Introduction
The stable gastric pentadecapeptide BPC 157 (GEPPPGKPADDAGLV, MW 1419) has been described as a novel mediator of Robert's cytoprotection and adaptive cytoprotection (Sikiric et al. 2010), and consequently, as a drug that reverses toxicity caused by non-steroidal anti-inflammatory drugs (NSAIDs). Initially, BPC 157 counteracted aspirin-, indomethacin- and diclofenac-induced gastrointestinal lesions and adjuvant arthritis (Sikiric et al., 1996, Sikiric et al., 1997a). Very recently, it was shown to reduce liver and brain lesions caused by NSAIDs (Ilic et al. 2010). In addition, the authors analyzed its effects on paracetamol, which rapidly induces hepatic encephalopathy with generalized convulsions unless BPC 157 is given intraperitoneally or intragastrically in the early or advanced stages of paracetamol toxicity (Ilic et al. 2010).
In this study, we focused on BPC 157's ability to antagonize triad lesions after repeated doses of diclofenac, which causes gastrointestinal, liver and brain toxicity (of note, sudden onset diclofenac encephalopathy has still not been demonstrated in rats). This allowed us to further define the potential of this agent in the reversal of side effects caused by NSAIDs.
Besides an anti-ulcer effect, the more extensive combined lesions induced by the NSAIDs [liver/brain (i.e., paracetamol-induced) to gastrointestinal/liver/brain (i.e., diclofenac-induced); Sikiric et al., 2010, Bergman et al., 1996, Richy et al., 2004] delineate the more extensive combined protective range of BPC 157, and thus, its special use as an antidote against NSAID-induced toxicity. It is likely that BPC 157 acts to prevent these lesions. It is an anti-ulcer peptide produced in both the upper and lower gastrointestinal tract (Sikiric et al., 2010, Sikiric et al., 1996, Sikiric et al., 1997a, Sikiric et al., 1997b, Sikiric et al., 2001, Klicek et al., 2008, Skorjanec et al., 2009, Sever et al., 2009) that is stable in human gastric juice and was proven to be effective in inflammatory bowel disease trials (PL 14736) (for review see Sikiric et al. 2010) and for various wound treatments (Skorjanec et al., 2009, Sever et al., 2009, Sikiric et al., 2003, Tkalcevic et al., 2007) with no toxicity reported (for review see Sikiric et al. 2010). It may also affect many disturbances of the central nervous system (Blagaic et al., 2004, Boban Blagaic et al., 2005, Tohyama et al., 2004, Jelovac et al., 1998, Jelovac et al., 1999, Sikiric et al., 1999, Tudor et al., 2010) and contain various hepatoprotective effects (Ilic et al., 2010, Ilic et al., 2009, Sikiric et al., 1993a, Prkacin et al., 2001b). In support of these studies, there is evidence that BPC 157 antagonizes stomach–liver–brain lesions induced by an overdose of insulin (Ilic et al. 2009). BPC 157-treated rats showed no fatal outcome, and most were without hypoglycemic seizures, but they did have apparently higher blood glucose levels (glycogen was still present in hepatocytes); normal liver weight; a less fatty liver; a counteracted increase in ALT, AST and amylase serum values; markedly fewer damaged neurons in the brain and only occasional small gastric lesions (Ilic et al. 2009).
We gave rats diclofenac to induce gastrointestinal, liver, and encephalopathy lesions, thereby creating a rat NSAID-toxicity model. In theory, BPC 157, given either intraperitoneally or in drinking water, might fully counteract the NSAID's complex toxicity. Alternatively, in terms of the combined stomach–small intestine–liver–brain lesions and prolonged sedation in diclofenac-treated rats, BPC 157 may attenuate the lesions in various combinations; i.e., more lesions simultaneously, individual lesions separately or not at all.
Section snippets
Animals
Male Albino Wistar (200 g) rats were used in all of the experiments (at least 10 rats per experimental group and interval). Experiments were approved by the Local Ethics Committee and assessed by observers unaware of the given treatment.
Drugs
Medication, without carrier or peptidase inhibitor, included pentadecapeptide BPC 157 (a partial sequence of the human gastric juice protein BPC, freely soluble in water at pH 7.0 and in saline). It was prepared as a peptide with 99% (HPLC) purity (1-des-Gly
Diclofenac gastric injury in rats
Gastric lesions were noted in all of the animals. Most of the lesions were located close to the pylorus (Fig. 1; Table 1).
Diclofenac-induced gastric injury in rats that received pentadecapeptide BPC 157
Considerably fewer lesions were noted in rats that received the pentadecapeptide BPC 157 medication (Fig. 1; Table 1).
Diclofenac-induced small bowel injury in rats
Numerous lesions were noted in all of the animals (Fig. 1; Table 1). Histologically, they appeared as mucosal defects ranging from one half of the mucosal thickness to full-blown ulcers. The defect bed was debris-covered, partially by erythrocytes, and it was
Discussion
The consistent beneficial potential of pentadecapeptide BPC 157 may indicate its ability to resolve the demonstrated combined gastrointestinal lesions, liver lesions and hepatic encephalopathy in diclofenac-treated rats and in NSAID-treated rats in general.
There in diclofenac-treated rats, these gastrointestinal lesions and their antagonization are decisive (Deng et al., 2008a, Deng et al., 2008b), because together with the NSAIDs therapy, in addition to paracetamol-induced liver lesions and
Conclusions
In conclusion, this study provides convincing evidence for the counteraction by BPC 157 of diclofenac-induced extensive toxicity and triad lesions that are prototypic in NSAID treatment (gastrointestinal lesions, liver lesions, and hepatic encephalopathy after repeated diclofenac administration in rats). Importantly, these results could be further used to substantiate potential agents being considered as drugs that reverse NSAID toxicity. In particular, for BPC 157 and the treatment of
Conflict of interest statement
The authors declare that there are no conflicts of interest.