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

Abstract

Abstract. 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 μg / 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-α-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.

Pentadecapeptide BPC157 reduces bleeding and thrombocytopenia after amputation in rats treated with heparin, warfarin, L-NAME and L-arginine

“…Likely, this might also be the supportive part to the general interaction. Namely, very similar interactions of BPC 157 and the NO system, with both L-NAME and L-arginine, have been demonstrated by a large number of other previous studies [14,15,[18][19][20][21][22][23][24][25][26]. For instance, counteraction of both the L-arginine-induced disturbance and L-NAME-induced disturbance was seen, while maintaining blood pressure against both L-arginine (hypotension) and L-NAME (hypertension) (note, BPC 157 by itself does not affect basal blood pressure values [25] and likewise, BPC 157 by itself does not affect basal coagulation/platelets values [1]).…”

“…BPC 157 has been shown to exert beneficial effects against different pathological conditions [1,2,10-26], it induced gastroprotective, analgesic and anti-inflammatory wound healing effects [1,2,10-17], also effective against experimental colitis [10][11][12][13][14][15][16] and showing a particular interaction with the NO-system [14,15,[18][19][20][21][22][23][24][25][26]. Recently, we demonstrated the effect of BPC 157 against bleeding/thrombocytopenia after amputation, with or without anticoagulant and aspirin administration and abdominal aorta anastomotic site-thrombosis [1,2].…”

“…For instance, counteraction of both the L-arginine-induced disturbance and L-NAME-induced disturbance was seen, while maintaining blood pressure against both L-arginine (hypotension) and L-NAME (hypertension) (note, BPC 157 by itself does not affect basal blood pressure values [25] and likewise, BPC 157 by itself does not affect basal coagulation/platelets values [1]). Thus, this analogy might be the principal advantage for this and previous studies [14,15,[18][19][20][21][22][23][24][25][26], with a challenge in methodology and in general, since in other studies (not related to this model) L-NAME-thrombocytopenia antagonization was not attempted [3][4][5][6][7][8][9]32], nor were L-arginine and L-NAME simultaneously investigated. Furthermore, we could argue that with the prolonged bleeding time, specifically disturbed coagulation factors, with heparin (less) and warfarin (more), would affect BPC 157, L-arginine and L-NAME.…”

“…To counteract the consequences of L-NAME and/or L-arginine administration with the disturbed hemostasis, we administered the stable gastric pentadecapeptide BPC 157 [1,2,[10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26] not only due to its special effect on hemostasis [1,2], but also owing to a particular beneficial combining [1,2,[10][11][12][13][14], wound healing capacity [1,2,[10][11][12][13][14][15][16][17] and particular interaction with NO-system [14,15,[18][19][20][21][22][23][24][25][26]. Previously, BPC 157 as an originally anti-...…”

“…Also, interactions with NO-system are shown in different models and various species [12,13,[18][19][20][21][22][23][24][25][26]. As an illustrative analogy for counteraction of the opposite effects of L-NAME and L-arginine in haemorrhage, we should emphasize that the particular effects of BPC 157 on blood pressure [18,20,25] and the anti-arrhythmic effect [18][19][20][21] include antagonization of both L-NAME (hypertension) and L-arginine (hypotension) [25] and counteraction of endothelin serum increase [20].…”