title: 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: Neuromuscular Disease Unit, IRCCS Foundation "Carlo Besta" Neurological Institute, Via Celoria 11, 20133, Milan, Italy. bianchi.r@istituto-besta.it
authors: R
authors: R
authors: Bianchi
authors: I
authors: I
authors: Cervellini
authors: C
authors: C
authors: Porretta-Serapiglia
authors: N
authors: N
authors: Oggioni
authors: B
authors: B
authors: Burkey
authors: P
authors: P
authors: Ghezzi
authors: G
authors: G
authors: Cavaletti
authors: G
authors: G
authors: Lauria
mesh_terms: D000218:Adamantane / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000150:complications*; D003929:Diabetic Neuropathies / Q000188:drug therapy*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000494:pharmacology*; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D004326:Drinking / Q000187:drug effects; D004435:Eating / Q000187:drug effects; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism; D005951:Glucose Tolerance Test; D008297:Male; D009431:Neural Conduction / Q000187:drug effects; D009570:Nitriles / Q000737:chemistry / Q000494:pharmacology*; D017288:Pain Threshold / Q000187:drug effects; D010523:Peripheral Nervous System Diseases / Q000188:drug therapy*; D011759:Pyrrolidines / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism; D000077597:Vildagliptin
chemical_list: C569631:1-((2-adamantyl)amino)acetyl-2-cyano-(S)-pyrrolidine, monohydrochloride; D054873:Dipeptidyl-Peptidase IV Inhibitors; D009570:Nitriles; D011759:Pyrrolidines; D052216:Glucagon-Like Peptide 1; D000254:Sodium-Potassium-Exchanging ATPase; D000077597:Vildagliptin; D000218:Adamantane