Electroencephalographic changes induced by some inhibitors of prostaglandin synthetase in the rat

NeuropharmacoZogy,

16,

1977,

873-875.

Pergamon Press. Printed in Great Britain PRELIMINARY NOTES

ELECTROENCEPHALOGRAPHIC INHIBITORS

M.

OF

Avoli,

Cattedra

M.

CHANGES

PROSTAGLANDIN

Deodati,

di Tecnica

F.

Eusebi,

Fisiologica

well

delle

00100

Roma,

6

Aspirin,

as inhibitors

paracetamol

evoked

which pattern

(PGs)

and Horton,

(Feldberg intake

according

1974).

to the route

The

1968;

Horton,

1964;

changes

in the discharge

Purkinje

cells

This

evidence

effector

cells

synaptic

suggests

a role

in response

sedative-

a desynchronization

the central fluid,

nervous

where

state only

1971;

challenge

(i.e.

during

cortex,

idea is that

varying

injections, effect

while

(Holmes

studies

and

have

stem neurones

and Wolstencroft,

these substances

neurotransmitters)

of food

its intensity

in brain

Bradley

fever

effects,

to regulation

microiontophoretic

Avanzino,

A current

of PGs as modulators.

functions

from intraventricular

in the cerebral

and Bloom,

augments

ranges from behavioural

sedative-tranquillizer

In addition

1976).

level

by means of PGE,

results a mild

system both in tissue

PGE

and motor-control is obtained

produces

Hoffer

of the activity

to regulate

and 1966).

are formed

by

or curtail

the

nervous

system,

process.

The multi-enzyme and although known

actions

A stuporous

to an appropriate

is able to produce

of these compounds

rate of neurones

(Siggins,

the 3rd ventricle

during

throughout

and Morley,

in cerebellar

into

this activity.

sedation

injected,

demonstrated

have been studied.

which

of action

species,

Nistico

by some substances,

and in many cases an epileptic

cerebrospinal

cardiovascular

of administration.

induced

synthetase,

injected

attenuated

spectrum

In several

parenterally

(PG)

PGET

present

di Roma,

1977)

intraventricularly

and in mammalian

1972).

the same compound, Horton,

by aspirin,

of body temperature,

(Coceani,

injected

are diffusely

1968)

and Gupta,

regulation

minutes.

effects,

induced

Prostaglandins (Holmes

for several

lasted

tranquilizer

Studi

Barra

Italy

changes

pattern

RAT

ond P.F.A.

degli

stpambm

and phenoprophen, EEG

THE

Scienze,

of prostaglandin

an excitatory

BY SOME

IN

Picardo

dell’Universita

Electroencephalographic

known

rot,’

M.

Piazzale

(Accepted

SUMMARY:

INDUCED

SYNTHETASE

(Flower

and Vane,

The purpose injected

into

on cardiac

complex,

the component

1972;

as “PG

are not well

Flower,

of the present

the 3rd cerebral

rate.

referred

enzymes

synthetase”,

located

many inhibitors

in centml of “PG

synthetase”

are

1974).

study was to determine

ventricle

In most cases rectal

is also

determined,

of rats,

the effects

of scme inhibitors

on the electroencephalogmphic

temperature

of “PG

activity

synthetase”,

and,

secondarily,

was measured. METHODS

Each mt (Wistar, gallamine

200-250

and artificially

ear bars.

Screw

electrodes

the second at a point on the same side 3-4 by stereotaxic electrode The were:

properties). diluted

All

control

injected

the reticular

was started

animals

ether

the first

procedures

formation

except

to pH 7.4. 20 min.

over

immobilized

with

the wound areas and stereotoxic

the nasal bone (reference

and 3 mm anterior a steel

needle

cr in the caudate

electrode),

to the bregma, electrode

the third

was introduced

The subcortical

nucleus.

histologically. by stereotaxic

and phenoprophen indomethacin, The activity before

for tracheothomy, around

Furthermore,

intraventricularly

indomethacin

and buffered

graph and recording ally,

to the bregma.

in either

the compounds,

in tyrode

were fixed:

in most cases was checked

paracetamol,

with

was infi I trated

3 mm to one side of the midline

mm posterior

compounds,

aspirin,

Novocaine

for recording

located

techniques

placement

g) was anaesthetized

respired.

which

cannula

(the volume

(a new molecule was dissolved

was recorded

the drug injection

for

with

being always

lC+.rl),

antiphlogistic

in ethyl

alcohol

(SO”),

were

on a conventional

electroencephalo-

the following

hours.

2-3

Occasion-

were performed. RESULTS

Aspirin, activity

injected

changes,

intraventricularly

not directly

related

in

15 rats in a dose of 0.5-2.5

to the dose.

The

873

electrocortical

mg., trace

caused electracortical showed,

in all

animals,

an

a74

Preliminary

Notes

excitation pattern, i.e. low voltage and high frequency, but never before 8 min. In 9 rats excitation reached highest effect after 25-40 min., giving rise to typical seizure activity (Fig. 1A). In 7 rats the cardiac rate was reduced by 20% simultaneously with the maximum cortical effect. The reticular formation was more activated than cortex. Paracetamol (bacetamidophenol) was tested in 10 rats in dose of lo-50 pg. An activation pattern but epileptic activity was never was elicited only by doses over 20 pg., 18-29 min after the injection, reached (Fig. 1 B). 3 animals showed a reduction in cardiac rate of 30% after 25 min. Phenoprophen was tested in 9 rats in a dose of 5-25 ug. and always caused a desynchronization pattern. Epileptic activity was observed in 4 rats (Fig. 2);24-38 min.‘after the injection. The cardiac rate was diminished

.c E

only in 2 trials.

A

C

B

120

T

90

60

I 30

I’ 0.5

1 ld

I 25

mg

L

I

20

35

50

L i.4

5

15

25

be4

Figure 1. Diagram of EEG changes induced by the drugs tested. A: aspirin; B: paracetamol; C: phenoprophen. Thin line: low voltage-high frequency activity (desynchronization pattern); The delay in the onset of the evoked activity is recognizable in thick line: epileptic activity. every trial. Although it was difficult to distinguish the action of indomethacin, owing to the masking effects of the solvent (see Methods), nevertheless an activation pattern of cortical trace and epileptic fits, 30-35 min. after the injection, was observed in 3 rats. The delayed action, noted in other trials, suggests that a direct action of this well known inhibitor

of “PG synthetase” is most likely.

Figure 2. Seizure activity induced by phenoprophen (20 pg), A: before; B: 35 min. after the drug injection; C: 90 min. later. F: frontal; P: parietal; CN: caudate nucleus.

875

Preliminary Notes

In addition,

the effect of PGET and aspirin,

the same experiment.

both injected intraventricularly, were assayed during in sedative dose (10 pg) in 3 rats before aspirin (2 mg.) and in

PGET, administered

other 2 rats after, attenuated the desynchronization pattern very similarly in all animals. Temperature values did not show meaningful changes, however, when PGE, were used, an increase in rectal temperature, which lasted for several minutes, was observed 12-16 min. after the PGEi injection (+0.83 I! 0.08). DISCUSSION The delayed effect, (always more than 15 min.) observed during these trials, suggests that the EEG patterns induced by the antiphlogistic drugs tested are due to an inhibition of “PG synthetase”, not to Furthermore, the attenuation of the aspirin-activity by the a direct action on neuronal behaviour. injection of PGE emphasises the role of PG in the mammalian CNS, so that “PG synthetase” depression causes an increase of bioelectric activity with the ultimate appearance of a generalized epileptic pattern. Differences in the results (i.e. dose-effect independence) can be ascribed to the variable PG level present in each rat (i.e. PG biosynthesis depending mainly on: neuronal activity, endogenous substrate and biogene amine level) (Coceani, 1974), as well as to the conditions for the “PG synthetase” inhibitor action

(e.g. tissue pH) (Flower, 1974). It is the purpose of this study to enlarge this first set of data to correlate

with temperature

in detail

EEG patterns

changes. ACKNOWLEDGEMENTS

The authors thank Professor A.

Brancati for helpful suggestions and constructive

criticism.

REFERENCES AVANZINO,

G.L.,

BRADLEY,

P.B.

and WOLSTENCROFT,

ET, E2 and F2, on brain stem neurones. COCEANI,

F. (1974).

J.F.

Br.J.Pharmacol.

Prostaglandins and the Central

(1966).

Actions of prostaglandins

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Nervous System.

Arch.

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Med.

-133:

119-129. FELDBERG, W. and GUPTA, K.P. (1972). Pyrogen fever and prostaglandin fluid. J. Physiol., Lond. -228: 41-53. FLOWER,

R.J.

and VANE,

anti-pyretic FLOWER,

activity

R. J. (1974).

J.R.

(1972).

Inhibition

of paracetamol

of prostaglandin

(4-acetamidophenol).

Drugs which inhibit

prostaglandin

like activity

in cerebrospinal

synthetase in brain explains the

Nature

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-240: 410-411. Pharmacol.

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E.W. (1968). Prostaglandins and the Central Nervous System. In: HOLMES, S.W. and HORTON, Worcester Symposium on Prostaglandins (Rampwell, P.W. and Shaw, J.E., Eds.), pp. 21-36. John Wiley and Sons Inc., New York. HORTON, E.W. (1964). Actions of prostaglandins Br. J. Pharmacol. -22: 189-192. NISTICO, fowls.

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and MARLEY,

E. (1976).

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SIGGINS, G., HOFFER, B. and BLOOM, F. (1971). Prostaglandin-norepinephrine brain: Microelectrophoretic and histochemical correlates. Ann. N.Y. Acad.

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