Effects of the histamine H3 receptor ligands thioperamide and (R)-α-methylhistamine on histidine decarboxylase activity of mouse brain

Vol. 185, No. 1, 1992

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS

May 29, 1992

Pages 121-126

EFFECTS (R)-a

OF

THE

HISTAMINE

H3

-NETHYLHISTAMINE

ON

RECEPTOR

LIOANDS

HISTIDINE

THIOPERAMIDE

DECARBOXYLASE

AND

ACTIVITY

OF MOUSE B R A I N

Naruhiko Sakai,

A t s u s h i Sakurai,

~ i k o Sakurai,

hzuhiko

Yanai,

gazutaka ~aeyama,

and Takehiko f a t a n a b e

Department

of P h a r m a c o l o g y

I,

2-1 S e i r y o - m a c h i ,

Tohoku U n i v e r s i t y Aoba-ku,

Sendai

School 980,

of M e d i c i n e ,

Japan

Received April 6, 1992

The e f f e c t s of t h e h i s t a m i n e Ha r e c e p t o r l i g a n d s t h i o p e r a m i d e and ( R ) - a m e t h y l h i s t a m i n e on t h e h i s t i d i n e d e c a r b o x y l a s e (HDC) a c t i v i t y and h i s t a m i n e c o n t e n t of mouse b r a i n were e x a m i n e d . T h i o p e r a m i d e , a h i s t a m i n e H3 a n t a g o n i s t , significantly i n c r e a s e d t h e HDC a c t i v i t y i n t h e b r a i n of ddY, W/Wv and ICR mice 2-6 h r a f t e r i t s i n t r a p e r i t o n e a l (i.p.) injection. On t h e o t h e r hand, ( R ) - a methylhistamine, a h i s t a m i n e H 3 - r e c e p t o r a g o n i s t , c a u s e d no s i g n i f i c a n t change i n t h e HDC a c t i v i t y . The whole b r a i n h i s t a m i n e c o n t e n t o f ddY mice d e c r e a s e d significantly to 60-70 % of the control level 2-8 hr after injection of t h i o p e r a m i d e (25 mg/kg, i . p ) , b u t t h e n i n c r e a s e d to 90 % of t h e c o n t r o l l e v e l 10 hr after the injection. These in vivo results showed that btockade of the presynaptic histamine a3-receptor, which causes release of presynaptic hist a m i n e , i n c r e a s e d t h e HDC a c t i v i t y . ® 1992 Academic Press, Inc.

Recently,

in the

ONS h a s been e s t a b l i s h e d

receptor agonist, a l. by

has

been

(R)-a

formation

-methylhistamine

and t h e p r e s e n c e

development

of

of r a t

on t h e a c t i v i t y

E.C.4.1.1.22)

between

intrinsic

the

brain

not

histamine

or neuromodulator

the presynaptic

specific

(8).

(7,8).

However,

release

and

and

Arrang et

and d e c r e a s e d since

decarboxylase

been s t u d i e d ,

H3

antagonist

by t h i o p e r a m i d e

of h i s t i d i n e

have

of

respectively

was i n c r e a s e d

in slices

ligands

carboxylyase,

relationship

(1-6),

by t h e

and ( R ) - a - m e t h y l h i s t a m i n e ,

histamine

of H 3 - r e c e p t o r

histidine

proved

thioperamide

showed t h a t

fects

vivo

the presence of histamine as a neurotransmitter

the

ef-

(HDC, L-

the possible HDC a c t i v i t y

in is

unknown.

Abbreviation E.C. 4. 1. 1.22.

used:

HDC, h i s t i d i n e

decarboxylase,

121

L-histidine

carboxylyase,

0006-291X/92 $4.00 Copyright © 1992 by Academic Press, Inc. All rights of reproduction in any form reserved.

Vol. 185, No. 1, 1992

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS

We p r e v i o u s l y brain

histamine

by K i t a m u r a induced

et

reported

content al.

H2-receptors, injection activity

with concomitant

in the hypothalamus

in

the brain

histamine

of

we r e p o r t e d

hypothalamus.

possibly

that

content

behavior

and

(11).

strains

and

histamine

of mice,

results,

thioperamide

t h e HDC we a s -

histamine

assumption, ddY,

1 hr a f t e r

increased

of i n t r i n s i c this

thioperamide

level,

Based on t h e s e

(R)-a-methylhistamine

of ddg mice a f t e r

i.p.),

m e d i a t e d by H~ a n d / o r

thioperamide

To c o n f i r m

of t h r e e

thioperamide

on t h e

and 25 mg/kg,

in the brain

of W/W ~ mice

in the brain

injections

(12.5

of a mechanism for up-regulation

the posterior

t h e HDC a c t i v i t y after

thioperamide

of t h e mice,

decrease

Subsequently,

sumed t h e e x i s t e n c e thesis

activity

of

which were shown t o be m a s t - c e l l - d e f i c i e n t

At lower d o s e s

locomotor

(10).

effects

of W/W~ mice,

(9):

increased

the

syn-

we m e a s u r e d

W/Wv and ICR mice, and a l s o

measured

injection.

MATERIALS AND METHODS A n i m a l s and Drug T r e a t m e n t Male ddY, W/W~ and ICR mice of 5 weeks o l d w e r e p u r c h a s e d from Funabashi Farm ( F u n a b a s h i , Chiba, J a p a n ) . They were h o u s e d a t a c o n s t a n t t e m p e r a t u r e of 22 + 2 °C w i t h c o n t r o l l e d lighting ( 7 : 0 0 - 1 9 : 0 0 ) and had f r e e a c c e s s to food and water. T h i o p e r a m i d e was d i s s o l v e d in 1 M ~Cl, d i l u t e d and a d j u s t e d to pH 7 w i t h sodium b i c a r b o n a t e , while (R)-~-methylhistamine was d i s s o l v e d in s a l i n e . These d r u g s were i n j e c t e d i n t r a p e r i t o n e a l l y (i.p.) during light period. At t h e i n d i c a t e d t i m e s , mice were k i l l e d by d e c a p i t a t i o n and t h e i r brains were quickly removed and s t o r e d a t -80°C u n t i l use.

M e a s u r e m e n t oJ_f HDC A c t i v i t y o f Mouse B r a i n The HDC a c t i v i t y of mouse brain was{easured-as d e s c r i b e d by W a t a n a b e e t al. (12). Briefly, b r a i n s were h o m o g e n i z e d in 10 v o l u m e s o f HDO s o l u t i o n [100 mM p o t a s s i u m phosphate, pH 6 . 8 , 0 . 2 mM d i t h i o t h r e i t o l , 0.01 mM p y r i d o x a l 5 ' phosphate, 1% polyethyleneglycol ( a v e r a g e m o l e c u l a r w e i g h t 300) and 100 Z g/ml phenylmethanesulfonylfluoride] in a Polytron homogenizer (Kinematica, Lucern, Switzerland) a t a maximum s e t t i n g f o r two 1 0 - s e e p e r i o d s i n an i c e b a t h . The h o m o g e n a t e was c e n t r i f u g e d a t 1 0 , 0 0 0 x g f o r 30 min and t h e s u p e r n a t a n t was d i a l y z e d a g a i n s t ~DC s o l u t i o n o v e r n i g h t . The HDC r e a c t i o n was s t a r t e d by a d d i n g 0 . 5 mM L - h i s t i d i n e (final concentration) and a f t e r 4 h r t h e h i s t a m i n e p r o d u c e d was m e a s u r e d by t h e H P L e - f l u o r e s c e n c e m e t h o d d e s c r i b e d by Y a m a t o a d a n i e t a t . (13). S h o r t l y , h i s t a m i n e was s e p a r a t e d by t h e HPLC s y s t e m , p o s t l a b e l l e d with ophthalaldehyde and d e t e c t e d fluorometrically w i t h an F S - 8 0 1 0 f l u o r o m e t e r (Tosoh, Tokyo, J a p a n ) u s i n g e x c i t a t i o n and e m i s s i o n w a v e l e n g t h s o f 360 and 450 nm, r e s p e c t i v e l y . M e a s u r e m e n t of H i s t a m i n e C o n t e n t of Mouse B r a i n B r a i n s were h o m o g e n i z e d in 2.6 ml of 3 % p e r c h l o r i c acid containing 5 mM BDTA-Na2 i n a P o l y t r o n , and t h e h o m o g e n a t e was c e n t r i f u g e d a t 1 2 , 0 0 0 x g f o r 20 min. The h i s t a m i n e in t h e r e s u l t i n g s u p e r n a t n a t was t h e n m e a s u r e d by t h e HPLCfluorescence

method as d e s c r i b e d

above.

122

Vol. 185, No. 1, 1992

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS

Statistics Data were a n a l y z e d by S t u d e n t ' s

L-test

and v a l u e s o f P < 0 . 0 5

were t a k e n

as

significant.

KESOLTS

Effect

o f H3-Ligands on t h e HDC A c t i v i t y

As shown in Fig. creased after

1A and B,

t h e HDC a c t i v i t y

its

hr

after

treatment,

of

ICR mice 6 h r s a f t e r

contrary,

of

thioperamide

nifieantly sistent

Effect

and t h i s

rhioperamide its

(data (6.25,

increased

with

previous

not 12.5

in b o t h

activity

increased at

respectively,

persisted

until

t h e HDC a c t i v i t y

effect

As shown in T a b l e

25 m g / k g ,

the cortex

significantly

in

at

i.p.)

the

1,

on t h e

in2 hr

least

the

6

brain

25 mg/kg ( d a t a not shown).

had no s i g n i f i c a n t

and

i.p.)

of ddY and W/W ~ mice,

also

shown).

results

(25 mg/kg,

increased

administration

(R)-a -methylhistamine

o f ddY mouse b r a i n

thioperamide

in t h e b r a i n

administration,

of Mouse B r a i n

On t h e

HDC a c t i v i t y

3 hr a f t e r

HDC a c t i v i t y

injection was

sig-

and m i d b r a i n of ddY and W/W" mice,

con-

(11).

of H3-Ligands on t h e H i s t a m i n e C o n t e n t o f Mouse B r a i n

As shown in Fig. nificantly

deereased

2, 2 hr

t h e whole b r a i n after

histamine

injection

!A

o

of

~

content

thioperamide

o f ddY mice was s i g (25

mg/kg,

i.p.),

B

1.0

~0.8

~0.8

o - 6 t U

0.6 .o

oJ 0.4 Q

0.4

¢= =5 ;= :r 0.2

,1-

0.2

<3 I <3

i

0 Time After Administration (hr)

Time After Administration (hr)

Fig. i. Time course of i n c r e a s e in HDC a c t i v i t y induced by thioperamide, ddY (k) and W/W~ (B) mice were t r e a t e d i . p . with 25 mg/kg of t h i o p e r a m i d e and k i l l e d by d e c a p i t a t i o n at the i n d i c a t e d t i m e s . T h e i r b r a i n s were q u i c k l y taken out and HDC a c t i v i t y was measured as d e s c r i b e d in M a t e r i a l s and Methods. *P< 0.05. 123

V o l . 185, No. 1, 1992

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS

Table

1.

HDC a c t i v i t y treated

Strain

ddy

Region

with

in

the

Dose of t h i o p e r a m i d e (mg)

Cortex

0.0

0.838 + 0.029"

0.0 6.25

0.607 ± 0.101 0.665 + 0.056 0.664 + 0.094

12.5 W/W v

Cortex Midbrain

Mice were i n j e c t e d by d e c a p i t a t i o n

i.p.

3 hr

HDC a c t i v i t y (pmol / mi n/ mg p r o t . )

0.264 + 0.040

12.5 Midbrain

of mice

0.216 L 0.016

6.25 ddy

brain

thioperamide

25

0.953 + 0.075"

0.0 25 0.0 25

0.390 0.414 0.559 0.832

with saline

later.

± + + +

0.059 0.084 0.056 0.321"

or t h i o p e r a m i d e and k i l l e d

Their brains

were q u i c k l y t a k e n

out and HDC a c t i v i t y was measured as d e s c r i b e d and Methods. " P < 0 . 0 5 , n= 4.

in M a t e r i a l s

500

400

8

._~

300

J

._~ "I" .~

200

In

© ©I IO0

2 4 6 8 10 Time After Administration (hr)

Fig. 2. Time c o u r s e of c h a n g e s i n b r a i n h i s t a m i n e c o n t e n t of ddg mice a f t e r thioperamide injection, ddY m i c e w e r e t r e a t e d i.p. w i t h 25 m g / k g o f thioperamide and k i l l e d by d e c a p i t a t i o n a t t h e i n d i c a t e d t i m e s . B r a i n s were q u i c k l y t a k e n out and h i s t a m i n e c o n t e n t was m e a s u r e d as d e s c r i b e d in M a t e r i a l s and Methods.

"P<

0.05.

124

Vol. 185, No. 1, 1992 remained

at

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS

a reduced

level

until

8 hr

after

t o 90 % of t h e c o n t r o l

level

after

10 hr.

the

injection,

and t h e n

increased

DISCUSSION Intrinsic

Its

release

histamine

is highly

is

controlled

a histamine-synthesizing the

posterior

thought

few r e p o r t s

histamine

(14).

presynapses,

in t h e b r a i n

neuron system

(10,11).

that

histamine

content

that

histamine

the

activity minals

after

after

that

histamine

in

caused

after

and t h e n i0

thesis.

the

this

release

of

is

work,

Our ' r e s u l t s

level

the

of be-

(20,21).

release

from

and i t s

meta-

histaminergic

thioperamide

that

to

histamine

levels

(Sakai

a small

the

showed a c l o s e

in HDC a c t i v i t y

t h e amount of h i s t a m i n e

level

induced released

related

relationship

aI.,

spite

was slow, of

the

submitted

with

up-

injec-

c a u s e d marked i n t o Eur.

i n HDC a c t i v i t y

after with

in

our

assay

thioperamide intrinsic

between

was s y n t h e s i z e d

125

it

by

in p r e s y n a p s e s .

of the brain

although

of The

(R)-a -methylhistamine

by t h i o p e r a m i d e :

e n h a n c e m e n t of HDC a c t i v i t y .

increased. may be c a u s e d

of histamine

in

ter-

J.

Phar-

the

brain

system,

would be i n t e r e s t i n g .

HDC a c t i v i t y is

HDC

histamine

gradually

of the

the brain

would n o t be d e t e c t e d

release

t o 90 % of

in

continued

decrease

of HDC mRNA l e v e l

we s t u d i e d

et

We that

histamine

content

by t h i o p e r m i d e

that

injection.

to 60-70 % o f

administration

On t h e c o n t r a r y ,

of

the

HDC a c t i v i t y

by d e c r e a s e

strains

enhancement of brain

replenish

injection,

t h e HDC

the change in the

was r e s t o r e d the

of W/W"

of

two o t h e r

decreased

c h a n g e in HDC a c t i v i t y ,

possibe

in

after

but

activity

and i n c r e a s e

we f o l l o w e d

of t h e h i s t a m i n e

induced

whether histamine

and i n c r e a s e

by

are only a

and s y n t h e s i s

study,

thioperamide

triggered

the recovery

brain

was

the brain

hr a f t e r

on c h a n g e i n l e v e l

In

(I-3).

nucleus

there

of h i s t a m i n e

confirmed

we assumed

t h e HDC a c t i v i t y ,

As i t

determine

replenished

the locomotor

injection,

thioperamide

by ( R ) - a - m e t h y l h i s t a m i n e

studies

drug,

Thus,

c a u s e d no s i g n i f i c a n t

crease

is

but

activity

increased

were

thioperamide

of HDC a c t i v i t y

because

macol.).

levels

the

period

release.

experiment,

tlon

release

of t h e b r a i n

injection

In t h i s

of

a long

presynaptic

histamine

up-regulation

regulation

(15-19),

the histamine

content

10 hr.

ddY mice d e c r e a s e d , of

of

thioperamide its

We f o u n d

increase

the

In t h e p r e s e n t

for

6 hr a f t e r

after

thioperamide

study.

found

level

CN$

h a v e shown a r e l a t i o n s h i p

rhythm

and m o d i f y i n g

decrease

brain

control

it

the

in t h e t u b e r o m a m m i l l a r y

reports

affecting

These observations

mice in the present

for

and

in

(7,8).

concomitant

controls

(4-8)

role

h a s b e e n f o u n d to e n h a n c e h i s t a m i n e

thus

(22,23)

We h a v e r e p o r t e d with

important

between histamine

an H 3 - a n t a g o n i s t ,

activity

Several

on t h e r e l a t i o n s h i p

histaminergic

mice

HDC, p r e s e n t

and t h e c i r c a d i a n

Thioperamide,

bolites

an

by H 3 - r e c e p t o r s

enzyme,

hypothalamus

tween i n t r i n s i c

to have

injection

histamine

decrease

to syn-

in histamine

after

injection

within

10 hr owing t o t h e

of

this

Vol. 185, No. 1, 1992

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS

ACKNOWLEDGMENTS

We thank the Sumitomo Pharmaceutical Co., Osaka, Japan, for g e n e r o u s l y supp l y i n g t h i o p e r a m i d e and ( R ) - a - m e t h y l h i s t a m i n e and Mr. h. Umezu for help in experiments. This work was p a r t l y supported by G r a n t s - i n - A i d from the Japanese M i n i s t r y of Education, Science and C u l t u r e (#63065004), C h i b a - G e i g y R e s e a r c h F o u n d a t i o n and Suzuken Research Foundation.

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