Prolyl Endopeptidase Enzyme Inhibitors of Plant Origin

Home , Endopeptidase inhibitor, Oligopeptidase B, Prolyl endopeptidase

FABAD J. Pharm. Sci., 27, 231-237; 2002

SCIENTIFIC REVIEWS Prolyl Endopeptidase Enzyme Inhibitors of Plant Origin

0 İlkayORHAN* , Gürdal ORHAN**, Bilge ŞENER*

Prolyl Endopeptidase Enzyme ltıhibitorsof Plaııt Origin Bitkisel KaynaklıProlil Endopeptidaz Enzim İnhibitörleri

Summary : Prolyl endopeptidase (PEP) is a serine protease Özet : Prolil endopeptidaz (PEP), öğrenmeve hafıza sü• which is known ta play a role in degradation proline of recinde etkili prolin içerikli nöropeptitlerin yıkılnıasındarol containing neııropeptidesinvolved in the processes of learn oynadığıbilinen bir serin proteazdır.PEP inhibitörlerinin ing and nıenıory.PEP inhibitors are expected to exert their sinirleri hasar ve hücre ölümüne karşıkorıjyan, tanıma beneficial effects by increasing the brain levels of those neu fonksiyonlarınıyeniden yapılandırıpiyileştirebilen nö• ropeptides ıvhichmay improve and restore cognitive func ropeptitlerin beyin düzeylerini artırarakyararlı olnıaları tions and protect vulnerable nerves against damage and celi beklenir. Bugüne kadar, sentetik eşdeğerleriolduğu kadar, death. Therefore, they are considered to have therapeutic Alzheimer hastalığınakarşıterapötik bir potansiyele sahip potential against Alzheimer's Disease. To date many com pounds have been isolated from natura! sources including PEP inhibitör aktiviteli pek çok bileşik,bitkiler, mantarlar plants, fungi and bacteria. Their synthetic counterparts have ve bakteriler de dahil olmak üzere doğalkaynaklardan izole been alsa studied. This revie1v covers PEP inhibitors iso edilmiştir.Bu derleme, bitkilerden elde edilen PEP in hibitörlerini kapsamaktadır. lated fronıplants. Key Words: Prolyl endopeptidase, Alzheimer's disease, Anahtar kelimeler: Profil endopeptidaz, Alzheinıerhas neuropeptide, PEP inhibitory activity, plant talığı,nöropeptit, PEP inhibitör ak tivite, bitki Received 14.11.2002 Revised 17.01.2003 Accepted 18.02.2003

INIRODUCTION There is also some evidence that psychiatric dis orders, such as major depression, schizophrenia and Prolyl endopeptidase (PEP, also called prolyl olig post-traumatic stress disorder are associated with sig opeptidase) is a cytosolic endopeptidase involved in nificant alterations in the activity of some enzymes in the degradation of several proline-containing neuro cluding prolyl endopeptidase (PEP), ac peptides iınplicatedin leaming and memory pro etylcholinesterase (AChE) and dipeptidyl peptidase cesses. ~fheseneuropeptides such as vasopressin, N (DPP-IV). Therefore, poleni, selective and perma substance P, thyrotropin-releasing hormone (TRH), nent inhibitors of PEP could serve as probes to assess oxytocin, neurotensin, angiotensins and opioids are the genuine contribution of !his enzyme in Alz affected in Parkinson Disease. Proline endopeptidase heiıner'spathology3-5 (PEP) contributes to the degradation of many of these neuropeptides, some of which are linked to a variety Formation of beta-amyloid and neurofibrillary tan of cognitive functions1,2 and could also control the gles in the brain due to genetic or other factors and production of the amyloidogenic peptide A-beta. marked reduction of certain brain neurnpeptide lev-

* Gazi University, Department of Pharmacognosy, Faculty of Pharmacy, 0633 Ankara, Turkey. ** Numune Education and Research Hospital, 2nd Clinic-of Neurology, Ankara, Turkey. ° Correspondence

231 Orhan, Orhan, Şener

els are consistent findings in patients with Alz proposed to be essential for the rnorphogenetic pro heimer's Disease, together with the deterioration of cess of imaginal discs and to participate in DNA syn cholinergic neurons 6-ZO. thesis in insect proliferation31,32.

Currently, !here is a great demand for the develop Inhibitors of PEP ment of new drugs to improve memory deficits or to delay the neurodegenerative process. Up to the Since PEP can hydrolyze a number of peptide hor present, various studies have been focused on con rnones and neurotransmitters, abnorrnal increases or stituents with PEP inhibitory activity isolated from decreases in PEP activity could result in diseases re-· plants as well as their synthetic counterparts. In !his lated to rnemory and cognition33-41. Thus, PEP in ·review, general inforrnation is given about PEP and hibitors are expected to exert their beneficial effects plants possessing PEP inhibitory activity. by increasing the brain levels of those neuropeptides which may improve and restore cognitive functions Functions of PEP and protect vulnerable nerves against damage and celi death. Proline is unique among 20 amino acids in its cyclic structure. This property imposes many restrictions PEP inhibitors rnay have unique clinical relevance in on the structure of peptides and proteins and confers the prevention and treatrnent of a wide range of age _particular biological properties upon a wide range of related disorders including: physiologically important biomolecules. In order to deal with such peptides, nature has developed a -Memory deficits due to cerebro-vascular sclerosis group of enzymes !hat recognize this residue specif -Dementia of Alzheimer's type ically21. -Dementia and cogrtitive damage secondary to stroke, AIDS ete. Proline-specific peptidases fall into two classes. Pro lidase and aminopeptidase P cleave the N-terminal Specific PEP inhibitors are also expected to have anti

amino acid from a peptide that is followed by proline amnesic effect. To date, ınanycandidate compounds at the carbonyl-imino bond. Prolinase and proline with PEP inhibitory activity have been synthesized imino peptidase cleave proline at the N-terminal po for treatrnent of the neuropathological disorders men sition of peptides. Endoproteases !hat have specific tioned above42-47_ ity for proline are HIV-1 protease, prolyl endo peptidase and carboxypeptidase P. HIV-1 protease These studies suggest that PEP inhibitors may im

cleaves the carbonyl-imino bond. PEP and car prove ınemoryby blocking the metabolism of endog boxypeptidase P cleave the carboxyl side of the pro enous neuropeptides and have possible potential for

line residue22. As a cytoplasmic protease, PEP has preventing rneınorydeterioration. been characterized frorn several organisms (mush room, plant, bacteria) and in some organs of various PEP Inhibitors Isolated frorn Plants nmunals (cow, human, rabbit, pig and rat)23. PEP is composed of 705.arnino acids including a signal pep Recently, research has been concentrated on plan! tide of 20 residues. After cleavage of the signal pep constituents in order to discover novel PEP inhibitory tide, the mature protein which is composed of 685 compounds. For this purpose, sake (alcohol beverage residues is secreted. It is a serine protease of a novel in Japan, rnade frorn rice) and its by-product were type and does not present a proenzyrne form. Al studied. Pepsin hydrolysates of sake cake as a by though the three dimensional structure of PEP is un product and sake concentrate were subjected to some known, a structural pattern composed of several do chromatographic procedures. Three inhibitory pep 2 3 mains has been suggested 4- D. PEP has also been tides were obtained from sake cake as well as three

232

a a

of of

-2-

(-)

cis-

233 233

of of

and and

glu

and and

glu

epi

also also

Enı

PEP PEP

non

(Per

com

med

active active

found found

evalu

acid acid

mono

(1) (1)

against against

the the

for for

PEP PEP

the the

be be

extract extract

identified identified

folk folk

of of

significant significant

traditional traditional

was was

aJ.54,55 aJ.54,55

new new

were were

formula formula

extracts extracts

as as to to

a a

known known

gallic gallic

caused caused

addition, addition,

known known

(-)-epicatechin (-)-epicatechin

licuroside, licuroside,

et et

three three

1;2,3,6-tetra-O

were were

3-0-gallate 3-0-gallate

five five

in in

4'-0-~-D-(2,6-di

this this

compounds, compounds,

lndian lndian

. .

extract extract

3-0-galloyl 3-0-galloyl

inhibition inhibition

plaots plaots

found found

Fan Fan

compounds compounds

of of

in in

Tokaku-joki-to Tokaku-joki-to

fourteen fourteen

have have

officinalis officinalis

isolated isolated

methanolic methanolic

showed showed

!hem, !hem,

sachalinensis sachalinensis

new new

methanol methanol

gallate, gallate,

4-(4-hydroxyphenyl)-2-

gallate gallate

to to

extract, extract,

was was

twenty-five twenty-five

that that

the the

3-0-gallate 3-0-gallate

used used

4-(4-hydroxyphenyl) 4-(4-hydroxyphenyl)

the the

was was

activity

work, work,

from from

two two

activity57_ activity57_

twenty-two twenty-two

methanol methanol

in in

namely namely

4'-0-~-D-(6-0-galloyl) 4'-0-~-D-(6-0-galloyl)

this this

of of

medicinal medicinal

with with

of of

Among Among

Embelia Embelia

1,2,3,4,6,-penta-O-galloyl-_-D

rhodiosin, rhodiosin,

been been

the the

found found

Rhodolia Rhodolia

found found

their their

.and .and

glucopyranoside, glucopyranoside,

al. al.

-epigallocatechin -epigallocatechin

E.xamination E.xamination

with with

noncompetitive noncompetitive

!hem, !hem,

of of

for for

From From

has has

purposes, purposes,

embelin embelin

combination) combination)

et et

. .

along along

--> -->

and and

also also

of of

inhibitory inhibitory

(1) (1)

inhibitors inhibitors

activities activities

with with

1,2,6-tri-O-galloylglucose, 1,2,6-tri-O-galloylglucose,

)-gallocatechin )-gallocatechin

4~ 4~

isolated. isolated.

studied studied

isolation isolation

(2), (2),

and and

+ +

(-)-epicatechin (-)-epicatechin

components components

( (

along along

inhibition. inhibition.

which which

was was

Bangladeshi Bangladeshi

porlion porlion

activity. activity.

4'-0-~-D-(2-0-galloyl-6-0-cinnamoyl) 4'-0-~-D-(2-0-galloyl-6-0-cinnamoyl)

4'-0-~-D-(6-0-galloyl-2-0-cinnamoyl) 4'-0-~-D-(6-0-galloyl-2-0-cinnamoyl)

activity. activity.

rhedionin, rhedionin,

the the

PEP PEP

(-)-Epigallocatechin (-)-Epigallocatechin

various various

leaves

strong strong

also also

displayed displayed

disease52_ disease52_

Twelve Twelve

of of

were were

Rhubarb Rhubarb

Khaoom Khaoom

PEP PEP

a a

formulas formulas

and and

tea tea

responsible responsible

in in

al. al.

active active

tea tea

. .

for for

ribes, ribes,

by by

inhibitory inhibitory

4-(4-hydroxyphenyl)2-butanone 4-(4-hydroxyphenyl)2-butanone

et et

and and

connection connection

the the

have have

(2), (2),

to to belia belia

number number

PEP PEP

O-galloY,l)glucopyranoside, O-galloY,l)glucopyranoside, against against

ic:ine ic:ine

as as

competitive competitive 0~~-D,(6-0-galloyl) 0~~-D,(6-0-galloyl)

epicatechin, epicatechin,

copyranoside copyranoside

pound pound butanone butanone Green Green

ated ated

copyranoside, copyranoside,

copyranoside copyranoside

green green

3,5,4'-trihydroxystilbene 3,5,4'-trihydroxystilbene

pounds. pounds.

sia sia

sulted sulted

hibitors. hibitors.

inhibitory inhibitory gallate gallate

butanone butanone

Kampo Kampo

galloyl-~-D-glucose, galloyl-~-D-glucose,

screened screened

terpenoids terpenoids

PEP

rosiridin rosiridin

in in

derground derground gallocatechin-( gallocatechin-(

glucose, glucose,

pounds pounds heimer's heimer's

inhibitory inhibitory

Fan Fan

a a

%) %)

far far

the the

lac

tra

this this

in in

that that

!hat !hat

acu

Alz-

(76.9 (76.9

3-0-

(84.3 (84.3

exist exist

acid, acid,

com

activ

water water

biloba biloba

z-pro

(~) (~)

of of

the the

to to

of of

known known

activity activity

was was

portion portion

of of

(57.2 (57.2

(77.4 (77.4

venetum venetum

from from

indicated indicated

% %

offilinalis offilinalis

4-0-(~-D

Salvia Salvia

on on

inhibitory inhibitory

except except

inhibition. inhibition.

faund faund

found found

which which

Paeonia Paeonia

inhibitor. inhibitor.

yao yao

activity activity

another another

veitchii veitchii

50 50

eleven eleven

concentration concentration

%), %),

49 49

Angelica Angelica

Ginkgo Ginkgo

PEP PEP

orientalis orientalis

PEP PEP

forty-six forty-six

controls, controls,

a a

is is

deserta deserta

%), %),

Related Related

and and

extracts extracts

inhibitory inhibitory

aJ.

have have

inhibitory inhibitory

of of

nineteen nineteen

at at

Comus Comus

3-0-gallate, 3-0-gallate,

the the

lor lor

selected selected

inhibitory inhibitory

(86.1 (86.1

el el

%), %),

pathology pathology

%), %),

2002 2002

inhibitors inhibitors

of of

protocatechuic protocatechuic

inhibitors inhibitors

we we

Biota Biota

Flavobacterium Flavobacterium

inhibitors inhibitors

peptides peptides

investigation investigation

Tabanus Tabanus

(79.8 (79.8

Apocynum Apocynum

Paeonia Paeonia

vitra48. vitra48.

showed showed

underground underground

epigallocatechin epigallocatechin

Out Out

%), %),

Salvia Salvia

inhibitory inhibitory

which which

the the

of of

had had

positive positive

Fan Fan

rhynchophylla rhynchophylla

PEP PEP

competitive competitive

in in

%), %),

screened screened

(63.3 (63.3

plants plants

(49.9 (49.9

showed showed

--> -->

of of

arbutin arbutin

%) %)

the the

a a

methanol methanol

these these

from from

in in

significant significant

manner51_ manner51_

These These

plants, plants,

far far

(72.8 (72.8

addition, addition,

is is

231-237, 231-237,

namely namely

medicine medicine

inhibition inhibition

two two

alsa alsa

PEP PEP

isolation isolation

of of

alsa alsa

A, A,

(65.2 (65.2

(81.7 (81.7

acid acid

(60.2 (60.2

acetylcholinesterase acetylcholinesterase

the the

from from

in in

davatum davatum

% %

(65.4 (65.4

27, 27,

from from

showed showed

multiflorum multiflorum

extracts extracts

role role

Uncaria Uncaria

sake. sake.

with with

the the

on on

50 50

sinensis sinensis

!hem, !hem,

a a

which which

showed showed

ten ten

medicines, medicines,

isolated isolated

Sci., Sci.,

Turkish Turkish

study study

catechu catechu

in in

Chinese Chinese

Phytochemical Phytochemical

of of

while while

noncompetitive noncompetitive

screening screening

aod aod

constituents constituents

z-pro-prolinaL z-pro-prolinaL

from from

jojoba jojoba

µg/ml. µg/ml.

water water

inhibited inhibited

than than

extracts extracts

extract extract

clavatum clavatum

(-)-epigallocatechin (-)-epigallocatechin

acid acid

tenuifolia tenuifolia

study study

Six Six

asphodeloides asphodeloides

sacra sacra

PEP PEP

plays plays

%) %)

mi, mi,

trichocarpa trichocarpa

sugiyamae sugiyamae

the the

researchers researchers

together together

100 100

some some

were were

Areca Areca

Plıarm. Plıarm.

and and

sacranoside sacranoside

Lycopodium Lycopodium

Polygonum Polygonum

kinetic kinetic

our our

Chinese Chinese

more more

acetylcholinesterase, acetylcholinesterase,

isolated, isolated,

at at

of of

!hem, !hem,

of of

resulted resulted

µg/ µg/

acid, acid,

that that

var. var.

in in

glutelin glutelin

(58.2 (58.2

%), %),

traditional traditional

peptides peptides

%), %),

Ziziphus Ziziphus

same same

they they

Eupolyphaga Eupolyphaga

methaool methaool

systematic systematic

The The

methanol methanol

Polygala Polygala

against against

100 100

of of

a a

Rhodolia Rhodolia

rice rice

tiflora tiflora

tiloba tiloba

(60.2 (60.2

(85.3 (85.3

emarrhena emarrhena

serta serta

Lycopodium Lycopodium

%), %),

showed showed

%), %),

(80.4 (80.4

and and of of

and and

vestigated vestigated

against against

that that

hibition hibition Among Among

activity activity

pounds pounds

glucopyranosyl)-gallic glucopyranosyl)-gallic

prolinol prolinol

galloylepigallocatechin-(4~ galloylepigallocatechin-(4~ concentration-dependent concentration-dependent

sis sis

gallate, gallate,

zyme zyme

the the

protocatechic protocatechic

of of The The

gallic gallic

ditional ditional

work, work, compounds. compounds.

ity. ity. extract extract

FABADJ. FABADJ.

ity ity

other other

ningosepticum. ningosepticum.

in in in in Orhan, Orhıın,Şener

In Anis et al.'s59 work on PEP inhibitory constituents Syzygium samarangense afforded nine PEP in from Duranla repens, they isolated five inhibitory hibitory compounds, five of which were of flavonoid compounds, 2 of which were isoprenylated flav type and four of which were identified as triterpene onoids, 5,7-dihydroxy-3'-(2-hydroxy-3-methyl-3- type compounds. butenyl)-3,6,4'-trimethoxyflavone, 3,7-dihydroxy-3' (2-hydroxy-3-methyl-3-butenyl) - 5,6,4 '-trimethoxy CONCLUSIONS flavone, an isoprenylated acetophenone derivative, 5- hydroxy-3,6,7,4'-tetramethoxyflavone and ro Prolyl endopeptidase (PEP) is a proteolytic enzyme senonolactone. with neuropeptide catabolising activity in the central nervous system. PEP has been reported to be abun Kobayashi et aJ.60 worked on the PEP inhibitory con dant in the hippocampal region of the brain in am stituents of the roots of Lindera strychniflora against nesic patients1,2. Therefore, PEP inhibitors are ex PEP from Flavobacterium meningosepticum and that pected to be the remedy for memory dysfunction. from rat brain supernatant. The isolated compounds The high activity of PEP in the human cortex sug were identified as the tannins, epicatechin (1) and gests that PEP could play a role in the functions of aesculitannin B (2), as well as the terpene de this brain area as well. rivatives, namely linderene (3), linderene acetate (4), linderelactone (5), and isolinderalactone (6). Out of s;nce medicinal plants have been proved to be rich these compounds, (1), (2), and (4) inhibited PEP of F. sources of biologically active compomı.dswhich meningosepticum origin more strongly than that could be used against the diseases that threaten hu from rat brain supernatant. However, (3), (5) and (6) man health, many recent studies have been carried inhibited the enzymes from both origins ti:ıthe same out on plants in o.rder to find new PEP inhibitors to extent. The kinetic study indicated that (1) and (2) be primarily used in the treatment of Alzheimer's dis were noncompetitive inhibitors while (3)-(6) acted ease. Any treatment that could positively modulate competitively. central neuropeptide levels would provide a prom ising therapeutic approach to the treatment of cog

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Specific

the

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1997.

dementia

prolyl T,

prolyl

1996.

vascular

therapeutics

KA, prolyl

prolyl

283,

Prevention

arcaeon

improves

slices,

endopeptidase

ofa

safety

endopeptidase

shows

Behav.,

peptidase

anxiety,

Alzheimer's

three-panel

neurons

Brit.

)TP-4819,

Ishitani

novel

senile

427-434,

with

Psychopharmacol.

Saito a 641-645,

Serum

and

1997.

Nishiyama

potentiation

2002

NGlOS-15

227-235,

m(3)-muscarinic

prolyl

Fujiwara

56,

Z-321,

Lines

1998. T,

drug,

behavioral

Therap., Kobayashi

Watanabe

Iwamoto

S, suppresses senescence-accelerated 3613-3618,

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selective

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A. with

235,

21,

the

inhibitor,

T, endopeptidase Y, 1998.

those

D. T,

its

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treatment

treating

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Biochem.

179,

inhibitor,

dipeptid

active

17-29,

disease, hippocampal

serum

147-151, Y,

Robinson-Bidle

cholinergic

Behav.,

volunteers,

Ootani

the for

Haruki

Tanabe

deficits

231-237,

Nutr.,

characterization

Ikeda Guez

prolyl

increases

Chuang

83,

stress-induced

protein patients and

rat

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1997.

JD,

and

hyperthermophilic

485-495, Miyazaki

Ohsawa enzyme

for

lwamoto

orally

27,

Fujiwara

Sakai

Y-29794,

JTP-4819

Commun.,

male

Watanabe

augments K, of

and

1997.

higher

antidementia

Yamamoto 23,

and M,

central

the

Bacteriol.,

beta M,

endopeptidase

novel

Pharmacol.

1996.

Pharmakokinetics

type Biochem.

Sci.,

potential Res.

Biochem

Neurosci., Denson

deposition

213-216,

Kondo

and

specific;

Alzheimer's

from

Nakajima endopeptidase

BrainReş.,

Toide healthy

cleaving

rats, Sunaga

Neuman

Furushiro

Uchiyama

Pharmacol

K, 613-618,

prolyl

inhibitor, activities 83, effects

inhibitor,

VJ,

properties

inhibitor,

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with

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humans:

Shinoda

K.,

Shinoda is M,

Ohno

Rew.

343-352, potential

amyloid

N.,

Fukunari

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43,

for

endopeptidase

novel

furiosus,

K, Biophyş.

in N,

ischernia-induced

K, K,

prolyl

transmission

a Res.,

of Behav.

32,

yl Alzh~imer Pharmacol.

task

1996.

memory

Overexpression

Uemura

prol tivity

activity

Toide peptidase

chemical disease, neuroendocrinol.,

peptidase the mentia, chem. Yoshida

Takano Shinoda

amyloidclike hibitor mouse, 1997.

Umemura Kata

peptidase inhibitor, macol., Nakashima Harwood

4819, dopeptidase coccus Toide novel tial HJ. rats,

Brain Toide K,

ease, _tion

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rebral way

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16.

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Yasin Yasin

activ

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novel novel

Rhod

2001. 2001.

J J

7, 7,

Pharm. Pharm.

and and

An An

S, S,

292-296, 292-296,

a a

Abstract Abstract

157-161, 157-161,

prepara

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of of

2001. 2001.

hypoper

2000. 2000.

improves improves

forms forms

2002, 2002,

inhibitory inhibitory

Kadota Kadota

1022-1030, 1022-1030,

24, 24,

age-related age-related

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22, 22,

embelin embelin

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the the

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Screening Screening Prolyl Prolyl

1996. 1996.

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part part

plants, plants,

underground underground and and

12, 12,

of of

Chem. Chem. 49, 49,

396-401, 396-401,

mirabilitum mirabilitum

Nasim Nasim

T, T,

S. S.

65-72, 65-72,

K. K.

517092, 517092,

K. K.

inhibitory inhibitory

Res., Res.,

Memory, Memory,

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595-600, 595-600,

endopeptidase.8. endopeptidase.8.

formulas formulas

of of

the the

49, 49,

Bull., Bull.,

cerebral cerebral

endopeptidase endopeptidase

Lycopodiunı Lycopodiunı

endopeptidase endopeptidase

1030, 1030,

using using

Chemical Chemical

MI, MI,

byproducts, byproducts,

non-peptidyl non-peptidyl

different different

398, 398,

1999. 1999.

and and

endopeptidase.7. endopeptidase.7.

a-Onocerin: a-Onocerin:

49, 49,

model model

Namb.i Namb.i

(Persia (Persia

of of

on on

its its

occurring occurring

Aoyagi Aoyagi

March March

Aoyagi Aoyagi

2003. 2003.

Bull., Bull.,

from from

Kadota Kadota

SMA. SMA.

1022-

medicinal medicinal

Leam. Leam.

Huperzine Huperzine

B. B.

Effcet Effcet

Kadota Kadota

prolyl prolyl

endopeptidase, endopeptidase,

Pharm. Pharm.

K, K,

2000. 2000.

Antibiot., Antibiot.,

Prolyl Prolyl

Tadasa Tadasa

1997. 1997.

from from

endopeptidase endopeptidase

Prolyl Prolyl

Kampa Kampa

prolyl prolyl

Pharm. Pharm.

Suginami Suginami

Bull., Bull.,

chronic chronic

M, M,

R, R,

S. S.

underground underground

and and

prolyl prolyl

49, 49,

J J

S. S.

of of

tacrine tacrine

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mouse mouse

197-203, 197-203,

between between

of of

Hai Hai

A, A,

H; H;

of of

KM, KM,

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activity activity

a a KS. KS.

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of of

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Choudhary Choudhary

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Arch. Arch.

constiluents constiluents

6, 6,

Biol. Biol.

prolyl prolyl

endopeptidase endopeptidase

265-267, 265-267,

prolyl prolyl

naturally naturally

sake sake

N, N,

Pharmacol., Pharmacol.,

·in ·in

Nagai Nagai

837-840, 837-840,

Ni Ni

of of

inhibitors inhibitors

of of

720-724, 720-724,

inhibitor, inhibitor,

of of

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S., S.,

Tang Tang

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Kadota Kadota

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indigenous indigenous

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2000. 2000.

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Y, Y,

inhibitor inhibitor

Song Song

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Y, Y,

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Y, Y,

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analogues, analogues,

inhibitor inhibitor

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S, S,

WZ, WZ,

inhibitory inhibitory

of of

Chem. Chem.

Kayahara Kayahara

Med., Med.,

Europ.]. Europ.].

dissociation dissociation

Eurasii'ı. Eurasii'ı.

new new

study study

Institute Institute

MA, MA,

and and

new new

extracts extracts

Han Han

a a

Chem., Chem.,

a a

Fan Fan

F, F,

expressions expressions

Tezuka Tezuka

a a

Terzioğlu Terzioğlu

Kim Kim

inhibitors inhibitors

Rahman Rahman

deficits deficits

Muraoka Muraoka inhibitors inhibitors

Muraoka Muraoka

Tezuka Tezuka

decline: decline:

1055-1061, 1055-1061,

rats, rats,

7th 7th

activity activity

constituents constituents

activity activity

Biochem., Biochem.,

from:green from:green

Phytomedicine, Phytomedicine,

Ohura Ohura

Y, Y,

S, S,

Res. Res.

Rhodiola Rhodiola

1, 1,

Flanta Flanta

Bangladeshi Bangladeshi

for for

LM, LM,

in in

endopeptidase endopeptidase

M, M,

endopeptidase endopeptidase

of of

drug drug

48, 48,

JH, JH,

analogues,J. analogues,J.

method method

Pakistan. Pakistan.

Y, Y,

J J

Food Food

WZ, WZ,

of of

WZ, WZ,

sachalinensis, sachalinensis,

2000. 2000.

derivatives derivatives

Kalhoro Kalhoro

Biotech. Biotech.

H.E. H.E.

Book Book

2001. 2001.

hibitors hibitors

its its

relationship relationship

BulJ., BulJ., Kim Kim

scavenging scavenging

Anjum Anjum achi, achi,

tion tion

hibitory hibitory vatum, vatum,

ities ities

A, A, Khanom Khanom

hibitory hibitory

combination), combination),

forrnularization: forrnularization: Fan Fan

Fan Fan

etylcholinesterase etylcholinesterase

peptidase peptidase

iola iola

cognitive cognitive

activity, activity,

,hibitory ,hibitory

1999. 1999. Orhan Orhan

fusion fusion

Wang Wang

crude crude

part part

Prolyl Prolyl

ricul. ricul.

Tezuka Tezuka

1996. 1996.

Saito Saito

Fan Fan

cycloalkylamide cycloalkylamide

Poststatin, Poststatin,

peptidase peptidase

Endopeptidase Endopeptidase statin statin

Poststatin, Poststatin,

prolyl prolyl

Tsuda Tsuda

mnemonic mnemonic cognitive cognitive

169, 169,

Tsuda Tsuda

idence idence

58. 58.

56. 56.

57. 57.

55. 55.

54. 54.

53. 53.

51. 51.

52. 52.

50. 50.

49. 49.

48. 48.

47. 47.

46. 46.

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to to

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the the

15-

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cul

def

rats rats

age

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pro

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1997. 1997.

of of

mem

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Yoshi

A. A.

Hash

in in

basalis basalis

Ishitani Ishitani

Hiraga Hiraga

Pharm. Pharm.

in in

2000. 2000.

the the

T, T,

1998. 1998.

Affected Affected

isolation isolation

Res._, Res._,

of of

ZTTA, ZTTA,

A, A,

antibiotic antibiotic

42, 42,

synthesis synthesis

M, M,

detay detay

M, M,

). ).

prolyl prolyl avoidance avoidance

Grellier Grellier

novel novel

1999. 1999.

Further Further

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M, M,

Torrea Torrea

2000. 2000.

sensitive sensitive

Pharmacol. Pharmacol.

S. S.

a a

Chem. Chem.

inhibitor inhibitor

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spatial spatial

cognitive cognitive

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J J

volunteers, volunteers,

slices, slices,

potential potential

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291-296, 291-296,

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47-56, 47-56,

are are

of of

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monkeys, monkeys,

neurons neurons

nucleus nucleus

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Jolles Jolles

drug, drug,

P. P.

171-174, 171-174,

on on

Salomone Salomone

active active

17-25, 17-25,

50, 50,

parallel parallel

of of

passive passive

overexpression overexpression

Med. Med.

endopeptidase endopeptidase

161, 161,

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FP, FP,

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27, 27,

the the

a a

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male male

99, 99,

potentiates potentiates

Furushiro Furushiro

Morain Morain

Chuang Chuang

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8835-8838, 8835-8838,

2002. 2002.

reaction-deprotection

cortical cortical

S, S,

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library: library:

Nishimoto Nishimoto

Watanabe Watanabe

in in

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of of

S, S,

H, H,

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neurons, neurons,

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lesions, lesions,

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K. K.

isotetracenone isotetracenone

H, H,

Morain Morain

S, S,

dehydrogenase dehydrogenase

Y, Y,

41, 41,

incorporation incorporation

Res., Res.,

prolyl prolyl

Meng Meng

RF, RF,

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Russo Russo

1999. 1999.

and and

fTP-4819, fTP-4819,

M. M.

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peptidergic peptidergic

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a a

endopeptidase endopeptidase

M, M,

E, E,

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healthy healthy

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J J

antidementia antidementia

J\IIPTP-treated J\IIPTP-treated

Tanabe Tanabe

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176-182, 176-182,

suppresses suppresses

Lett., Lett.,

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K, K,

lesions lesions

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Nutt Nutt

a a Ikeda Ikeda

Neurol. Neurol.

Shibata Shibata

systern systern

inhibitor, inhibitor,

Davioud-Charvet Davioud-Charvet

Passerini Passerini

1999. 1999.

Tanabe Tanabe

in in

.and .and

Aishita Aishita

Koshino Koshino

Shibata Shibata

C. C.

M, M,

inhibitor inhibitor

A, A,

J J

26, 26,

forebrain forebrain

D, D,

Wolf Wolf

L, L,

K, K,

Luisi Luisi

T, T,

prolyl prolyl 462-470, 462-470,

Alzheimer's disease disease Alzheimer's

F, F,

dose dose

impairment impairment

and and

K, K,

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ZTTA, ZTTA,

J, J,

T, T,

inhibitor, inhibitor,

S, S,

6-13, 6-13,

inhibitors, inhibitors,

in in

specific specific novel

novel novel

39, 39,

Behav. Behav.

1999. 1999.

of of

strategy, strategy,

the the

based based

amygdaloid amygdaloid

potential potential

Biochem. Biochem.

basal basal

Guez Guez

a a

low low

Touzani Touzani

Nakashirna Nakashirna

a a

endopeptidase.l. endopeptidase.l.

properties, properties,

nervous nervous

Giardiniere Giardiniere

a a

288, 288,

Bourel Bourel

of of

Kondo Kondo

G, G,

rat rat

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hypoxia, hypoxia,

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A, A,

Tanaka Tanaka

Y/ Y/

Tetrahedron Tetrahedron

Sunaga Sunaga

Miyazaki Miyazaki

Florio Florio

Furushiro Furushiro

cholinergic cholinergic

via via

S, S,

memory memory JS, JS,

1998. 1998.

with with

Segheraert Segheraert

1999. 1999.

Bothmer Bothmer

K, K,

in in

Prog. Prog.

SNA-8073-B, SNA-8073-B,

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apoptosis apoptosis

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endopeptidase endopeptidase

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M. M.

rats rats

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of of

2001. 2001.

migration migration

ibotenate-induced ibotenate-induced

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in in

16, 16,

biological biological

tetrahydroisoquinolin-based tetrahydroisoquinolin-based

of of

and and

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synthesis synthesis

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endopeptidase endopeptidase

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ON0-1603, ON0-1603,

a a

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7th

JS,

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1997.

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1999.

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2002.

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strychnifolia

2002.

Hwang

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2000.

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