Pentadecapeptide BPC 157 Interactions with Adrenergic

Since superior protection against different gastrointestinal and liver lesions and antiinflammatory and analgesic activities were noted for pentadecapeptide BPC (an essential fragment of an organoprotective gastric juice protein named BPC), the beneficial mechanism of BPC 157 and its likely interactions with other systems were studied. Hence its beneficial effects would be abolished by adrenal gland medullectomy, the influence of different agents affecting alpha, beta, and dopamine receptors on BPC 157 gastroprotection in 48 h restraint stress was further investigated. Animals were pretreated (1 hr before stress) with saline (controls) or BPC 157 (dissolved in saline) (10 microg or 10 ng/kg body wt intraperitoneally or intragastrically) applied either alone to establish basal conditions or, when manipulating the adrenergic or dopaminergic system, a simultaneous administration was carried out with various agents with specific effects on adrenergic or dopaminergic receptors [given in milligrams per kilogram intraperitoneally except for atenolol, which was given subcutaneously] phentolamine (10.0), prazosin (0.5), yohimbine (5.0), clonidine (0.1) (alpha-adrenergic domain), propranolol (1.0), atenolol (20.0) (beta-adrenergic domain), domperidone (5.0), and haloperidol (5.0) (peripheral/central dopamine system). Alternatively, agents stimulating adrenergic or dopaminergic systems--adrenaline (5.0) or bromocriptine (10.0)--were applied. A strong protection, noted following intragastric or intraperitoneal administration of BPC 157, was fully abolished by coadministration of phentolamine, clonidine, and haloperidol, and consistently not affected by prazosin, yohimbine, or domperidone. Atenolol abolished only intraperitoneal BPC 157 protection, whereas propranolol affected specifically intragastric BPC 157 protection. Interestingly, the severe course of lesion development obtained in basal conditions, unlike BPC 157 gastroprotection, was not influenced by the application of these agents. In other experiments, when adrenaline and bromocriptine were given simultaneously, a strong reduction of lesion development was noted. However, when applied separately, only adrenaline, not bromocriptine, has a protective effect. Thus, a complex protective interaction with both alpha-adrenergic (eg, catecholamine release) and dopaminergic (central) systems could be suggested for both intragastric and intraperitoneal BPC 157 administration. The involvement of beta-receptor stimulation in BPC 157 gastroprotection appears to be related to the route of BPC 157 administration. The demonstration that a combined stimulation of adrenergic and dopaminergic systems by simultaneous prophylactic application of adrenaline (alpha- and beta-receptor stimulant) and bromocriptine (dopamine receptor agonist) may significantly reduce restraint stress lesions development provides insight for further research on the beneficial mechanism of BPC 157.

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Pentadecapeptide BPC 157 Interactions with

Adrenergic and Dopaminergic Systems in

Mucosal Protection in Stress

PREDRAG SIKIR IC

Â, PhD , BRANKA MA ZUL, MD, SVEN SEIW ER TH, PhD,

ZELJKO GRABAREV IC

Â, PhD , RU DOL F RU Ï

CM AN , PhD, MARIJAN PETEK, Ph D,

VJEKOSLAV JAGIC

Â, PhD, BR ANKO TURKOVIC

Â, PhD, IVO RO TKVIC

Â, PhD, STJEPA N M IÏ

SE, PhD,

IVA N ZO RI Ï

CIC

Â, MD, LJUBICA JU RIN A, MD, PAÏ

SKO KONJEVO DA, MD,

M IRO SLAV HA N Ï

ZEV A Ï

CKI, MD, MIRO SLA V GJURA Ï

SIN, MD, JADRA NKA Ï

SEPAR OVIC

Â, PhD,

DANICA LJUBANOVIC

Â, MD, BR ANKA AR TUKOV IC

Â, MD, MIRNA BRATU LIC

Â, MD,

MARINA TIÏ

SLJAR , MD, PAV AO MIK LIC

Â, PhD , and J AGO DA SU MAJ STOR Ï

CIC

Â, PhD

Since superior protection against different gastrointestinal and liver lesions and antiin ̄ ammatory

and analgesic activities were noted for pentadecapeptide BPC (an essential fragment of an organo-

protective gastric juice protein named BPC), the bene® cial mechanism of BPC 157 and its likely

interactions with other systems were studied. Hence its bene® cial effects would be abolished by adrenal

gland medullectomy, the in ̄ uence of different agents affecting a,b, and dopamine receptors on BPC

157 gastroprotection in 48 h restraint stress was further investigated. Animals were pretreated

(1 hr before stress) with saline (controls) or BPC 157 (dissolved in saline) (10 mg or 10 ng/kg body

wt intraperitoneally or intragastrically) applied either alone to establish basal conditions or,

when manipulating the adrenergic or dopaminergic system, a simultaneous administration was carried

out with various agents with speci® c effects on adrenergic or dopaminergic receptors [given in

milligrams per kilogram intraperitoneally except for atenolol, which was given subcutaneously] phen-

tolamine (10.0), prazosin (0.5), yohimbine (5.0), clonidine (0.1) (a-adrenergic domain), propranolol

(1.0), atenolol (20.0) (b-adrenergic domain), domperidone (5.0), and haloperidol (5.0) (peripheral/

central dopamine system). Alternatively, agents stimulating adrenergic or dopaminergic systemsÐ

adrenaline (5.0) or bromocriptine (10.0)Ð were applied. A strong protection, noted following intra-

gastric or intraperitoneal administration of BPC 157, was fully abolished by coadministration of

phentolamine, clonidine, and haloperidol, and consistently not affected by prazosin, yohimbine, or

domperidone. Atenolol abolished only intraperitoneal BPC 157 protection, whereas propranolol

affected speci® cally intragastric BPC 157 protection. Interestingly, the severe course of lesion devel-

opment obtained in basal conditions, unlike BPC 157 gastroprotection, was not in ̄ uenced by the

application of these agents. In other experiments, when adrenaline and bromocriptine were given

simultaneously, a strong reduction of lesion development was noted. However, when applied sepa-

rately, only adrenaline, not bromocriptine, has a protective effect. Thus, a complex protective inter-

action with both a-adrenergic (eg, catecholamine release) and dopaminergic (central) systems could

be suggested for both intragastric and intraperitoneal BPC 157 administration. The involvement of

b-receptor stimulation in BPC 157 gastroprotection appears to be related to the route of BPC 157

administration. The demonstration that a combined stimulation of adrenergic and dopaminergic

systems by simultaneous prophylactic application of adrenaline (a- and b-receptor stimulant) and

bromocriptine (dopamine receptor agonist) may signi® cantly reduce restraint stress lesions develop-

ment provides insight for further research on the bene® cial mechanism of BPC 157.

KEY W OR DS: p ent ade cap epti de B PC 157; p ept id e BPC ; gas trop rot ect ion ; ad rene rgic/d o pami ner gic syst ems; str ess;

int eract ion.

Dige stiv e Disea ses and Sci ences, V ol. 42, No. 3 (M arch 199 7), pp. 6 61± 671

661

Digestive Diseases and Sciences, Vol. 42, No. 3 (M arch 1997)

0163-21 16/97/0300 -0661$1 2.50/0 q1997 Plenum Publishing Corporation

Because of the physiologic sign i® cance of gu t pep-

tides and their possible therapeut ic applicatio n in

gastrointestinal protection , the discovery of new pep-

tides, their structure and actions has received consid-

erable attention (1, 2). W e identi® ed a new gastric

juice protein with mucosal protective properties and a

huge range of organoprot ective effects, named BPC

(mol wt 40,000, determined by gel chro matography),

(3± 11). Standard procedures, ie, controlled dialysis of

gastric juice, lyophyliza tion, chromatographic separa-

tion on weak anion-exch ange resin (DEAE), cation

exchange resin (S), followed by gel chromatography

and ® nally HPLC we re applied. In line with this, a

15-am ino acid fragment (B PC 157), with apparently

no sequence homology to known gut peptides,

thought to be essential for activity of entire peptide,

was syn thesize d and characteri zed (3± 11). Th is frag-

men t w as inde pend e ntly in vest igate d an d c on® rme d

by others (12± 18), and it was recently con® rmed that

BPC 157 appears to be a very stable protein (3± 18).

When incubat ed in human gastric ju ice or in water,

this pentadecapeptide was not subjected to any deg-

radat ion during 24 hr (18). In contrast, h-EGF and

h-TGF-a, were stable in w ater but degraded in hu-

man gastric juice as soon as 15 min (18). A cute

toxicology shows a very high therapeutic index, since

no death or pathologic changes we re observed despite

the administration of a very high dosage (50 mg/kg)

(3).

Therefore, the recent focus has been on BPC 157,

and its ef® cacy on gastrointe stinal lesio ns w as suc cess-

fully evaluated in differe nt experim en tal models (3,

19) in comparison with conven tio nal agents and other

gut peptides. Considerin g the protective effects of

different peptides given centrally and/or peripherally

(17± 24), as well as their physiologic signi® cance (1, 2),

a bene® cial capability, although associated with a

relatively short-h alf time (1, 2), appears to be com-

mon for various gut pe ptid es. T he noted positive

effects of B PC 157 and other gut peptides (secretin,

glucagon, and NPY) are in line with the suggested

physiologic signi® cance of peptides and the impor-

tanc e of B PC ( 3, 6 ± 11, 28) .

From this point of view, particular interest in the

mechanism(s) of its bene® cial activity appears to be

justi® ed . A study of this problem using ablation of

different organs initially suggested that the putative

mechanism was very complex (3). It m ight be medi-

ated by hormones of the adrenal, parathyroid , thy-

roid, and ovarian glands (3). Along with a signi® cant

pool in the stomach and the brain (3), BPC has been

demonstrated immunohi stochem ically in differe nt or-

gans in the body. Recently, an interaction with the

prostaglandin system and somatosensory neurons has

been also suggested (5, 7, 10, 13± 15, 28). In the

presence of neurotoxic doses of capsaicin, the nega-

tive in ̄ uence of capsaicin on restraint, ethanol, or

ind omethacin gastric lesions consistently affecte d

BPC 157 bene® cial activity (7). However, BPC 157

protection was still evident in capsaicin-t reated rats

(either treated as adults or as newborns) in all of

these assays (7). Interestingly, the bene® cial effect

was not affected by prior vagotomy (3), although it

was complete ly abolished b y adrenal gland medullec -

tomy (3). Of n ote, the im po rt an ce of the cat-

echolamine rgic system for gastrointestinal mucosal

integrity is clear (28, 36 ± 38) [ie, dop amine antago-

nists would potentiate or even induce mucosal lesions

(28 ± 3 3)]. Th us, keeping in mind the known signi® -

cance of the catechola minergic systems in stress (28,

36 ± 38), th e po ssibilit y that BPC 157 wo uld interact

wit h th e ad rene rgic an d/or d opam ine rgic sy stem s wa s

the focus of the present study. Using a well-de® ned

approach (29, 30)Ð the application of various agents

affecting a,b, an d do pam i ne r ece pto rs ( 25± 36 ),

show n to have their own activity on gastric lesions

(28 ± 45) Ð the already noted in ̄ u ence on BPC 157

gastroprotection in 48-hr restraint stress (3, 6, 7) was

further evaluated. Theoretic ally, a prolongatio n of

the restraint st ress period and an increase in the

severity o f condition s wo uld most likely decrease the

usual drug treatment ef® cacy (eg, unlike pentade-

capeptide salutary activity (3, 4, 6, 7), dopamine pro-

motor protection disappeared after a 6-hr period)

(44, 45). Hence, it was used as a basis for selecting the

more ef® cacious agents (3, 6, 7). The interference

with the bene® cial effects noted after either intraperi-

toneal o r intragastric BPC 157 app lication was stud-

ied sim ultaneo usly.

MATERIAL S AN D M ETH OD S

Preparation of BPC 157. Pen tadecapeptide BPC 157

(G ly Gl uP ro Pr oP ro Gl yL ysP ro A laA s pA sp A la Gly L eu Va l,

mol wt 1419) is part of the sequ enc e of human gastric j uice

pro tei n BPC, freely solub le in w ater at pH 7.0 and in sal ine,

prepared as described before (3± 11). P eptide with 99%

Man uscript received Au gust 14 , 1995; a ccept ed No vemb er 7,

1996.

From t he Dep artmen t o f Pharm acol ogy, Medical F aculty, Un i-

versit y of Zagr eb, Z agreb, Repub lic o f Cro atia .

Thi s study was sub sidized b y gran ts f rom M ini stry o f Sci ence of

Rep ubl ic of C roatia an d Pliva, Za greb, C roat ia.

Ad dress fo r repri nt reques ts: Dr. Pred rag S iki ric, Depart ment o f

Pharm acol ogy, Me dical Facu lty, Univ ersity of Zagr eb, S alat a 11,

POB 916, 100 00 HR Zag reb, Repub lic o f Cro atia.

SIKIRI C

ÂET AL

662 Dig esti ve Dis eases an d Sci ences, V ol. 42, No. 3 (M arc h 1997)

(HPL C) purity (1-d es-Gly peptide as impurity, biologically

inactive) was used.

Ulcer M ode ls. Mal e W istar albino rats, ran domly as-

sign ed to grou ps o f 6 ± 10 rats an d w eigh ing 250 g, w ere u sed

and th en k illed 48 hr after re straint stress as described

pre viously (6, 7, 37, 38, 44 ± 46). An imals we re pretre ated (1

hr b efore stress) w ith saline (controls, 5.0 ml/kg) or BPC

157 (dissolve d in salin e) (10 mg o r 10 ng/kg body wt in tra-

perito neally) ap pli ed alone to establish basal conditio ns.

Altern atively, i f the adr energic o r do pam inergic system was

challenged , a simu ltaneous administration was carried ou t

with various age nts w ith sp eci® c effects o n these rece pto rs

(28 ± 45) (doses i n milligrams per kilogram intraperitoneally

exce pt to aten olol, gi ven su bcu tane ously): phento lamine

(10. 0), p razosin (0.5), yohi mbine (5.0), clon idine (0.1)

(a-adren ergic domain ), propr anol ol (1. 0), ate no lol (20.0)

(b-adren ergic dom ain ), do mperido ne (5.0), an d halop eri-

dol (5.0) (perip heral /central d op amine). A dd itionally, to

test the possib ility th at th e cou rse of restraint-stre ss lesions

cou ld b e po siti vely affected b y th e proph ylactic stimulation

of ad renergic and do paminergic system s, th e agents stimu-

lating adren ergic or do pam inergic syste ms, ad ren alin e (5.0)

or brom ocriptin e (10.0), were app lied either al on e or i n

com binatio n.

Assessment. Immed iately after th e death, stomach s were

rem oved a nd th e l esio ns wer e ass essed b y n aive o bserv ers as

described previou sly (6 ± 10, 31± 35, 44, 45). Representative

sections of the sto mach w ere p rocessed fo r fu rther histo -

logic an alysis. The in ̄ ammatio n i n th e su rroundi ng le sions

was assessed microscopicall y on th ree to ® ve hi gh-p owe r

® elds usi ng a semi quantitative appro ach (9, 10) (0, no ne ; 1,

few in ̄ amm ator y ce lls ; 2, medi um i n ̄ a mmato r y r eact ion ;

3, d ense i n ̄ ammato ry cells p op ulation).

Statistical Analysis. The K olm ogo rov-Smirno v test was

performed to estimate no rmality o f the data distribution .

Furthe r stati stical analyses were p erformed by means o f

anal ysis of varian ce (ANOVA ) an d/o r Kruskal-W allis, Stu-

den t-Newman-K eul s, Du nn ’s, and Du nnett’ s tests. Th e dif-

ferences were c on sidered to b e signi® can t at P,0.05.

RESULTS

The application of such a prolonged stress proce-

dure produced substantia l gastric lesions in control

animals that could hardly be further aggravated (Fig-

ures 1± 4). The intragastric and intraperito neal ad-

ministration of BPC 157 as a protective agent had a

strong bene® cial effect. Essentially the same positive

resu lt was o btai ned wit h th e ap plic atio n o f m icro gram

and nanograms dosages (Figures 1± 3).

Hal ope rid ol, dom pe rid one , y ohim bin e , ph ent ol -

amin e, p razo sin, clo nidin e , ate nolo l, a nd p ropra nol

were applied as the agents having a know n receptor-

affecting activity leading to an inhibition of the activ-

ities of either adrenergic or dopaminergic systems

(28 ± 45) . Intere stingly, no in ̄ u ence o f the m entioned

agents could be demonstrated on control lesions,

since neither of them , when given alo ne, showed any

effect on the development of restraint lesions (Fig-

ures 1± 3). On the other hand, concerning their in ̄ u-

ence on gastric mucosal integrity in BPC 157-

pro tec ted r ats , the i r neg ati ve effe ct a p peared

Fig 1. The interaction of pentadecapeptide BPC 157 with adrenergic and dopaminergic systems in

muco sal pro tect ion i n stress: th e a-adre nergi c syst em. Med icat ion w as given 1 hr befo re stress

ini tiation. S aline (5 m l/kg) or BP C 157 (10 mg o r 10 ng /kg) w as gi ven ei ther in traperitoneally or

int ragast rical ly. Cloni dine (0. 1 m g/kg), phento lamin e (10 mg/kg), prazo sin (0.5 mg/kg) , or yohimbin e

(5.0 mg/kg) was given in traperitoneally. *P,0.05 vs co rrespond ing c ont rols;

P,0.05, at least, vs

corre sponding BPC 157-treat ed gro up. N56 ± 10 rats p er exp erimen tal grou p.

BPC 157, GASTROPROTECTION, AND STRESS

663

Digestive Diseases and Sciences, Vol. 42, No. 3 (M arch 1997)

selec tive. Af ter sim ultan eo us app licatio n wit h age nts

negatively affecting adrenergic and/or dopaminergic

systems, intragastric and intraperito neal, BPC 157

protection was completely abolished by the coadmin-

istration of halope ridol, ph entolamin e, and clonidine .

However, the bene® cial effect of BPC 157 was com-

pletely resistant to administration of domperidone,

prazosin, and yohimbine (Figures 1± 3). In the case of

agents speci® cally affecting the b-adrenergic system,

the effect was different; atenolol inhibited the salutary

effect of intraperitoneal pentadeca peptide but not

that of intragastric BPC 157. Propranolo l abolished

intragastric BPC 157 bene® cial activity, whereas in-

traperitoneal BPC 157 was not affected.

From the se data, the conseq uen t possibility that

BPC 157 may interact with adrenergic and dopami-

nergic systems was tested by investigati ng the pro phy-

lact ic effect s of the ag ents st imu latin g adre nerg ic or

dopaminer gic systems, adrenaline and bromocriptine

(Figure 4). When given simultane ously, a strong re-

duction o f lesio n de velopme nt w as noted. H owever,

when applied separately, adrenaline , but not bro-

mocriptine , had a pro tective effect.

All these data are fully supported by our m icro-

scop ic assessm ent. Gastric mucosal lesions in re-

straint stress-exposed animals correspond to stress

ulcers as described before (3, 6, 7). In restraint, in

BPC-treated rats the extent of lesions was consis-

ten tly smaller and the surround ing in ̄ ammation

much less pronounced (Figure 5), generally con® rm-

ing m acro scop ic ob servat ion s.

DISCU SSION

The primary use of restraint stress methodology is

for drug evaluation (3, 6, 7, 20 ± 26, 28, 36 ± 38, 44 ± 46).

The strong similarity of these lesions with stress ulcer

in patients has been noted (28, 36 ± 38). Theoretically,

drug ef® cac y w ould be fully highlighte d by gradually

modulatin g/increasing the level of stress (ie, usual

3-hr restraint stress 148C cold vs 6-hr or 48-hr

restraint stress) (3, 6, 7, 12, 28, 36 ± 38, 44, 45). In this,

the contribut ion of particular elements (ie, cold or

food or water deprivatio n) usually involved in the

stress studies oft en was not speci® cally evaluated (36 ±

38, 46). However, food and water deprivation appear

to be not essentially related to lesions development.

In our studies, if they were applied without a stress

procedure, no lesion was noted (3). In other ulcero-

genic procedures (ie, cysteamine), the food depriva-

tion even attenuated lesion developme nt (47).

Interestingly, in this stress model (see for review, 3,

6, 7, 28, 44, 45), H

-receptor blockers, somatostat in,

and dopam inergics as in our previous investigati ons

Fig 2. The inter actio n of p ent adecapep tid e BPC 1 57 with ad renergic and dopam iner gic sy stems in

muco sal p rotection in stress: th e b-adr energic syst em. Medica tio n was given 1 h r bef ore stress

initiation. Saline (5 ml/kg) or BPC 157 (10 mg or 10 ng/k g) w as giv en either i ntra peritoneally o r

int ragast rical ly. Propr anolol (1.0 mg /kg) o r atenolol (20 mg/kg) w as giv en intrap eritonea lly o r

sub cutaneously. * P,0.05 v s correspon di ng con trol s;

P,0.05, at le ast, vs correspondin g BPC

157-t reated gro up . N56 ± 10 rats per exp erimen tal g roup .

SIKIRI C

ÂET AL

664 Dig esti ve Dis eases an d Sci ences, V ol. 42, No. 3 (M arc h 1997)

(3, 6, 44, 45) and other stress studies (see for review,

6, 28, 36 ± 38), showed limited effectiveness (6, 28,

36 ± 38). Likew ise, regarding pentad ecapeptide BPC

157 as well as entire peptide BPC (6, 25± 28), the

strong ef® cacy in t his stress m odel (see for review , 6,

28, 36 ± 38), m erit additional atte ntion. It is probably

more than a simple coinciden ce t hat besides this

pentadecapeptide only adrenaline was protective in

this stress model.

Therefore, concerning the activity of the agent

under scrutiny, the putative bene® cial mechanism of

BPC 157 could have particular signi® cance. Consid-

ering our previous ® nding suggesting its close inter-

action with the catecholaminergic system in gastric

protection against stress (3), the effects of the agents

affecting adrenergic and dopaminer gic systems (28 ±

45) were further investigate d. In this study, the strong

protection noted following intragastric or intraperito -

neal a dmin istrat io n of BPC 1 57 w as com plet ely ab ol-

ished by coadministration of phentolamine, clonidine,

and hal operi do l an d w as co nsist ent ly n ot a ffec ted by

prazosin, yohimbine, or domperido ne. Atenolol abol-

ished only intraperitoneal BPC 157 protection,

whereas propranolo l speci® cally affected intragastric

BPC 1 57 protect ion. These agen ts are gen erally

known to affect quite speci® cally a,b, or dopam ine

receptors (28 ± 45) given in the doses used in the

present re port. Thus, from a general poin t of view, a

particular interactio n of BPC 157 pentadecapeptide

with these two systems, adrenergic and dopaminer gic,

widely im plicated in stress ulcer diseases (28, 36 ± 38),

could be suggested.

Along with this general connectio n, a rather par-

ticular interaction could also be suggested. Unlike an

evident affection of BPC 157 gastroprote ction (both

intragastrical and intraperitoneal) by these agents

application , all of them given alone, witho ut this

pentadecapeptide coadministration, appeared to be

unable to affect the ulcer development in basal stress

con ditio n s. Thi s app eared to be a rat her u nusu al

® nding, since ulcer deve lopment was otherwise ap-

parently affected by the agents used, although in

different ways, for example, ulcer reduction (phentol-

amine, prazosin, and clonidine) , ulcer aggravat ion

(propranolol, yohimbine , haloperido l, domperidone)

or ulcer induction (h aloperid ol, domperido ne) (28 ±

39, 44, 45, 48 ± 51). In this respect, such a consistent

inactivity of all of them in these basal condition s

seem s to be importan t, particularly since it was p re-

viously noted in studies with dopamine agents (6, 44,

45). This could be at least partly explained by a known

ulcer complexit y caused by different mechanism s in-

volve d in ulcer pro ductio n (28, 36 ± 38). H owever, t he

evident inactivity of these agents could be also due to

Fig 3. The int eract ion of p entadecap eptid e BPC 1 57 with ad renergic and do pami nergic syst ems i n

muco sal protecti on in stress: th e dopaminergi c syst em. Medi cati on w as gi ven 1 hr b efore stress

initiation. Saline (5 ml/kg) o r BPC 157 (10 mg o r 10 ng/kg) w as giv en ei ther i ntra peritone ally o r

int ragast rical ly. Domperido ne (5 .0 mg/k g) o r halo perid ol (5.0 mg/k g) was given i ntraperit oneally.

*P,0.05 vs corresponding con trols;

P,0.05, at least, vs co rresp ond ing BPC 157- treated g roup .

N56 ± 10 rats per exp erimen tal grou p.

BPC 157, GASTROPROTECTION, AND STRESS

665

Digestive Diseases and Sciences, Vol. 42, No. 3 (M arch 1997)

a majo r derangement induced by the extremely rig-

oro us experimental stres s conditions (52 ) in the

present study. Under such stress (basal) circum-

stances the physiologic systems (ie, adrenergic and

dopaminergic), and all of their e ffects an d corre-

sponding mechanisms could be essentially and non-

speci® cally inhibited (52). If these systems are inhib-

ited in this way, the agents affecting adrenergic o r

dopaminergic systems might also not operate as a

result of an almost complete exhaustion in severely

stressed an imals (52). Importantly, and as men tion ed

earlier, unlike other agents, when given alone the

protectiveness of this pentadecapeptide was consis-

tently noted despite competition with the described

negative stress circumstan ces (3, 6, 7). This seems to

be not the only exception, since a similar protection

was noted with adrenaline applicatio n as we ll. T hus,

this pentadec apeptide could probably, as a supple-

ment, at least partly replace the deranged systems.

Consequen tly, its coadministration leads to and/or

triggers the special effects of the other agents that

were previously obscured. Seen from this point of

view and in line with previous data (3), its particular

in ̄ ue nce on the corresponding catechol aminergic

systems could be suggested.

Concernin g the in ̄ uence of BPC 157 on the a-re-

ceptors domain, it seems that BPC 157 could exert an

in h ib i to r y e ffe c t o n p re sy n ap t ic i n hi b it o ry a

receptors, thereby stimulating catecholam ine release.

At the same time, it could have an indirect, possibly

stimulatory effect on a

(postsynaptic) receptors. In

the former, this assumption seems to be fully sup-

ported by a strong inhibition of BPC 157 bene® cial

acti vity b y clon idine ap plicat io n. Du e t o the p oten t

agonistic activity of clo nidine o n a

receptors, neural

release of n orep inephrine is inhibited. This could lead

to a reduction o f central sympathetic activit y, which

might then be responsibl e for the reduced p eripheral

sympathetic out ̄ ow (53± 55). In line wit h this, it was

not changed by yohimbine, a relatively selective in-

hibitor of a

receptors, which enhances neural release

of nor epine phr ine (55, 56 ). A ddit ional ly , ben e® cia l

activity of BPC 157 was reversed by coadm inistration

of phentolam ine, an antagonist of both a

and a

receptors (56). With reference to the described effect

of clonidine/yohimbine, the interference with a

re-

ceptors could be responsible for the abolition of pro-

tect ion of this pentadecapeptide fo llowing phentol-

amin e adm inist rat ion. H ow ever, si nce th is w as not

chan ged following prazosin ad ministra tion, a selec-

tive a

-receptor antagonist (55± 57), as would be ex-

pected in the case of sim ple interference with a

Fig 4. The in ̄ u ence of stimu lat ion of t he adre nergi c or do paminergic systems on stress lesion

deve lopmen t. Medic atio n was given 1 h r bef ore st ress i nitiatio n. Salin e (5 ml/kg) , ad renal ine (5.0

mg/k g), bromo criptin e (10.0 mg/ kg), o r adrena lin e (5.0 mg/ kg) t oget her wi th bro mori ptine (10.0 mg/kg)

were given int raperiton eally. *P,0.05 vs co rresp ond ing control s. N56 ± 1 0 rats p er e xperi ment al

grou p.

SIKIRI C

ÂET AL

666 Dig esti ve Dis eases an d Sci ences, V ol. 42, No. 3 (M arc h 1997)

receptors, a more complex interaction app ears to be

lik e ly . For i nstan ce, the e xisten ce of p razo sin-

resist ant a

receptors was proposed (57). Whatever

the interference (inhibitio n or no inhibition ) of the

agents affecting a-adrenergic domain with BPC 157

protection , it appears supporting ly to be a rather

common for both intragastrical and intraperitoneal

BPC 157 administrations. Thus, based on these ® nd-

Fig 5. Restrain t-st ress indu ced gastric ero sion s in control animals and BPC 157-pro tect ed rats; H& E sta in,

340. L arge are as of erosi on are see n partial ly penetr atin g th e entire mucosa t hick ness in co ntrols (a ),

un like the con sist ently small er dam age an d the much l ess pronou nced s urround ing i n ̄ ammatio n in

pro tected rats ( b).

BPC 157, GASTROPROTECTION, AND STRESS

667

Digestive Diseases and Sciences, Vol. 42, No. 3 (M arch 1997)

ings, th e precise nature of th is pentadecapeptide in-

terference with the adomain remains to be clari® e d.

Furthermore, the evid ence th at clonid ine also affects

imid azol in e rec epto rs (39) , i n a ddit ion t o a

recep-

tors, could probably also explain the observed com-

plexity. Further study will probably clarify possible

pentadecapeptide BPC 157/imidazoline receptor in-

terplay. For example, a high concentra tion of a pos-

sible endogenous imidazoline agonist, agmatidine, in

the ro dent stomach (58) was recently reported. This

evidence, taken together with this pentadeca peptide

special and unusual presence in gastric juice (3, 18),

merits further attention, although at present the in-

volve men t of im idazo lin e b indi ng si tes in t hese fu nc-

tio nal ac tivit ies remains un certain (59), and the

clonidine effect was show n to be re lated to a

recep-

tors (39).

Regarding the interference with the b-adrenergic

domain, atenolol inhibited only intraperitoneal BPC

157 protectio n. Propranolo l speci® cally hampe red in-

tragastric BPC 157 pro tection. Th is is probably m ore

than a simple coincidence, since such a variable in-

̄ uence occurred in the case of bagents, and not wit h

aor dopamine agents. These b-receptor blockers

affect b- recep tor s d ifferen tly [ prop ranol o l (b

) vs

atenolol (mainly b

)] (55). Thus, their variable in ̄ u-

ence on BPC 157 protection could be interpreted as a

particular in ̄ uence of this pentadecapeptide on the

b-adrenergic domain, depending on whether it was

given intragastrically or intraperitoneally.

The evidence that b

receptors are mainly located

in the heart (55), along with the relatively higher

speci® city of atenolol for b

receptors compared with

propranolo l, could at least partly explain both special

effects: the lack of inhibit ion of intragastric BPC 157

protection after atenolol coadministration and the

resist ance o f in trape rito ne al B PC prot ect ion to pro -

pranolol medication. The well-know n presence of b

receptors on gastrointestinal vasculature and their

blockage by proprano lol (55) could accou nt f or th e

inhibition of intragastric BPC 157 protection if pro-

pranolol was coadministered. Finally, the evidence

that this pentadecapeptide would have a particular

in ̄ uence also when applie d intragastrically is in line

with its unusual high stability in gastric juic e (3, 18).

When incubated in human gastric ju ice, BPC 157 was

not subjected to any degradatio n at least for 24 hr

(18), unlike other peptides. This seems compatible

with the su ggestion that the bene® cial activity of BPC

157 in st ress con siste nt ly a cco mpan ie s a stim ula tio n

of sympathet ic out ̄ ow. This could occur through its

particular bene® ts related to peroral or parenteral

rout es of BPC 157 ap plicat io n.

The in ̄ uence of BPC 157 on the dopamine system

was uniformly observed using both routes of penta-

dec apept i de BP C 157 app licat io n. I t is int erest in g

that its bene® cial effect is c ompletely resistant to

application of domperidone and is fully inhibited

following haloperido l cotreatm ent. Dom peridone is a

dopamine antagonist acting primarily peripherally,

whereas haloperido l also has signi® cant central activ-

ity (2 8 ± 38, 55, 60 , 61) . Th us, i t seem s l ikely t hat B PC

157 protection involves a stimulation of the central

rather than the peripheral dopamine system. The

involvemen t of t he pe ripheral dopamin e system in

gastrointestinal tract protection is consistently sug-

gested (62), and the dopamine agents brom ocript ine

and am antad in e have b een s ucces sful ly app lied in th e

prevention of peptic ulcer recurrence (62). However,

the role of the central dopamine system appears to be

emphasized even mo re (36 ± 38, 60, 61). Likewise,

such an interaction with the central dopamine system

has already been positively implicated for the bene® -

cial effect of other peptides (for example, neuroten-

sion an d bombesin) (36). Finally, a p entadec apeptid e

BPC 157/dopam ine interaction seems to be favored

by a similar effect o f dopamine antagonists on dopa-

mine promotor protection, noted after a shorter re-

straint period. In support of this, after a 48 hr period,

dopamine antagonist s were inactive by themselves

when given alone, as early as 6 hr (44, 45). Thus, from

this point of view, for such a particular central inter-

action, the ulcerogenic activity o f the given do pamine

antagonists , evidenc ed in th ese partic ularl y stressed

animals just in the pentadecapeptide treated rats (a

strong effect with halo perido l, but not with domperi-

done), could b e indeed indicative . Namely, as me n-

tioned earlier, both of them could otherwise either

indu ce mucosal lesions in naive animals (34, 35), or

potentiate the lesions induced by other procedures

(eg, pylorus ligation or indomethacin or cysteamine

application ) (30 ± 33).

Thus, based on the speci® c actions of these agents,

it seem s quite likely that BPC 157 gastroprote ction in

stress is at least partly based on a speci® c interaction

with adrenergic and dopaminer gic systems. In sup-

port of this, the removal of adrenal gland medulla

would completely abolish the BPC gastroprotective

effect in restraint stress (3). Theoretic ally, the app li-

cation of agents interfering with these two systems

would to various degrees inhibit the endogenous cop-

ing response to the stress. For instance, prazosin was

shown to not impair the body’ s n atural response to

SIKIRI C

ÂET AL

668 Dig esti ve Dis eases an d Sci ences, V ol. 42, No. 3 (M arc h 1997)

cold and exercise (56), and it did not inhib it this

pen tad eca pep tid e gastr oprote ction in s tre ss in

present report. Such a possibility seems to be further

strengthened, although indirectly. A combined stim-

ulation of adrenergic and dopaminergic systems by a

simu ltan eou s prop hylac t ic appl icati on of a drena line

(a- and b-receptor stimulants) and bromocrip tine

(dopamine receptors agonist) may signi® cantly re-

duce restraint stress lesions development. In this, the

activation of the adrenergic system appears to be

more important, since in keeping w ith previous ® nd-

ings (6, 37, 38, 63), adrenaline (63) applied alone was

also e ffective, unlike bromo crip tine, which was inac-

tive (6, 44, 45).

Finally, from the viewpoint of th e brain± gut con-

cept, BPC 157, present in both the gastrointestinal

tract and the brain (3), could be an additional impor-

tant bene® cial mediator between the gut and brain. It

has been consistent ly n oted that, besides a salutary

effect on ulcerogenesis, BPC 157 positively affects

other consequences of stress injury. For example, a

strong decrease of the stress-induced thymolymphatic

invo lutio n an d ad renal gl and hype rtro ph y wa s not ed

(12). Apparently, the salutary activity of BPC 157

involves the entire gastrointes tinal tract and different

lesions as w ell (3, 4, 6, 15, 17, 28). In line w ith its

previously described antiin ̄ ammatory activity and

the lower in ̄ ammation in p entadecapeptide-t reated

rats noted in this study (3, 5, 10, 13± 15), interference

wit h r elease of arac hido ni c acid me tabo lit es w as also

suggested (13± 15). This pentadecapeptide also de-

creased the MPO level in in ̄ amed tissues (13± 15).

Rec ently, in addition to a pow erful mucosa protec-

tion , a c lose inte ractio n with cap saici n- sens itive neu -

rons was clearly demonstrated for BPC 157 (3, 5, 7).

Consequen tly, it has been suggested to be one of the

neuropeptides implicated in conductio n of nocicep-

tive informatio n (3, 5, 7). Taken together with previ-

ous data (3± 18, 28), the p articular connectio ns of

BPC 157 with the adrenergic and dopaminergic sys-

tems, supporting ly noted with a large range of the

pentadecapeptide dosage (eg, mg to ng range), p ro-

vide a suitable basis for further investigati on of the

bene® cial actions of this pentadeca peptide.

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BPC 157, GASTROPROTECTION, AND STRESS

671

Digestive Diseases and Sciences, Vol. 42, No. 3 (M arch 1997)

... basic fibroblast growth factor (bFGF), platelet-derived growth factor (PDGF), and epidermal growth factor (EGF) [3,9,30,31,32,34]. Thus, whether the noted beneficial effect of a novel stomach pentadecapeptide BPC 157 (thought to be essential for beneficial activity of an organoprotective protein isolated from human gastric juice) [1,4,7,8,11,[14][15][16][17][18][19][20][21][22][23][24][25][26][36][37][38][39] could be mediated by an angiogenic property is the focus of this study. ...

... Based on its salutary effect on ethanol [14,18,20,22] and other gastrointestinal lesions induced by various challengers (i.e. prolonged stress [11,18,20,22,24], NSAIAs [18,22,27], cysteamine [14,18,20,25], trinitrobenzene sulphonic acid [36][37][38], dinitrofluorbenzene sulphonic acid [16], acute pancreatitis and somatosensory neurone depletion [18,23]), BPC 157 was recently claimed to have a 'cytoprotective' effect particularly in the gastrointestinal mucosa, along with a particular beneficial effect on endothelium integrity [18,20,25]. Considering the existence of BPC 157 in gastric juice and its unusual stability [1,4,7,8,11,[14][15][16][17][18][19][20][21][22][23][24][25][26][36][37][38][39] (i.e. ...

... prolonged stress [11,18,20,22,24], NSAIAs [18,22,27], cysteamine [14,18,20,25], trinitrobenzene sulphonic acid [36][37][38], dinitrofluorbenzene sulphonic acid [16], acute pancreatitis and somatosensory neurone depletion [18,23]), BPC 157 was recently claimed to have a 'cytoprotective' effect particularly in the gastrointestinal mucosa, along with a particular beneficial effect on endothelium integrity [18,20,25]. Considering the existence of BPC 157 in gastric juice and its unusual stability [1,4,7,8,11,[14][15][16][17][18][19][20][21][22][23][24][25][26][36][37][38][39] (i.e. incubated in human gastric juice or in water, this pentadecapeptide was not subjected to any degradation during 24 h unlike standard peptides, e.g. ...

... Thus, it may be that BPC 157 as a cytoprotective agent [1][2][3][4] essentially combines the processes responsible for both stomach and skin ulcer healing [25]. Therefore, it may have an exceptionally wide range of beneficial effects against different gastric lesion models [1][2][3][4], gastric acid non-dependent, gastric acid dependent, besides the models commonly thought to be prostaglandin related [1][2][3][4][6][7][8]24,26] and in turn, with PGs-system failure [1][2][3][4] in the models that implicate dopamine [27][28][29][30], glucose (hyperglycemia or hypoglycemia) [31,32], as well as those that involve NO-system disbalance [33]. Therefore, besides NSAIDcounteraction, on the base of counteraction of acute and chronic alcohol lesions [22][23][24][33][34][35], the cytoprotective and adaptive cytoprotective BPC 157 activities (noted also in vitro studies [36,37]) even in the longer-term [22][23][24][33][34][35], are obviously a part of a larger array of beneficial effects of BPC 157 administration (note, BPC 157 counteracts gastric stress lesions [22,24,29]). ...

... Therefore, it may have an exceptionally wide range of beneficial effects against different gastric lesion models [1][2][3][4], gastric acid non-dependent, gastric acid dependent, besides the models commonly thought to be prostaglandin related [1][2][3][4][6][7][8]24,26] and in turn, with PGs-system failure [1][2][3][4] in the models that implicate dopamine [27][28][29][30], glucose (hyperglycemia or hypoglycemia) [31,32], as well as those that involve NO-system disbalance [33]. Therefore, besides NSAIDcounteraction, on the base of counteraction of acute and chronic alcohol lesions [22][23][24][33][34][35], the cytoprotective and adaptive cytoprotective BPC 157 activities (noted also in vitro studies [36,37]) even in the longer-term [22][23][24][33][34][35], are obviously a part of a larger array of beneficial effects of BPC 157 administration (note, BPC 157 counteracts gastric stress lesions [22,24,29]). BPC 157 also inhibits pylorus-ligation-induced gastric lesions [26]. ...

... BPC 157 also inhibits pylorus-ligation-induced gastric lesions [26]. For the dopamine-blockade-gastric ulcer model, BPC 157 particularly affects the substantia nigra by alpha-[14C]methyl-L-tryptophan (alpha-MTrp) portrayed by the autoradiographic method [38], BPC 157 may also counteract haloperidol-, reserpine-, 1-methyl-4phenyl-1,2,3,6-tetrahydrophyridine (MPTP)-lesions [27][28][29][30]39]. Interestingly, the beneficial effect against gastric lesions is in conjunction with the antagonization of central dopamine system disturbances [27][28][29][30]39]. ...

Predrag Sikiric

Sven Seiwerth Rudolf Rucman Bozidar Sebecic

Stable gastric pentadecapeptide BPC 157 is an anti-ulcer peptidergic agent, proven in clinical trials to be both safe in inflammatory bowel disease (PL-10, PLD-116, PL 14736) and wound healing, stable in human gastric juice, with no toxicity being reported. Recently, we claim that BPC 157 may be used as an antidote against NSAIDs. We focused on BPC 157 beneficial effects on stomach, duodenum, intestine, liver and brain injuries, adjuvant arthritis, pain, hyper/hypothermia, obstructive thrombus formation and thrombolysis, blood vessel function, counteraction of prolonged bleeding and thrombocytopenia after application of various anticoagulants and anti-platelet agents and wound healing improvement. The arguments for BPC 157 antidote activity (i.e., the role of BPC 157 in cytoprotection, being a novel mediator of Roberts cytoprotection and BPC 157 beneficial effects on NSAID mediated lesions in the gastrointestinal tract, liver and brain and finally, counteraction of aspirin-induced prolonged bleeding and thrombocytopenia) obviously have a counteracting effect on several established side-effects of NSAID use. The mentioned variety of the beneficial effects portrayed by BPC 157 may well be a foundation for establishing BPC 157 as a NSAID antidote since no other single agent has portrayed a similar array of effects. Unlike NSAIDs, a very high safety (no reported toxicity (LD1 could be not achieved)) profile is reported for BPC 157. Also, unlike the different dosage levels of aspirin, as a NSAID prototype, which differ by a factor of about ten, all these beneficial and counteracting effects of BPC 157 were obtained using the equipotent dosage (μg, ng/kg) in parenteral or peroral regimens.

... BPC 157 therapy had counteracted disturbances caused by the application of the parkinsongenic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydrophyridine (MPTP) and vesicle depletion by reserpine application [120]. Likewise, BPC 157 counteracted the effects of dopamine receptor blockades that would appear in applications of haloperidol, fluphenazine, clozapine, and sulpiride [46,70,88,89,[121][122][123][124], both peripherally and centrally. Additionally, it might interfere with the interactions of the opioid-dopamine system, antagonizing the haloperidol potentiation of morphine analgesia and, also, morphine analgesia alone [125]. ...

... Counteracted disturbances caused by the application of the parkinsongenic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydrophyridine (MPTP) and vesicle depletion by reserpine application. [46,70,88,89,[121][122][123][124] Counteracted effects of blockaded dopamine receptors that would appear in haloperidol, fluphenazine, clozapine, and sulpiride applications, peripherally (gastric lesions, sphincter dysfunction, prolonged QTc intervals) and centrally (catalepsy, akinesia). ...

Predrag Sikiric

Slaven Gojkovic

Ivan Krezic

Sven Seiwerth

Conceptually, a wide beneficial effect, both peripherally and centrally, might have been essential for the harmony of brain–gut and gut–brain axes’ function. Seen from the original viewpoint of the gut peptides’ significance and brain relation, the favorable stable gastric pentadecapeptide BPC 157 evidence in the brain–gut and gut–brain axes’ function might have been presented as a particular interconnected network. These were the behavioral findings (interaction with main systems, anxiolytic, anticonvulsive, antidepressant effect, counteracted catalepsy, and positive and negative schizophrenia symptoms models). Muscle healing and function recovery appeared as the therapeutic effects of BPC 157 on the various muscle disabilities of a multitude of causes, both peripheral and central. Heart failure was counteracted (including arrhythmias and thrombosis), and smooth muscle function recovered. These existed as a multimodal muscle axis impact on muscle function and healing as a function of the brain–gut axis and gut–brain axis as whole. Finally, encephalopathies, acting simultaneously in both the periphery and central nervous system, BPC 157 counteracted stomach and liver lesions and various encephalopathies in NSAIDs and insulin rats. BPC 157 therapy by rapidly activated collateral pathways counteracted the vascular and multiorgan failure concomitant to major vessel occlusion and, similar to noxious procedures, reversed initiated multicausal noxious circuit of the occlusion/occlusion-like syndrome. Severe intracranial (superior sagittal sinus) hypertension, portal and caval hypertensions, and aortal hypotension were attenuated/eliminated. Counteracted were the severe lesions in the brain, lungs, liver, kidney, and gastrointestinal tract. In particular, progressing thrombosis, both peripherally and centrally, and heart arrhythmias and infarction that would consistently occur were fully counteracted and/or almost annihilated. To conclude, we suggest further BPC 157 therapy applications.

... However, more important is the practical evidence from a considerable number of the studies, particularly in gastrointestinal research, that intragastric administration or per os administration in drinking water, is equally effective as injections of the supplement administered to rodents, which has been performed in the majority of studies on BPC 157. 12,41,43,48,51,54,55,58,59,[61][62][63][82][83][84][85]89,[91][92][93]98,114,116,117,[143][144][145][146][147][149][150][151][152][153][154][155] In reality, in particular along with its safety profile, LD-1 is not achieved, and there are no reported adverse effects in clinical trials; 1-13 this evidence suggests the ease of practical clinical application. point of homeostasis (cytoprotection/adaptive cytoprotection, organoprotection) in the body's maintenance of integrity. ...

... But more important is the practical indicative evidence that even with the majority of studies on BPC 157 done on rodents given injection of the supplement, there are considerable number of the studies, particularly in gastrointestinal research, intragastric application or per-oral application in drinking water, correspondingly effective. 12,41,43,48,51,54,55,58,59,[61][62][63][82][83][84][85]89,[91][92][93]98,114,116,117,[143][144][145][146][147][149][150][151][152][153][154][155] In reality, in particular along with its safe profile, LD-1 not achieved, and no adverse effects in clinical trials, 1-13 this evidence suggests easy practical clinical application (Fig. 1). While introducing a new concept BPC 157 first strictly follows, and then, it considerably extends, with recently demonstrated recruitment of blood vessels to bypass vascular occlusion, 101,113,117,118 the guidelines of classic of stomach cells/endothelium cytoprotection 14-21 and Selye's concept of stress response against stress injury to reestablish disturbed homeostasis. ...

Predrag Sikiric Ki-Baik Hahm

Alenka Boban Blagaic

Sven Seiwerth

We reviewed again the significance of the stable gastric pentadecapeptide BPC 157 as a likely mediator of Robert's stomach cytoprotection/adaptive cytoprotection and organoprotection and as novel mediator of Selye's stress coping response to reestablish homeostasis. Specific points of BPC 157 therapy and the original concept of Robert's cytoprotection/adaptive cytoprotection/organoprotection are discussed, including the beneficial effects of BPC 157. First, BPC 157 protects stomach cells and maintains gastric integrity against various noxious agents (Robert's killing cell by contact) and is continuously present in the gastric mucosa and gastric juice. Additionally, BPC 157 protects against the adverse effects of alcohol and nonsteroidal anti-inflammatory drugs on the gastric epithelium and other epithelia, that is, skin, liver, pancreas, heart (organoprotection), and brain, thereby suggesting its use in wound healing. Additionally, BPC 157 counteracts gastric endothelial injury that precedes and induces damage to the gastric epithelium and generalizes "gastric endothelial protection" to protection of the endothelium of other vessels (thrombosis, prolonged bleeding, and thrombocytopenia). BPC 157 also has an effect on blood vessels, resulting in vessel recruitment that circumvents vessel occlusion and the development of additional shunting and rapid bypass loops to rapidly reestablish the integrity of blood flow (ischemic/reperfusion colitis, duodenal lesions, cecal perforation, and inferior vena caval occlusion). Lastly, BPC 157 counteracts tumor cachexia, muscle wasting, and increases in pro-inflammatory/procachectic cytokines, such as interleukin-6 and tumor necrosis factor-α, and significantly corrects deranged muscle proliferation and myogenesis through changes in the expression of FoxO3a, p-AKT, p-mTOR, and P-GSK-3β (mitigating cancer cachexia).

... Likewise, BPC 157 counteracts also the effect of dopamine over-release from dopamine nerve terminals and subsequent activation of dopamine receptors in striatum that may be induced by acute amphetamine administration (i.e., stereotypies, heightened startle response [156], and dopamine striatal receptors up-reguation following chronic amphetamine administration [157], or dopamine striatal receptor up-regulation as a delayed result of dopamine receptor antagonist application and dopamine receptors blockade (haloperidol/amphetamine-climbing behavior) [156], that both otherwise cause an over-effect upon amphetamine challenge [156,157]). Besides, BPC 157 completely counteracts also the gastric lesions that appear along with haloperidol, reserpine or MPTP application [155,156,[158][159][160]. ...

... And finally, in relation to its response to injury, BPC 157 promoted healing, this goes in parallel with the BPC 157 relation with early growth response 1 gene (egr-1)/nerve growth factor 1-A binding protein-2 (naB2), stimulated expression of egr-1 (responsible for cytokine and growth factor generation and early extracellular matrix (collagen) formation) but also its repressor naB2 [41][42][43]. In addition to BPC 157 specific relation with most important defense systems (i.e., dopamine [152][153][154][155][156][157][158], serotonin [160][161][162], NO-system [12,15,[33][34][35][36][37][38][39][40], this implies a strong advantage (i.e., BPC 157 and nab2 [226] could be part of a feedback mechanism that serves to regulate egr-1-mediated gene transcription) [99]), most complete healing effect accordingly demonstrated (for review see, i.e., [1][2][3][4][5][6]). And most importantly, although still far less investigated than the standard angiogenic growth factors [7,8], since always applied alone, with the same dose range, and same equipotent routes of application, regardless the injury tested, this could be clearly generalized, and thus, its own effect ascribed only to the given peptide (for review see, i.e., [1][2][3][4][5][6]). ...

Sven Seiwerth Rudolf Rucman Branko Turkovic

Predrag Sikiric

Commonly, the angiogenic growth factors signify healing. However, gastrointestinal ulceration is still poorly understood particularly with respect to a general pharmacological/pathophysiological role of various angiogenic growth factors implemented in growth factors wound healing concept. Thereby, we focused on the stable gastric pentadecapeptide BPC 157, a peptide given always alone vs. standard peptidergic angiogenic growth factors (EGF, FGF, VEGF), and numerous carriers. Further, we reviewed how the gastrointestinal tract healing could be generally perceived (i) in terms of angiogenic growth factors, and/or (ii) through the healing of extra-gastrointestinal tissues healing, such as tendon, ligament, muscle and bone, and vice versa. Respected were the beneficial effects obtained with free peptides or peptides with different carriers, EGF, FGF, VEGF, and BPC 157, their presentation along with injuries, and a healing commonality, providing their implementation in both gastrointestinal ulcer healing and tendon, ligament, muscle and bone healing. Only BPC 157 was consistently effective in all of the models of acute/chronic injury of esophagus, stomach, duodenum and lower gastrointestinal tract, intraperitoneally, per-orally or locally. Unlike bFGF-, EGF-, VEGF-gastrointestinal tract studies demonstrating improved healing, most of the studies on tendon, muscle and bone injuries provide evidence of their (increased) presentation along with the various procedures used to produce beneficial effects, compared to fewer studies in vitro, while in vivo healing has a limited number of studies, commonly limited to local application, diverse healing evidence with diverse carriers and delivery systems. Contrary to this, BPC 157 - using same regimens like in gastrointestinal healing studies - improves tendon, ligament and bone healing, accurately implementing its own angiogenic effect in the healing. Thus, we claim that just BPC 157 represents in practice a pharmacological and pathophysiological role of various peptidergic growth factors.

... A complex interaction with adrenergic and dopaminergic systems has been reported for BPC 157 [62]. The release of this pentadecapeptide from somatosensory neurones is suggested, based on experiments with neurotoxin capsaicin, in a nociception assay [63] and nasal [64] and intestinal [65] lesions studies. ...

... If this would be the case, then we should claim that BPC 157 may be a system of its own that may be quite important for NO-system functions. In support, in analogy with the original BPC 157/NO-system evidence [16], now largely extended with subsequent studies [17,27,[47][48][49][50][51], i. e., after the initial demonstration that BPC 157 interacts with dopamine system [62] and somatosensory neurons [63][64][65], and thereby investigated for interaction with NO-system, L-NAME and L-arginine, in vivo, and in vitro [16], further analyzing of its counteracting capabilities revealed that BPC 157 interacts with dopamine system even more closely, in gastrointestinal tract lesions [74,130,131] and central disturbances [73][74][75]78], dopamine release [73,78], receptor supersensitivity [73] and blockade [74], tolerance and reverse tolerance [75], dopamine vesicles depletion [75] or destruction [75], and also stimulates serotonin release particularly in nigrostriatal areas [132]. After capsaicin studies [63,64], we demonstrated strong neuroprotective capabilities in both peripheral nerve injuries [38] and traumatic brain injury [39]. ...

Predrag Sikiric

Sven Seiwerth Rudolf Rucman Bozidar Sebecic

We reviewed stable gastric pentadecapeptide BPC 157-NO-system-relation, its close participation in Moncada's (maintained vascular integrity, platelets control) homeostatic healing response of NO-system to injury. Namely, BPC 157 particular healing effect also affects all events after vascular integrity loss (dependent on circumstances, it reduces either thrombosis (abdominal aorta anastomosis) or bleeding/thrombocytopenia (amputation, heparin, warfarin, aspirin)) and in a series of different injurious models, acute and chronic, BPC 157 consistently advances healing after severe injuries in various tissues spontaneously unable to heal; stimulates egr-1 and naB2 genes; exhibits high safety (LD1 not achieved)). Hypothesis, that BPC 157 (since formed constitutively in the gastric mucosa, stable in human gastric juice, along with significance of NO-synthase and the basal formation of NO in stomach mucosa, greater than that seen in other tissues) exhibits a general, effective competing both with L-arginine analogues (i. e. , L-NAME) and L-arginine, and that this has some physiologic importance (NO-generation), later, practically supports its beneficial effects illustrating BPC 157 and NO-system mutual (with L-NAME/L-arginine; alone and together) relations in (i) gastric mucosa and mucosal protection, following alcohol lesions, in cytoprotection course, NO-generation, and blood pressure regulation; (ii) alcohol acute/chronic intoxication, and withdrawal; (iii) cardiovascular disturbances, chronic heart failure, pulmonary hypertension, and arrhythmias; (iv) disturbances after hypokalemia and hyperkalemia, and potassium-cell membrane dysfunction; and finally, in (v) complex healing failure, proved by the fistulas healing, colocutaneous and esophagocutaneous. However, how this advantage of modulating NO-system (i. e. , particular effect on eNOS gene), may be practically translated into an enhanced clinical performance remains to be determined.

Predrag Sikiric Marko Sever

Ivan Krezic

Sven Seiwerth

Since the early 1990s, when Robert’s and Szabo’s cytoprotection concept had already been more than one decade old, but still not implemented in therapy, we suggest the stable gastric pentadecapeptide BPC 157 as the most relevant mediator of the cytoprotection concept. Consequently, it can translate stomach and gastrointestinal mucosal maintenance, epithelium, and endothelium cell protection to the therapy of other tissue healing (organoprotection), easily applicable, as native and stable in human gastric juice for more than 24 h. These overwhelm current clinical evidence (i.e., ulcerative colitis, phase II, no side effects, and no lethal dose (LD1) in toxicology studies), as BPC 157 therapy effectively combined various tissue healing and lesions counteraction. BPC 157 cytoprotection relevance and vascular recovery, activation of collateral pathways, membrane stabilizer, eye therapy, wound healing capability, brain–gut and gut–brain functioning, tumor cachexia counteraction, muscle, tendon, ligament, and bone disturbances counteraction, and the heart disturbances, myocardial infarction, heart failure, pulmonary hypertension, arrhythmias, and thrombosis counteraction appeared in the recent reviews. Here, as concept resolution, we review the counteraction of advanced Virchow triad circumstances by activation of the collateral rescuing pathways, depending on injury, activated azygos vein direct blood flow delivery, to counteract occlusion/occlusion-like syndromes starting with the context of alcohol-stomach lesions. Counteraction of major vessel failure (congested inferior caval vein and superior mesenteric vein, collapsed azygos vein, collapsed abdominal aorta) includes counteraction of the brain (intracerebral and intraventricular hemorrhage), heart (congestion, severe arrhythmias), lung (hemorrhage), and congestion and lesions in the liver, kidney, and gastrointestinal tract, intracranial (superior sagittal sinus), portal and caval hypertension, aortal hypotension, and thrombosis, peripherally and centrally.

Predrag Sikiric Domagoj Drmic Marko Sever

Sven Seiwerth

This review is focused on the healing of fistulas and stable gastric pentadecapeptide BPC 157. Assuming that the healing of the various wounds is essential also for the gastrointestinal fistulas healing, the healing effect on fistulas in rats, consistently noted with the stable gastric pentadecapeptide BPC 157, may raise several interesting possibilities. BPC 157 is originally an anti-ulcer agent, native to and stable in human gastric juice (for more than 24 h). Likely, it is a novel mediator of Robert’s cytoprotection maintaining gastrointestinal mucosal integrity. Namely, it is effective in the whole gastrointestinal tract, and heals various wounds (i.e., skin, muscle, tendon, ligament, bone; ulcers in the entire gastrointestinal tract; corneal ulcer); LD1 is not achieved. It is used in ulcerative colitis clinical trials, and now in multiple sclerosis, and addressed in several reviews. Therefore, it is not surprising that BPC 157 has documented consistent healing of the various gastrointestinal fistulas, external (esophagocutaneous, gastrocutaneous, duodenocutaneous, colocutaneous) and internal (colovesical, rectovaginal). Taking fistulas as a pathological connection, this rescue is verified with the beneficial effects in rats with the various gastrointestinal anastomoses, esophagogastric, jejunoileal, colo-colonic, ileoileal, esophagojejunal, esophagoduodenal, and gastrojejunal. This beneficial effect occurs equally when the gastrointestinal anastomoses are impaired with the application of NSAIDs, cysteamine, large bowel resection, as well as concomitant esophageal, gastric, and duodenal lesions and/or ulcerative colitis presentation, short bowel syndrome progression, liver and brain disturbances presentation. Particular aspects of the BPC 157 healing of the fistulas are especially emphasized.

Predrag Sikiric

Sven Seiwerth

Gorana Aralica Ivo Sjekavica

After demonstration that cysteamine induced duodenal lesions in gastrectomized rats, while a number of antiulcer drugs mitigated these lesions, it was shown that one single intrarectal (i.r.) cysteamine application produced severe colon lesions in acute studies in rats. Thus, the further focus was on the protracted effect of cysteamine challenge (400 mg/kg b.w. i.r.) and therapy influence in chronic experiments in female rats. Regularly, cysteamine colon lesions were markedly mitigated by ranitidine (10), omeprazole (10), atropine (10), methylprednisolone (1), sulphasalazine (50; mg/kg), pentadecapeptide BPC 157 (PL-10, PLD-116; 10 μg or 10 ng/kg). Specifically, after 1 or 3 months following initial challenge (cysteamine 400 mg/kg i.r.) in female rat, the therapy [BPC 157 (PL-10, PLD-116 (10.0 μg or 10.0 ng/kg; i.g., i.p., i.r.), ranitidine, omeprazole, atropine, methylprednisolone, sulphasalazine (i.p.)] reversed the protracted cysteamine colon injury: the 1 week-regimen (once daily application) started after 1 month post-cysteamine, as well as the 2 weeks-regimen (once daily application), which started after 3 months. The effect on recidive lesion was also tested. These cysteamine lesions may reappear after stopping therapy (after stopping therapy for 3 weeks at the end of 2-weeks regimen started in 3 months-cysteamine female rats) in sulphasalazine group, while this reappearance is markedly antagonized in pentadecapeptide BPC 157 (PL-10, PLD-116)-rats (cysteamine-colon lesion still substantially low).

Predrag Sikiric

Sven Seiwerth

Zeljko Grabarevic Ivo Sjekavica

Recently, we showed cysteamine-duodenal lesions without gastric acid, since they were induced also in gastrectomized rats, as in naive rats, and they were inhibited by the novel stomach pentadecapeptide BPC 157 as well as standard antiulcer drugs (i.e. cimetidine, ranitidine, omeprazole, bromocriptine, atropine). Therefore, as an advantage of considering cysteamine as a directly acting cytotoxic agent and mentioned agents as direct cytoprotective agents, the present focus was on the ulcerogenic effect of cysteamine and protective effect of gastroduodenal antiulcer agents outside upper gastrointestinal tract (i.e. in colon). Intrarectal administration of the cysteamine (200 or 400 mg/kg b.w) produced severe colon lesions (i.e. transmural inflammation with serosal involvement) in rats (30 min–72h-experimental period), apparently distinctive from smaller lesions after non-specific irritant enema [diluted HCl solution, pH 3.8 (adjusted to pH of cysteamine solution (pH 3.8)]. All of the tested antiulcer agents were applied simultaneously with cysteamine enema (8 cm from the anus, in a volume of the 1.0 ml/rat) intraperitoneally (i.p.), intragastrically (i.g.) or intrarectally (i.r.). Pentadecapeptide BPC 157 (10 μg or 10 ng/kg b.w.), given in either regimen, previously shown to have, besides others, a particular beneficial activity just in the intestinal mucosa, inhibited these cysteamine colon lesions (assessed after 30 min, 60 min, 180 min, 24 h, 48 h, 72 h following cysteamine in a dose of either 200 or 400 mg/kg i.r.). Cysteamine-colon lesions were also attenuated by standard antiulcer agents (mg/kg b.w.), given i.p., i.g., or i.r., such as ranitidine (10), cimetidine (50), omeprazole (10), atropine (10), together with methylprednisolone (1), and sulphasalazine (50, i.r.), assessed 30 min following application of 200 mg of cysteamine. Finally, standard cysteamine duodenal lesions (assessed 24 h after a subcutaneous application of 400 mg/kg of cysteamine) were also attenuated by these agents application (given in the same doses, i.p., 1 h before cysteamine), with only exception to sulphasalazine. Thus, the extended cysteamine specific ulcerogenic effect, cysteamine colon/duodenum lesion-link and an extenuation of agents protection from upper to lower part of gastrointestinal tract (i.e. stomach pentadecapeptide BPC 157, standard antiulcer agents, cimetidine, ranitidine, atropine, omeprazole) and vice versa (remedies for inflammatory bowel disease) evidenced in the present study may be potentially important for both further experimental and clinical research.

Stefano Evangelista

Daniela Renzi Paola Guzzi

Carlo Alberto Maggi

This study investigated the changes of gastric levels of calcitonin gene-related peptide-like immunoreactivity (CGRP-li) following the induction of gastric ulcers in rats. Gastric CGRP-li is decreased in corpus samples from ulcerated stomachs induced by water-immersion stress (WIS) but not by indomethacin (20 mg/kg s.c.). WIS produced a significant decrease in CGRP-li in the whole thickness of the glandular portion of the stomach and not in its mucosal layers, indicating that the muscular layer of the stomach is the region involved in this phenomenon. Systemic administration of CGRP (25 microg/kg s.c.) produced a significant decrease in both length of ulcers and gastric acid secretion by WIS. The effect on gastric acid hypersecretion, which plays a pivotal role in WIS ulcers, may contribute to the protective effect of CGRP in WIS ulcers. These findings suggest that WIS induced a release of CGRP from the sensory nerve endings present in the muscular layers of the stomach and this peptide seems to play a defensive role in WIS-ulcers.

Zs. Sandor

Aron Vincze

Sandor Szabo

A putative organoprotective peptide (BPC) was recently isolated from human gastric juice and its 15 amino-acid terminal synthesized. We investigated the effect of this compound in acute gastric mucosal injury and acute and chronic duodenal ulcération. Fasted Sprague-Dawley rats (160-180g) were given intragastrically (i.g.) vehicle, or BPC (15-AK-2, Pliva) 1,10 or 100 μg/100g 30 min before 1 ml of 1% ammonia water or 75% ethanol, and killed 1 hr after the damaging agents. The areas of NH,-induced hemorrhagic mucosal lesions (% of glandular stomach) measured with stereomicroscopic planimetry were 15.3 ±2.3, 8.3 ±1.7 (p<0.05), 4.9 ±1.9 (p<0.005), 4.9 ±1.7 (jxO.005) in controls and 1,10 or 100μg BPC groups respectively, while the corresponding values in the ethanol model were 6.1 ±1.2, 4.1± 1.3, 3.1 ±1.1 (p<0.05), 2.5 ±0.6 (p<0.05). Duodenal ulcers were induced in non-fasted rats by cysteamine-HCl (25mg/100g) i.g.x3 at 4 hr intervals. On the third day rats were either killed (acute study) or laparotomized to keep only animals with perforated or penetrated ulcer for treatment with BPC 1 or 10 μg/100g i.g.x2/day for 3 weeks (chronic ulcers) The severity and area of acute duodenal ulcers were not significantly reduced by BPC at 10μg/100μg i.g. or s.c., or lOOug/lOOg s.c. The areas (mm) of chronic duodenal ulcers were 9.0 ±2.2, 2.7 ± 0.06 (p<0.05), 2.9 ±0.8 (p<0.05) after the 0, 1 or 10 ug BPC. Thus, the newly isolated gastric peptide BPC exerted a dose-dependent acute gastroprotection in the NHj and ethanol models, and although it did not effect the development of acute duodenal ulcers it accelerated the healing of cysteamine-induced chronic duodenal ulcers.

Predrag Sikiric Ivo Rotkvić S Mise V N Simicević

Ulcer disease is often referred to as a multifactorial overall disturbance of the body1. The intriguing complexity of ulcer etiology is currently in the focus of many different scientific approaches. However, in spite of these efforts, the problem of how to incorporate such a theoretical recognition into a meaningful integrative therapeutic management concept, remains to be solved. One possible solution may lie in dopamine research.

Louis S. Goodman AKred Goodman Gilman A.G. Gilman G.B. Koelle

The 5th edition of this world renowned textbook is the result of a thorough updating of every chapter with respect to the mechanism of action and use of older agents and the addition of important new drugs. The philosophy and objectives of the earlier editions are continued, however, together with the same thoughtful organization, clarity and authority that have long made 'Goodman and Gilman' the standard book in the field. Although less dynamic or outmoded sections have been condensed or eliminated, the basic organization remains the same, with major attention being given to the well established, safe and effective prototypal drugs. After a discussion of the general principles of pharmacokinetics, special attention is given to drugs acting on the CNS, local anesthetics, drugs acting at synaptic and neuroeffector junctions, autacoids, cardiovascular drugs, water, salts and ions, drugs affecting renal function and electrolyte metabolism, drugs affecting uterine motility, gases and vapors, heavy metals and antagonists, locally acting drugs, antiparasitic drugs, antimicrobial drugs, antineoplastic drugs, drugs acting on the blood and hematopoietic system, hormones and hormone antagonists, vitamins and even the principles of prescription writing and patient compliance instruction. There is a detailed subject index referring to both medical concepts and drug names, generic as well as proprietary. This book will prove invaluable to both students and graduates in many areas of the biomedical sciences.

Predrag Sikiric Ivo Rotkvić Stjepan Mise Tomislav Anic

Dopamine agents (saline in control groups) were coadministered with indomethacin by either single or repeated application. The ulcerogenic effect (erosions and/or ulcers) of repeated given indomethacin on gastric mucosa differed clearly from that on intestinal mucosa. The effect on intestinal mucosa was markedly greater than after a single dose. The effects of dopamine agents appeared to be more consistent. Domperidone and haloperidol, given as single or repeated doses, strongly aggravated both the gastric and intestinal lesions. Bromocriptine and amantadine had a protective effect. The adverse effects of both dopamine antagonists (increased after repeated administration) were strongly inhibited by the simultaneous administration of either bromocriptine or amantadine. The involvement of the dopamine system (central or peripheral) in the mechanisms that maintain gastric (probably related to cytoprotection also) and intestinal mucosa integrity is therefore suggested.

Gary B. Glavin Donald D. Smyth

1. Previous reports of the effects of alpha 2-adrenoceptor stimulation on gastric secretion are inconsistent because it was not clear whether the compounds were activating alpha 2-adrenoceptors and/or newly described imidazoline receptors. In the present experiments, the effects of moxonidine, an I1-imidazoline receptor agonist and antihypertensive agent, on gastric secretion and on experimental gastric mucosal injury were examined. 2. Moxonidine (0.01, 0.1 and 1.0 mg kg-1, i.p.) potently inhibited basal (non-stimulated) gastric acid secretion in conscious rats with an ED50 of 0.04 mg kg-1. Two hours following administration of the highest dose of moxonidine (1.0 mg kg-1), gastric acid output was completely suppressed. Moxonidine also significantly increased intragastric pH, at the two highest doses. 3. The alpha 2-adrenoceptor agonist, clonidine (0.01, 0.1 and 1.0 mg kg-1, i.p.) decreased basal acid secretion at the lowest dose (37%) and at the highest dose (46%), while the intermediate dose did not affect gastric acid output. 4. In an ethanol-induced model of gastric mucosal injury, moxonidine decreased the length of lesions at the lowest and highest doses (0.01 and 1.0 mg kg-1) as well as the number of the lesions, at the highest dose (1.0 mg kg-1). 5. In pylorus-ligated rats, moxonidine significantly decreased acid secretion (all doses), total secretory volume (1.0 mg kg-1) as well as pepsin output (1.0 mg kg-1). 6. In comparison to clonidine, moxonidine appears to be a more potent anti-secretory and gastric-protective compound.(ABSTRACT TRUNCATED AT 250 WORDS)

Michael J. Davey

: An account is given of the work performed in this laboratory to demonstrate that prazosin differs from the classical [alpha]-adrenoceptor antagonists in that it possesses a high degree of selectivity for [alpha]1-adrenoceptors as opposed to [alpha]2-adrenoceptors. This selectivity ensures the preservation of local feedback control of the release of noradrenergic transmitter by [alpha]2-adrenoceptors. It is considered to be largely responsible for the therapeutic success of prazosin and its relative absence of effects such as tolerance, tachycardia, diarrhoea, and renin release that severely limited the clinical application of the classical [alpha]-adrenoceptor antagonists. Mention is made of the potential use of prazosin as a research tool, especially as a radioligand in binding experiments, for the identification of [alpha]-adrenoceptors in different tissues and for the direct demonstration of changes in [alpha]1-adrenoceptor type and number in specific disease states.

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