 1
• Pages: 64-72
• Publication date: 2012-01-01
• DOI: 10.1124/jpet.111.181529
• EISSN: 1521-0103
• ISSN: 0022-3565
• Language: English
• Keywords: Body Weight; Peripheral Nervous System Diseases; Pyrrolidines; Glucagon-Like Peptide 1; Eating; Glucose Tolerance Test; Diabetic Neuropathies; Behavior, Animal; Nitriles; Drinking; Male; Pain Threshold; Rats; Sodium-Potassium-Exchanging ATPase; Adamantane; Diabetes Mellitus, Experimental; Disease Progression; Dipeptidyl-Peptidase IV Inhibitors; Dose-Response Relationship, Drug; Rats, Sprague-Dawley; Neural Conduction; Animals