Protektivan učinak pentadekapeptida BPC 157 na cijeljenje oštećenja želuca, duodenuma, jetara i mozga uzrokovanih visokom dozom celekoksiba u štakora [Protective effect of pentadecapeptide BPC 157 on healing of gastric, duodenal, liver and brain lesions induced by high dose of celecoxib in rats]

Drmić, Ivan Domagoj (2015) Protektivan učinak pentadekapeptida BPC 157 na cijeljenje oštećenja želuca, duodenuma, jetara i mozga uzrokovanih visokom dozom celekoksiba u štakora [Protective effect of pentadecapeptide BPC 157 on healing of gastric, duodenal, liver and brain lesions induced by high dose of celecoxib in rats]. PhD thesis, Sveučilište u Zagrebu.

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Abstract

With therapy with BPC 157 (known to inhibit nonselective NSAIDs- gastrointestinal, liver and brain-toxicity) and L-arginine, we attempted to discriminate the full complexity of lesions (stomach, liver, brain) after high dose celecoxib administration; the aggravation (that mimics attempt to relieve pain (i.e., selective NSAID as COX-2 inhibition) and NOS-blockade (L-NAME)) along with a possible therapy success and the mechanism(s) behind all of these phenomena. In Wistar rats celecoxib (1g/kg bw ip) induced severe gastric lesions with gradual increase from 24h to 48h after administration, and sustained level of liver and brain lesions. All these lesions were aggravated by L-NAME (5 mg/kg bw ip immediately after celecoxib). As the needed proof of NO-system specific involvement, (L-arginine; L-NAME+L-arginine), Larginine (100 mg/kg bw ip immediately after celecoxib) exhibited a limited beneficial effect (i.e., only after 48h) while L-NAME+L-arginine protocol turned down L-NAMEaggravation to the control-celecoxib presentation at both 24h and 48h period. Thus, L-arginine was consistently more active given together with L-NAME (thus, more against L-NAME, less against celecoxib, less against COX-2 inhibition, COX-2- inhibition remains mostly preserved). Contrary, given alone BPC 157 (10 >g, 10 ng/kg bw ip immediately after celecoxib) completely turned down lesions induced by celecoxib, both at 24h and 48h. Likewise, the same beneficial effect was consistently evident in all increasingly negative circumstances of celecoxib and L-NAME application and in all BPC 157-groups (L-arginine+BPC 157; L-NAME+BPC 157; LNAME+ L-arginine+BPC 157). Thereby, these findings evidenced that BPC 157 may equally counteract both COX-2 inhibition (celecoxib-noxious effect on all lesions counteracted) and additional NOS-blockade (celecoxib+L-NAME-noxious effect also equally counteracted).

Abstract in Croatian

Pomoću terapije BPC-om 157 (poznatom po inhibiciji gastrointestinalne, jetrene i moždane toksičnosti izazvane neselektivnim NSAIDs-ima) i L-argininom, pokušali smo razlučiti punu kompleksnost lezija (želučanih, jetrenih, moždanih) nakon administracije visoke doze celekoksiba; pogoršanje (koje oponaša pokušaj za oslobađanje od boli (npr. selektivni NSAID kao inhibitor enzima COX-2) i blokada enzima NOS-a (L-NAME)) zajedno sa mogućom terapijom iza svih ovih fenomena. U štakora soja Wistar, celekoksib (1g/kg tj.t. i.p.) je inducirao teške želučane lezije sa porastom oštećenja protokom vremena sa 24 na 48 sati, uz održanu razinu oštećenja jetre i mozga. Sva ta oštećenja su bila dodatno povećana uz primjenu L-NAME (5 mg/kg TT i.p. odmah nakon celekoksiba). Kao potrebni dokaz specifičnog upliva (Larginin, L-NAME+L-arginin), L-arginin (100 mg/kg tj.t. i.p. odmah nakon celekoksiba) je pokazao ograničeni korisni učinak (t.j. samo nakon 48 sati) dok je istovremeno zajedničko davanje L-arginina i L-NAME smanjuje pogoršanje izazvano L-NAME-om do lezija sličnih onima koje vidimo kod kontrolnih životinja tretiranih celekoksibom i nakon 24 i nakon 48 sati. Dakle, L-arginin je bio konzistentno više aktivan kad je dan zajedno sa L-NAME-om (stoga, više protiv L-NAME, manje protiv celekoksiba, manje protiv inhibicije enzima COX-2, inhibicija COX-2 enzima ostaje većinom sačuvana). Suprotno tome, BPC 157 dan samostalno (10 >g, 10 ng/kg tj.t. i.p. odmah nakon celekoksiba) umanjuje lezije izazvane celekoksibom i nakon 24 i nakon 48 sati. Poput toga, isti korisni učinak je bio konzistentno vidljiv kod svih inače povećanih negativnih okolnosti pri aplikaciji celekoksiba i L-NAME, kao i u svim grupama koje su primale BPC 157 (L-arginin+BPC 157; L-NAME+BPC 157; L-NAME+L-arginin+BPC 157). Stoga ovi nalazi pokazuju da se BPC 157 može jednako suprotstaviti inhibiciji enzima COX-2 (suprotstavljanje štetnom učinku celekoksiba u svim lezijama) kao i dodatnoj blokadi enzima NOS (suprostavljanje zajedničkom štetnom učinku celekoksiba i L-NAME).

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