Pentadecapeptide BPC 157, in clinical trials as a therapy for inflammatory bowel disease (PL14736), is effective in the healing of colocutaneous fistulas in rats: role of the nitric oxide-system.
We focused on the therapeutic effect of the stable gastric pentadecapeptide BPC 157 and how its action is related to nitric oxide (NO) in persistent colocutaneous fistula in rats (at 5 cm from anus, colon defect of 5 mm, skin defect of 5 mm); this peptide has been shown to be safe in clinical trials for inflammatory bowel disease (PL14736) and safe for intestinal anstomosis therapy. BPC 157 (10 microg/kg, 10 ng/kg) was applied i) in drinking water until the animals were sacrificed at post-operative day 1, 3, 5, 7, 14, 21, and 28; or ii) once daily intraperitoneally (first application 30 min following surgery, last 24 h before sacrifice) alone or with N(G)-nitro-L-arginine methyl ester (L-NAME) (5 mg/kg), L-arginine (200 mg/kg), and their combinations. Sulphasalazine (50 mg/kg) and 6-alpha-methylprednisolone (1 mg/kg) were given once daily intraperitoneally. BPC 157 accelerated parenterally or perorally the healing of colonic and skin defect, leading to the suitable closure of the fistula, macro/microscopically, biomechanically, and functionally (larger water volume sustained without fistula leaking). L-NAME aggravated the healing failure of colocutaneous fistulas, skin, and colon wounds (L-NAME groups). L-Arginine was effective only with blunted NO generation (L-NAME + L-arginine groups) but not without (L-arginine groups). All of the BPC 157 beneficial effects remained unchanged with blunted NO-generation (L-NAME + BPC 157 groups) and with NO substrate (L-arginine + BPC 157 groups) as well as L-NAME and L-arginine co-administration (L-NAME + L-arginine + BPC 157 groups). Sulphasalazine was only moderately effective, and corticosteroid even had an aggravating effect.
Klicek
Robert
R
Department of Pharmacology, Medical School, University of Zagreb, Croatia.
Sever
Marko
M
Radic
Bozo
B
Drmic
Domagoj
D
Kocman
Ivan
I
Zoricic
Ivan
I
Vuksic
Tihomir
T
Ivica
Mihovil
M
Barisic
Ivan
I
Ilic
Spomenko
S
Berkopic
Lidija
L
Vrcic
Hrvoje
H
Brcic
Luka
L
Blagaic
Alenka Boban
AB
Coric
Marijana
M
Brcic
Iva
I
Rokotov
Dinko Stancic
DS
Anic
Tomislav
T
Seiwerth
Sven
S
Sikiric
Predrag
P
D000758:Anesthesia; D000818:Animals; D000897:Anti-Ulcer Agents / Q000627:therapeutic use*; D001120:Arginine / Q000494:pharmacology; D003108:Colonic Diseases / Q000188:drug therapy*; D017577:Cutaneous Fistula / Q000188:drug therapy*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy*; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000096:biosynthesis / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D010446:Peptide Fragments / Q000627:therapeutic use*; D011506:Proteins / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar
D000897:Anti-Ulcer Agents; D004791:Enzyme Inhibitors; D010446:Peptide Fragments; D011506:Proteins; D009569:Nitric Oxide; C083833:BPC 157; D001120:Arginine; D019001:Nitric Oxide Synthase; D019331:NG-Nitroarginine Methyl Ester