Cyclophosphamide induced stomach and duodenal lesions as a NO-system disturbance in rats: l-NAME, l-arginine, stable gastric pentadecapeptide BPC 157

Abstract

We revealed a new point with cyclophosphamide (150 mg/kg/day intraperitoneally for 7 days): we counteracted both rat stomach and duodenal ulcers and increased NO- and MDA-levels in these tissues. As a NO-system effect, BPC 157 therapy (10 µg/kg, 10 ng/kg, intraperitoneally once a day or in drinking water, till the sacrifice) attenuated the increased NO- and MDA-levels and nullified, in rats, severe cyclophosphamide-ulcers and even stronger stomach and duodenal lesions after cyclophosphamide + L-NAME (5 mg/kg intraperitoneally once a day). L-arginine (100 mg/kg intraperitoneally once a day not effective alone) led L-NAME-values only to the control values (cyclophosphamide + L-NAME + L-arginine-rats). Briefly, rats were sacrificed at 24 h after last administration on days 1, 2, 3, or 7, and assessment included sum of longest lesions diameters (mm) in the stomach and duodenum, oxidative stress by quantifying thiobarbituric acid reactivity as malondialdehyde equivalents (MDA), NO in stomach and duodenal tissue samples using the Griess reaction. All these parameters were highly exaggerated in rats who underwent cyclophosphamide treatment. We identified high MDA-tissue values, high NO-tissue values, ulcerogenic and beneficial potential in cyclophosphamide-L-NAME-L-arginine-BPC 157 relationships. This suggests that in cyclophosphamide damaged rats, NO excessive release generated by the inducible isozyme, damages the vascular wall and other tissue cells, especially in combination with reactive oxygen intermediates, while failing endothelial production and resulting in further aggravation by L-NAME which was inhibited by L-arginine. Finally, BPC 157, due to its special relations with NO-system, may both lessen increased MDA- and NO-tissues values and counteract effects of both cyclophosphamide and L-NAME on stomach and duodenal lesions.

Stable Gastric Pentadecapeptide BPC 157, Robert's Stomach Cytoprotection/Adaptive Cytoprotection/Organoprotection, and Selye's Stress Coping Response: Progress, Achievements, and the Future

“…[1][2][3][4][5][6][7][8][9][10][11][12][13] BPC 157 also acts as a free radical scavenger, counteracts free radical-induced lesions, and normalizes NO and MDA levels in tissues and during ischemia and reperfusion. 101,113,114,[116][117][118] Subsequent studies from other groups 2,96-101 have confirmed our original findings. [65][66][67][68][69][70][71][72][73][74][75][76][77][78] Pleotropic effects involving distinctive receptors, including VEGFR2 and growth hormone receptors, distinctive pathways, including VEGFR2-AKT-eNOS, ERK ½, FAK-paxillin, FoxO3a, p-AKT, p-mTOR and p-GSK-3β, and distinctive loops, including stimulation of the egr-1 gene and its corepressor gene naB2, and counteraction of increases in pro-inflammatory and procachectic cytokines, 2,[96][97][98][99][100][101] likely minimize the inherent lack of full understanding of the mechanisms that may be involved.…”

“…112 Finally, the BPC 157-NOsystem-relation includes complex healing failure, proved by the fistulas healing, 82,[84][85][86] or particular anastomoses healing 88 or vessel occlusion 101,113 or cytostatic agents application (i.e., doxorubicin, cyclophosphamide). 41,114 The notation that BPC 157-NOsystem-relation interferes with the effects of neuroleptics merits further elaboration. 115,116 Finally, BPC 157 application lead to normalization of NO-level in tissues as well as counteraction of free-radicals formation.…”

“…115,116 Finally, BPC 157 application lead to normalization of NO-level in tissues as well as counteraction of free-radicals formation. 113,114,116 Of note, how this advantage of modulating NO-system (i.e., particular effect on eNOS gene), may be a practical background which could be further translated into an enhanced clinical performance. [1][2][3][4][5][6][7][8][9][10][11][12][13] BPC 157 may have a particular additional effect during the injury on the blood vessel activity: vessel recruitment to circumvent the vessel occlusion…”

Stable gastric pentadecapeptide BPC 157 in honeybee (Apis mellifera) therapy, to control Nosema ceranae invasions in apiary conditions

“…Therefore, the antioxidant system may play an essential role during midgut invasion, which is however, largely disabled in invaded honeybees (Dussaubat et al., ). Thus, although this was not specifically investigated in insect midgut, it should be noted that various free radicals‐induced lesions in other organs were also counteracted by BPC 157 administration (Ilic et al., ; Luetic et al., ; Sikiric, Seiwerth, et al., ), and in particular, ischemia/reperfusion injuries in rat colitis (Duzel et al., ). Thus, it was suggested that BPC 157 may serve as a possible antioxidant (i.e., BPC 157 contains four carboxylic groups, all of them could be active in scavenger process and if reactivated [e.g., by glutathione or by enzymes], the overall beneficial activity could be very high; Duzel et al., ).…”

Stable gastric pentadecapeptide BPC 157 can improve the healing course of spinal cord injury and lead to functional recovery in rats

“…In summary, this effect may be the cause or a consequence of the beneficial effects of BPC 157 on related disturbances [1][2][3][4][5][6][7][8][9][10][11]. As demonstrated, BPC 157 counteracts free radical formation and free radical-induced lesions [32,[82][83][84]. An interesting point would be the use of the same dose range in BPC 157 studies [1][2][3][4][5][6][7][8][9][10][11].…”