The combination of neurokinin-1 and galanin receptor antagonists ameliorates caerulein-induced acute pancreatitis in mice.
Both galanin and substance P have been separately implicated in the pathogenesis of acute pancreatitis. We compared the efficacy of the combination of the galanin antagonist galantide and the neurokinin-1 receptor antagonist L703,606 with that of either alone in the treatment of acute pancreatitis. Acute pancreatitis was induced in mice with 7-hourly caerulein injections. Galantide was co-administered with each caerulein injection commencing with the first injection (prophylactic) or 2h after the first injection (therapeutic). L703,606 was administered either 30 min before (prophylactic), or 2h after the first caerulein injection (therapeutic). Combination of the two agents was also administered. Control groups received galantide, L703,606, or saline, without caerulein. Pancreata were harvested for histological examination and estimation of myeloperoxidase activity. Plasma amylase activity was measured. Prophylactic and therapeutic administration of galantide reduced the hyperamylasemia by 37% and 30% respectively whereas only prophylactic L703,606 reduced hyperamylasemia (by 34%). Prophylactic administration of the combined antagonists reduced the hyperamylasemia by 44%. In contrast, therapeutic administration of the combination significantly increased plasma amylase levels by 27%. The plasma amylase activity in the control groups was similar to basal levels. Prophylactic and therapeutic administration of either antagonist or the combination significantly reduced myeloperoxidase activity. Galantide and L703,606 individually, and in combination, significantly reduced the acute pancreatitis-induced necrosis score. The administration of the combined antagonists does not offer any further benefit as compared to galantide alone. An interaction between neurokinin-1 and galanin receptors may occur to modulate amylase secretion.
Barreto
Savio G
SG
Department of General and Digestive Surgery, Flinders Medical Centre and Flinders University, Adelaide, South Australia, Australia.
Carati
Colin J
CJ
Schloithe
Ann C
AC
Toouli
James
J
Saccone
Gino T P
GT
D000681:Amylases / Q000097:blood; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology / Q000627:therapeutic use; D002108:Ceruletide / Q000494:pharmacology*; D004487:Edema / Q000473:pathology; D019004:Galanin / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D051379:Mice; D064729:Neurokinin-1 Receptor Antagonists; D010179:Pancreas / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D046790:Pancreas, Exocrine / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D010195:Pancreatitis / Q000139:chemically induced* / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D009195:Peroxidase / Q000378:metabolism; D011812:Quinuclidines / Q000494:pharmacology / Q000627:therapeutic use; D044088:Receptors, Galanin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018040:Receptors, Neurokinin-1 / Q000378:metabolism; D013373:Substance P / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use
D000894:Anti-Inflammatory Agents, Non-Steroidal; D064729:Neurokinin-1 Receptor Antagonists; D011812:Quinuclidines; D044088:Receptors, Galanin; D018040:Receptors, Neurokinin-1; C074975:galantide; C076851:L 703606; D013373:Substance P; D019004:Galanin; D002108:Ceruletide; D009195:Peroxidase; D000681:Amylases