Pre-clinical evaluation of cognition enhancing drugs

Prog. Neuro-Psychophormacol. & Biol. Psychiot. Printed in Great Britain. All rights reserved

PRE-CLINICAL

1989. Vol. 13. pp. S993115 0

EVALUATION OF COGNITION DRUGS

0278-5846189 $0.00 + 50 1989 Pergamon Press pk

ENHANCING

URSULA SCHINDLBR Department of CNS Pharmacology, Cassella AG, Frankfurt, Federal Republic of Germany (Final form, February, 1989) Contents 1.

2. 3. 3.1. 3.2. 3.2.1. 3.2.2. 3.2.3. 3.2.4. 3.2.5. 3.2.6. 4. 5. 6.

Abstract Introduction Cognition Enhancers: A Single Class of Compounds? Learning and Memory Facilitation of Learning and Memory Experimentally-Induced Cognitive Impairment Scopolamine Amnesia Iiemicholinium-3 Amnesia ECS Amnesia Cycloheximide Amnesia Ischemia-Induced Amnesia Chronic Cerebral Impairment Electrophysiology Brain Metabolism Conclusions References

s99 s100

SlOO s103 s103 s104 s104 S108 S108 S108 s109 SllO Sill Sill Sill s112

Abstract Schindler, Ursula: Pre-Clinical Evaluation of Cognition Enhancing & Biol. Psychiat. 1989, Drugs. Prog. Neuro-Psychopharmacol. 13 (suppl.):s99-s115 1.

2.

3.

The need of the treatment of cognitive impairment due to aging or dementia has led to the search for potential cognition enhancing drugs. The various compounds presently under development represent an alternative to the cholinomimetic therapy and include new chemical entities as well as piracetam and its newer analogs. Recent results from pre-clinical evaluation of the effects on learning on memory are summarized. Emphasis is put on learning and memory experiments under normal and pathological conditions. Most of the nootropics attenuate experimental amnesias induced by scopolamine, cycloheximide, ECS, hemicholinium-3 or forebrain ischemia. These findings suggest that the nootropics may be influencing a common mechanism underlying the amnesias. Biochemical data suggest a potential cholinergic neuronal activity

Dedicated to Prof. Dr. rer.nat. Hansgeorg Gareis on the occasion of his 60th birthday

s99

U.Schindler

SlOO

4.

of some of the piracetam analogs. They increase high-affinity choline uptake, and antagonize scopolamine- and ECS-induced decreases in acetylcholine concentrations in the hippocampus. The mode of action of these and all other nootropic compounds, however, is still not known. Despite the interesting results from learning and memory studies and from biochemical investigations, the clinical relevance of these results for amelioration of the cognitive impairment in humans remains to be proven for most of the compounds.

Kevwords: acetylcholine, ACTH-analogs, amnesia, animal models, aniracetam, bifemelane, idebenone, indeloxazine, learning and memory, minaprine, nootropics, oxiracetam, piracetam, pramiracetam, rolziracetam, tenilsetam, vinpocetine Abbreviations: Acetylcholine (ACh), Cholecystokinin octapeptide (CCK-8), Electroconvulsive shock (ECS), Hemicholinium-3 (HC-3), local cerebral metabolic rate of glucose (lCHMGlu), Long Evans (LE), methylazoxymethanol (MAM), N-methyl-d-aspartate (NMDA), guinuclidinyl benzilate (QNB), sodium dependent high affinity choline uptake (HACU), Sprague Dawley (SD) 1. Introduction The growing incidence of people with impaired cognition such as in Alzheimer's disease has spurred the search for compounds alleviating the deleterious symptoms.

The problem underlying the therapeutic strate-

gies for Alzheimer's patients has recently been reviewed by Hollister (1986).

Since more than 10 years the 'cholinergic hypothesis of geria-

tric memory dysfunction' has directed most of the work and therapeutic strategies towards the alterations of the cholinergic system.

However,

in Alzheimer's disease not only a degeneration of the cholinergic system but also deficits in noradrenergic, and serotonergic transmission

(Palmer

et al., 1987) as well as changes in the immunoreactivity of the neuropeptides somatostatin and corticotropin releasing factor have been reported (Beal et al., 1986; Whitehouse et al., 1987).

Last but not

least an imbalance in excitatory amino acid transmission in the early state of the disease has been discussed (Maragos et al., 1987). In the present paper the interest will be focused on the recent advances in the search for an alternative to the cholinomimetic therapy: that is on a group of compounds termed cognition enhancers.

These drugs,

also named nootropics, are thought to alleviate the symptoms of memory loss in patients suffering from dementia. 2. Coanition Activators: A Sinsle Class of Comvounds? A variety of cognition enhancing drugs are currently under

Pharmacology

of cognition

enhancing

Pyrrolidinone

SlOl

drugs

derivatives

0

4

-H

Piracetam NH2

Oxiracetam

-OH NH2 0 -H

Pramiracetam

4

NHwNxCH

4

-H

FH (CH31 2

0.

’:

(CH312

CH3

Aniracetam

0

WEB -CH2-NH2

Fig

1.

Chemical

Piracetam

was

structures

the prototype

of 2-pyrrolidinone compound.

derivatives.

1881

S102

U. Schindler

N

$3 k

0

Tenilsetam

(CAS

997)

0

Rolziracetam

(Cl 911)

0

A c1

0

0\Np3 . ‘CH3

Meclofenoxate

Minaprine

Bifemelane

-u

,-,

lndeloxazine

(MCI 2016)

(YM 08054)

0 CH30 CH20H

ldebenone

(CV 2619 1

CH30 0

Fig 2.

Chemical structures of new cognition enhancing drugs, showing

interesting pharmacological profiles.

Pharmacology

of cognition

enhancing

investigation in research laboratories. prototype nootropic piracetam

drugs

s103

Following the development of the

(Giurgea and Salama, 1977), new pyrroli-

dinone derivatives were synthetized and pharmacologically characterized (Fig.

1).

Their common feature include a) enhancing of learning, b)

alleviation of impaired learning and memory, c) protection against brain insults, and d) low toxicity.

They were mostly devoid of specific

psychopharmacologial effects.

In recent years additional compounds were

developed that showed interesting cognition enhancing effects but differed chemically from the pyrrolidinone structures (Fig.

2). When reviewing pharmacological profiles of cognition enhancers, also those drugs will be included, which are currently under development only in

Japan (bifemelane, idebenone, indeloxazine). Table 1 Summary of Behavioral Methods Used to Measure Drug Effects on Cognition

BEHAVIORAL METHODS Facilitation of learnina and memorv in vounu and old animals Passive avoidance Active avoidance Radial maze Exoerimentallv-induced

coanitive imoairment bv

Scopolamine Hemicholinium-3 Electroconvulsive shock Cycloheximide Ischemia, Hypoxia Chronic cerebral impairment

3. Learnina and Memorv Memory in animals reflects under experimental conditions changes in behavior which can be observed between the presentation of an information and the recall of the information.

Animal models of cognition are

therefore necessarily investigating behavioral parameters.

The behavioral measurements to evaluate the beneficial effects of drugs on memory or cognitive dysfunction include passive avoidance, active avoidance as well as maze learning tasks (Table 1). 3.1.

Facilitation of Learnins and Memory

Retention of a passive avoidance task, in which the animal is

LJ.Schindler

s104

punished

for performing

administrations (5x 100 mg/kg, in 18 months

old rats

Pretreating

mice

(Yamamoto

(Pontecorvo to a small

in rhesus

motivated

rats

memory

in rats

and monkeys

group

shown

P or vasopressin

Scooolamine and Leavitt learning

rise to the assumes demented Thereafter

investigation.

learning

in

p.o.) in monkeys

nootropic, ability

of a visual Chronic

treatment

on spatial

et al.,

2766

Hoe

427

with

of radial

learning

improved

maze

and

short-term

1984). of memory

storage,

in passive

ORG

enhanced

in a delayed discrimination

the acquisition

Rolziracetam

Cosnitive

Amnesia. (1974),

has

avoidance

(van Riezen

tasks.

and Rigter,

(Hock et al.,

1988),

substance

The basic

hypothesis

model

a potential

Imoairment findings

of

that the anti-muscarinic performance

deficits

are mainly

in young

of geriatric observed

amnesia

effect

cholinergic

avoidance

in

functioning.

has widely

model

gave

which

and

of the compounds

of the animal

in passive

scopolamine,

volunteers

dysfunction#,

of scopolamine-amnesia cholinergic

drug,

human

in aged humans

due to a deficient

Due to the simplicity

of scopolamine-induced

mice

Indeloxazine

performance

1983).

performance

analog

and memory

the animal

to investigate

1985).

another

the modulators

fragment

the cognitive

patients

or

to this group.

'cholinergic

that

i.p.)

avoidance

memory

an effect

(Marriott

Experimentally-Induced

impairs

testing

in normal

(25 mg/kg

learning

et al.,

1986).

fragment

belong

aniracetam

i.p.) enhanced

retest

such as the ACTH

et al.,

of active

improved

of compounds,

to facilitate

or the ACTH

3.2.1.

(18 to 30 mg/kg

(25,50 mg/kg

short-term

indicating

and Fibiger,

Drachman

effective

retention

acquisition

Pramiracetam,

(Poschel

(7.5, 15 mg/kg

in intact

Another

task

in rats and

monkeys

(Sansone

extent

(Murray

3.2.

before

matching-to-sample

1985).

memory

1978),

was also

1987).

significant

task

pramiracetam

Peptides

by multiple

ip) or piracetam

Vinpocetine

avoidance

acquisition

of delayed

and Evans, but

alternation

been

1985).

oxiracetam

training

and Shimizu,

accuracy

behavior

Aniracetam

administered

improved

facilitated

In an appetitively

task

i.p.)

to shuttle-box i.p.)

improved

et al.,

for 5 days with

(100 mg/kg

subjected

rats

(Yamada

old rats.

in rats when

to be enhanced

(5x 30 or 50 mg/kg,

1987).

piracetam

(2 mg/kg

was shown

aniracetam

ip) in 2 months

p.o.) was effective (DeNoble,

a response,

of either

been

used

under

the antagonism

learning

was chosen.

Pharmacology of cognitionenhancing drugs

In most

of the

investigations

scopolamine

s105

(0.6 to 3 mg/kg i.p.

or s.c.)

was administered either shortly before or shortly after the passive avoidance trial (step-through or step-down). Retention of acquisition was measured either 30 min or 45 min after training

(short-term reten-

tion) or several hours (up to 24 hr) after training. Table 2 summarizes those cognition enhancers that were shown to antagonize a scopolamine-induced amnesia.

Figure 3 shows the results

obtained with one of the new nootropics on short-term retention impairment by scopolamine.

';;‘ 250 : V 2\ 6 w0 -

200 150

Jz F

100

2 5 a

50

s VI

0

Tenilsetam I-

Scopolamine

(mg/kg

(1 mg/kg

s.c.) i.p.) _I

Saline

Fig 3. Tenilsetam leads to a dose-dependent attenuation of scopolamine-induced impairment of short-term retention in mice. Tenilsetam was administered S.C. 30 min before scopolamine (1 mg/kg i.p.) and 75 min prior to a step-through passive avoidance training (foot shock: 0.7 mA, 1 set). Retention was tested 30 min later. * = p< 0.05 (Student-Newman-Keuls test). The potent antagonism of the scopolamine-induced amnesia by cognition enhancing drugs raised the question whether or not these effects are due to an interference with the cholinergic system of the brain.

Up to now, none of the above mentioned nootropics showed any

specific affinity for muscarinic cholinergic receptors in brain synaptosomes in vitro.

However, slight effects of aniracetam or

piracetam on muscarinic receptor binding could be observed after in vivo administration.

Repeated administration of aniracetam to rats

slightly reduced 3H-QNB-binding in hippocampus, the decrease being

S106

U.Schindler

Table 2 Compounds Attenuating Scopolamine-Induced Amnesia for a Passive Avoidance Task in Mice and Rats.

Drug

Dose mg/kg

Administration Species before / after training

Reference

Short-term retention Aniracetam

100

p.0.

before

Rat

Oxiracetam

50-100

i.p.

before

Rat

WEB 1881-FD

10-100

p.0.

after

Spignoli and Pepeu 1987 Spignoli and Pepeu 1987 Kuhn et al. 1988

Tenilsetar.

3- 30

p.0.

before

mouse

Schindler et al. 1988

3- 30 50-100

p.0. p.0. p-0.

before before after

rat mouse mouse

DeNoble et al. 1986 Schindler et al. 1984 Cumin et al. 1982

Piracetam

62-250 1000

p.0. p.0.

before after

mouse

Schindler et al. 1984 Tobe et al. 1985

Bifemelane

25-100

p.0.

after

mouse

Tobe et al. 1985

Indeloxazine

4

i.p.

before

rat

Hydergine

1

i.p.

before

rat

Yamamoto and Shimizu 1987 DeNoble et al. 1986

200-300 7- 21

p.0. i.p.

before before

rat mouse

DeNoble et al. 1986 Groo et al. 1987

6-100 30-100

p.0. i.p.

before after

mouse mouse

Schindler et al. 1984 Rush and Streit 1987

Lons-term retention Aniracetam

Vinpocetine Tenilsetam

100

Hoe 427

0.001-0.003

S.C.

before

mouse

Hock et al. 1988

CCK-8

0.005-0.050

i.p.

before

rat

Itoh et al. 1988

significant in the dentate gyrus (Nakajima et al., 1986). Chronic treatment with piracetam, increased the m-cholinoceptor density in brains of aged rats (Pilch and Mueller, 1988). Further biochemical investigations showed that both aniracetam and oxiracetam attenuated the scopolamine-induced decrease in hippocampal

Pharmacology of cognition enhancing drugs

and cerebral cortical acetylcholine concentrations

307

(Spignoli and Pepeu,

1987) whereas both compounds did not change the ACh steady state levels. Bifemelane also antagonized the scopolamine- induced acetylcholine decrease in cerebral cortex, although at a dose which induced an increase in ACh concentration by itself (Saito et al., 1985). Piracetam attenuated the scopolamine-induced depression of regional cerebral glucose utilization (Piercey et al., 1987). The high affinity uptake of choline (HACU) in hippocampal synaptosomes was shown to be increased by piracetam and piracetamderivatives

(Table 3).

Aniracetam (50, 200 mg/kg p.o.) significantly antagonized the scopolamine-induced increase in sodium-dependent high-affinity choline uptake in hippocampal synaptosomes (Yoshizaki and Okada, 1986). Table 3 Ex vivo Effect of Cognition Enhancers on High Affinity Choline Uptake in Rat Hippocampal Synaptosomes Drug

Aniracetam Piracetam

Dose mg/kg

Effect

Strain

Reference

10-200 po 3-100 ip

no effect increase

LE

Shih and Pugsley 1985 Sethy 1983

100-500 ip 3-100 ip 300 ip

no effect increase increase

SD Wistar

Shih and Pugsley 1985 Sethy 1983 Pedata et al. 1984

SD LE

Pramiracetam

44- 88 ip

increase

LE

Pugsley et al. 1983

Oxiracetam

100 ip 300 ip 13x100 ip

no effect increase increase

Wistar Wistar Wistar

Spignoli et al. 1986 Pedata et al. 1984 Spignoli et al. 1986

Meclofenoxate

lo-100 ip

decrease

LE

Shih and Pugsley 1985

Minaprine Tenilsetam

30

ip

no effect

100 ip

no effect

Garattini et al. 1984 Wistar

Htway et al. unpublished

These data suggest that some of the compounds may exert their scopolamine-antagonism through an indirect interference with the cholinergic system.

However, the anti-amnestic effects of the compounds

U. Schindler

S108

could

also be the result

transmitter 3.2.2.

Hemicholinium-3

a deficient

cholinergic

cerebroventricular to a depletion increase

with

shock

effect

may,

Biochemical

findings

hippocampal tested

ACh

synthesis

for a passive aniracetam Streit,

and piracetam

1987)

significantly effective

when

(Franklin effect

exert

and CCK-8 ameliorate

after

in

task

in mice.

1986).

(100

In

was

apparent

at

These

protective

training

are shown

effects

by

long-term Using

memory

retention either

storage

1982),

and Itoh, after before

Piracetam

ineffective.

of cerebral

cycloheximide

(Cumin et al. (Katsuura

and

1986).

i.p.) was

Inhibitors

in a

in cortical

and Pepeu,

avoidance

Cognition

4.

attenuated

decrease

(Spignoli

in a passive

situation.

in Table

oxiracetam

Amnesia.

administered

test

Hoe 427

studies

communication).

(100 and 300 mg/kg

task.

analog

or pramiracetam

of tenilsetam

their

in

by the administration fragment

et al.,

in the retest

paradigm

attenuate

avoidance

potentiated,

In behavioral

i.p.)

that

levels.

an electroconvulsive

show that

Cvcloheximide

in Ach

in a passive-avoidance

the ECS-induced

doses

1988).

leads

in the hippocampus.

concentrations

at similar

3.2.4. protein

manner

induced

intra-

Compounds

fall

as piracetam

(Rush, personal

amnesia

in this

structures.

The ACTH

(30-100 mg/kg

therefore,

by the

(HC-3) which

induced

at the 24 hr retention

immediately

a profound

dose-dependent

training

Applying

(ECS) to rodents

active

et al.,

neurons

ECS Amnesia.

enhancers

as well

an antiamnestic i.p.

of HACU

brain

1986).

the amnesia

cholinergic

induces

i.p.)

before

mg/kg

enhancers

3.2.3.

affected

way to induce

the HC-3

the ACh decrease

piracetam

studies

of lo-100

stimulating

task

in several

(Wiemer

attenuated

preliminary

cognition

not directly

of hemicholinium-3

et al.,

effects

an amnestic

i.p.)

doses

of rats,

injection

Pretreatment

Another

potentiate

(Spignoli

similar

a HC-3

mg/kg

levels

(100 and 300 mg/kg

of 15 ug HC-3

produced

of other,

is the blockade

administration

of ACh

the hippocampus

mice

Amnesia. system

Ach utilization

Oxiracetam

showed

of an activation

systems.

leading

tenilsetam

1986) were

24 hr.

to amnesia

as the amnestic (Rush and

shown

Tenilsetam

or after

agent,

training.

to was

equally

Pharmacology of cognition enhancing drug:

s109

Table 4 Compounds Attenuating ECS-Induced Amnesia for a Passive Avoidance Task in Mice and Rats.

DIWJ

Dose mq/kq

Administration

Species

Aniracetam

50- 60

p.0.

mouse

Cumin et al. 1982

Oxiracetam

50-100

i.p.

rat

Spiqnoli et al. 1986

60

i.p.

mouse

Tobe et al. 1985

2.5-20

i.p.

mouse

Poschel et al. 1983

30

i.p.

mouse

Tobe et al. I985

mouse

Hock et al. 1988

rat

Katsuura and Itoh 1986

Piracetam Pramiracetam Bifemelane Hoe 427

0.001-0.003

S.C.

CM-8

0.001-0.010

i.p.

after training before training before retention after training after training before training before training

Reference

3.2.5. Ischemia-Induced Amnesia. A complete forebrain ischemia in mongolian gerbils of 3 min or 5 min duration leads to an impairment of passive avoidance learning when training the animals 24 hr after the ischemic insult (Schindler, 1983).

Tenilsetam administered

orally before training 24 hr after ischemia attenuated the learning impairment induced by a 5 min ischemia in pentobarbital anesthesia (Schindler et al., 1984) or by a 3 min ischemia in halothane anesthesia (Schindler, unpublished).

Piracetam or aniracetam at an oral dose of loo

mq/kq were almost ineffective under these experimental conditions.

The immediately after the end of an ischemia of 3 min duration is shown in Fig 4. These results

protective effect of tenilsetam administered i.p.

indicate that tenilsetam reverses the immediate as well as the prolonged effects of a cerebral ischemia. Similar protective effects could be induced by an i.p. administration of CAS 633, a calcium-antagonist of the dihydropyridine type or by an i.c.v.

administration of the tiMDA-antagonist a-amino-

7-phosphono-heptanoic

acid (AP-7) (Schindler, unpublished).

A

prophylactic treatment of gerbils with minaprine 30 min before a 5 min ischemia also attenuated a learning deficit (Araki et al, 1987). These compounds also partially prevented the 'delayed neuronal death' of CA1

U.Schindler

Fill0

hippocampal neurons (Schindler, unpublished; Boast et al., 1987; Araki et al., 1987; ). Idebenone (Yamazaki et al., 1984) on the other hand was shown to induce an anti-amnestic effect in rats subjected to a short ischemia immediately after the training session. Ischemia may exert its deleterious effects by an excessive glutamatergic transmission leading to increased intracellular calcium ion concentrations.

Protection against the ischemic impairment may therefore be the results of a direct or indirect inhibiton of these effects.

‘;;‘

160

3

120

5 E L

100

F e

60

5 I 4

40

WI

0

80

20 0

I-

0.3

1

3

10

30

100

Tenilsetam (mg/kg i.p.) 3 min lschemia ,-I

0

Sham-Op.

Fig 4. Effect of tenilsetam, administered i.p. after the end of a 3 min ischemia, on learning deficit in a one-trial passive avoidance task in mongolian gerbils. Training was performed 24 hr after the ischemic episode, retention was measured 24 hr after the training session. * = p ~0.05 (Scheffe test).

3.2.6.

Chronic Cerebral Imnainnent.

Active avoidance

behavior and water maze learning is impaired in spontaneously hypertensive rats with cerebrovascular lesions induced by chronic drinking of saline solutions.

Comparable impairments can be evoked in microence-

phalic offsprings of methylazoxymethanol-treated

pregnant rats. Daily during lear-

treatment with oxiracetam at doses of 10 to 60 mg/kg i.p.

ning of the avoidance task improved the learning rate in these rats with chronically impaired cognition (Banfi and Dorigotti, 1986).

Piracetam

(100 mg/kg S.C. for ten days) compensated the impaired passive avoidance learning in MAM-induced microencephalic rats (Giurgea et al., 1982).

Pharmacologyof cognition enhancing drugs

4.

Sill

ElectroDhvsioloay

As early as 1972 Giurgea and Moyersoons suggested that the

facilitation of the transcallosal response seen with piracetam could be related to its effects on learning and memory.

Recently it was shown

that other cognition enhancing drugs such as aniracetam, idebenone, bifemelane and meclofenoxate increased the negative wave of the transcallosal response, thereby facilitating interhemispheric transfer (Okuyama and Aihara, 1988).

The authors conclude that the functional

increase in interhemispheric neurotransmission by nootropic drugs may be related to the improvement of cognitive functions. 5. Brain Metabolism Piracetam (250 mg/kg i.v.) produced a significant increase in local cerebral glucose utilization in the whole brain of rats (Grau et al., 1987).

Tenilsetam

(15 mg/kg i.v.) also increased 1CMRGlu in rats

mostly in cortical and subcortical relay structures (Grome, personal communication). 6.

Conclusions

The pre-clinical evaluation of cognition enhancing compounds in learning and memory experiments under normal or pathological conditions showed prominent effects of piracetam, of piracetam-derivatives

as well

as of some structurally unrelated nootropic drugs.

Whereas the mode of action of all of these drugs still remains to be elucidated, some results seem to indicate the involvement of the brain cholinergic system. However, since most of the cognition enhancers antagonize the amnestic effectiveness of various treatments, it may be suggested that the nootropics act through common neurobiological mechanisms rather than by interference with specific transmitter systems. The development of efficacious drugs for rehabilitating cognitive function in dementias of aging has to rely on animal models which are predictive for the clinical efficacy of new compounds.

However, the

clinical relevance of the protective effects of nootropics in learning and memory models is not unequivocally established.

The outcome of

clinical trials with the nootropics of the 'second generation' might help to further improve pharmacologically relevant models to test potential cognition enhancing drugs.

U.Schindler

s112

References ARAKI, H., NOJIRI, M., KIMURA, M. and AIHARA, H. (1987) Effect of minaprine on delayed neuronal death in mongolian gerbils with occluded common carotid arteries. J. Pharmacol. exp. Ther. 242: 686-691. BANFI, S. and DORIGOTTI, L. (1986) Experimental behavioral studies with oxiracetam on different types of chronic cerebral impairment. Neuropharmacol. 9 Suppl. 3: S19-S26.

Clin.

BEAL, M.F., MAZUREK, M.F., SVENDSEN, C.N., BIRD, E.D. and MARTIN, J.B. (1986) Widespread reduction of somatostatin-like immunoreactivity in the cerebral cortex in Alzheimer's disease. Ann. Neurol . g: 489-495. BOAST, C.A., GERHARDT, S.C. and JANAK, P. (1987) Systemic AP7 reduces ischemic brain damage in gerbils . In: Excitatory Amino Acid Transmission, T.P. Hicks, D. Lodge and H. McLennan (Eds), pp. 249-252. Alan Liss, New York. (1982) Effects CUMIN, R., BANDLE, E.F., GAMZU, E., HAEFELY, W.E. of the novel compound aniracetam (Ro 13-5057) upon impaired learning and memory in rodents. Psychopharmacology 78: 104-111. (1987) Vinpocetine enhances retrieval of a DeNOBLE, V.J. step-through passive avoidance response in rats. Pharmacol. Behav. a: 183-186.

Biochem.

DeNOBLE, V.J., REPETTI, S.J., GELPKE, L.W., WOOD, L.M. and KEIM (1986) Vinpocetine: Nootropic effects on scopolamine-induced and K.L. hypoxia-induced retrieval deficits of a step-through passive avoidance response in rats. Pharmacol. Biochem. Behav. 24: 1123-1128. (1974) Human memory and the DRACHMAN D.A. and LEAVITT, J.I. cholinergic system. Arch. Neurol. 30: 113-121. (1986) Amnesia FRANKLIN, S-R., SETHY, V.H. and TANG, A.H. produced by intracerebroventricular injections of hemicholinium-3 in mice was prevented by pretreatment with piracetam-like compounds. Pharmacol. Biochem. Behav. 2: 925-927. GARATTINI, S., FORLONI, G.L., TIRELLI, S., LADINSKY, S. and (1984) Neurochemical effects of minaprine, a novel CONSOLO,S. psychotropic drug, on the central cholinergic system of the rat. Psychopharmacology 82: 210-214. GIURGEA, C. and MOYERSOONS, F. (1972) Differential pharmacological reactivity of three types of cortical evoked potentials. Arch. int. Pharmacodyn. 188: 401-404. (1977) Nootropics drugs. Prog. GIURGEA, C. and SALAMA, M. 1:235-247. Neuro-Psychopharmac. GIURGEA, C., GREINDL, M-G., PREAT, S. and PUIGDEVALL, J. (1982) Piracetam compensation of MAM-induced behavioral deficit in rats. In: Alzheimer's Disease: A Report of Progress in Research (Aging, Volume 19), s. Corkin, K.L. Davis, J.H. Growdon, E. Usdin and R.J. Wurtman (Eds.), pp. 281-286. Raven Press, New York. (1987) Effect of GRAU, M., MONTERO, J.L. and BALASCH, J. piracetam on electrocortigram and local cerebral glucose utilization in the rat. Gen. Pharmac. Is: 205-211. GROO, D., PALOSI, E.

and SZPORNY, L.

(1987) Effects of

Pharmacology of cognition enhancing drugs

vinpocetine

Drug Dev.

in scopolamine-induced Res. =:29-36.

54113

learning and memory impairments.

and GEIGER, R. GERHARDS, H-J., WIEMER, G., USINGER, P. F.J., (1988) Learning and memory processes of an ACTH4-9 analog (Ebiratide; Hoe 427) in mice and rats. Peptides 9: 575-581.

HOCK,

(1986) Drug therapy of Alzheimer's disease: HOLLISTER, L.E. & Biol. Psychiat. realistic or not? Prog. Neuro-Psychopharmacol. lo: 439-446. (1988) Preventive effect ITOH, S., TAKASHIMA, A. and KATSUURA, G. of cholecystokinin octapeptide on scopolamine-induced memory impairment in the rat. Drug Dev. Res. 12: 63-70. KATSWRA, G. and ITOH, S. (1986) Prevention of experimental amnesia by peripherally administered cholecystokinin octapeptide in the rat. Drug Dev. Res. 2: 269-276. KUHN, F.J., SCHINGNITZ, G., LEHR, E., MONTAGNA, E., HINZEN, H.D. (1988) Pharmacology of WEB 1881-FU, a central and GIACHETTI, A. cholinergic agent, which enhances cognition and cerebral metabolism. Arch. int. Pharmacodyn. Ther. 292: 13-34. MARAGOS, W.F., GREENAMYRE, J.T., PENNEY, JR. J.B. and YOUNG, A.B. (1987) Glutamate dysfunction in Alzheimer's disease: an hypothesis. TINS lo: 65-68. MARRIOTT, J.G., POSCHEL, B.P.H., VOIGTMAN, R.E., ABELSON, J.S. and BUTLER, D.E. (1984) Cognition activating properties of dihydrolH-pyrrolizine 3,5 (2H,6H)-dione (CI-911) in animal models. sot. Neurosci. Abstr. lo Part 1: 252. MURRAY, C.L. and FIBIGER, H.C. (1986) The effect of pramiracetam (CI-879) on the acquisition of a radial maze task. Psychopharmacology 89: 378-381. NAKAJIMA, T., TAKAHASHI, M., OKADA, T. (1986) Pharmacological study of aniracetam (VI). Effects of aniracetam on muscarinic acetylcholine receptors in the rat hippocampus. Japan. Pharmacol. Ther. 14 supp1. 4: 85-91. OKUYAMA, s. and AIHARA, H. (1988) Action of nootropic drugs on transcallosal responses in rats. Neuropharmacology 27: 67-72. PALMER, A.M., FRANCIS, P.T., BOWEN, D.M., BENTON, J.S., NEARY, D., MANN, D.M.A. and SNOWDEN, J.S. (1987) Catecholaminergic neurones assessed ante-mortem in Alzheimer's disease. Brain Res. 414: 365-375. PEDATA, F., MORONI, F. and PEPEU G.C. (1984) Effect of nootropic agents on brain cholinergic mechanisms. Clin. Neuropharmacol. 2, SUPPl. 1: 772-773. PIERCEY, M.F., VOGELSANG, G.D., FRANKLIN, S.R. and TANG, A.H. (1987) Reversal of scopolamine-induced amnesia and alterations in energy metabolism by the nootropic piracetam: implications regarding identification of brain structures involved in consolidation of memory traces. Brain Res. 424: 1-9. PILCH, H. and MUELLER, W.E. (1988) Piracetam elevates muscarinic cholinergic receptor density in the frontal cortex of aged but not of young mice. Psychopharmacology 94: 74-78. PONTECORVO, M.J. and EVANS, H.L. (1985) Effects of aniracetam on delayed matching-to-sample performance of monkeys and pigeons.

s114

U.Schindler

Pharmacol.

Biochem.

Behav.

2:

745-752.

POSCHEL, B.P.H., MARRIOTT, J.G. and GLUCKMAN, M.I. (1983) Pharmacology of the cognition activator pramiracetam (CI-879). exp. clin. Res. 9: 853-871.

Drugs

PUGSLEY, T.A., SHIH, Y.-H., COUGHENOUR, L. and STEWART, S.F. (1983) Some neurochemical properties of pramiracetam (CI-879), a new cognition-enhancing agent. Drug Dev. Res. 3: 407-420. RUSH, D.K. and STREIT, K. (1987) Memory enhancement with tenilsetam: Antagonism of scopolamine and cycloheximide induced amnesia of passive avoidance in mice. sot. Neurosci. Abstr. 13 Part 2: 847. SAITO, K.I., HONDA, S., TOBE, of bifemelane hydrochloride by scopolamine, hypoxia and Japan. J. Phannacol. 18:

A. and YANAGIYA, I. (1985) Effects (MCI-2016) on acetylcholine level reduced ischemia in the rats and mongolian gerbils. 375-380.

SANSONE, M., CASTELLANO, C. and AMMASSARI-TEULE, M. (1985) Improvement of avoidance acquisition by the nootropic drug oxiracetam in mice. Arch. int. Pharmacodyn. 275: 86-92. SETHY, V.H. (1983) Effect of piracetam on high affinity choline Neurosci. Abstr. 9 Part 1: 429. uptake. sot. (1983) The effect of graded cerebral ischemia on SCHINDLER, U. brain water content and learning ability in the mongolian gerbil. Cereb. Blood Flow Metabol. 1 supp1. 1: S335-S336.

J.

(1984) Nootropic SCHINDLER, U., RUSH, D.K. and FIELDING, S. drugs: Animal models for studying effects on cognition. Drug Dev. Res. 4: 567-576. SCHINDLER, U., OSTROWSKI, J. and BEYERLE, R. (1988) Anti-amnestic properties of the anti-dementia drug tenilsetam (CAS 997). In: Proceedings of the International Symposium on ALzheimer's Disease, H. Soininen (Ed.), p. 113. Publications of the University of Kuopio. (1985) The effects of various SHIH, Y.H. and PUGSLEY, T.A. cognition-enhancing drugs on in vitro rat hippocampal synaptosomal sodium dependent high affinity choline uptake. Life Sci. 36: 2145-2152. (1986) Oxiracetam prevents SPIGNOLI, G. and PEPEU, G. electroshock-induced decrease in brain acetylcholine and amnesia. J. Phannacol. 126: 253-257. SPIGNOLI, G., PEDATA, F., GIOVANNELLI, L., BANFI, S., MORONI, F. (1986) Effect of oxiracetam and piracetam on central and PEPEU, G. cholinergic mechanisms and active-avoidance acquisition. Clin. 2 supp1. 3: 539-547. Neuropharamcol. (1987) Interactions between oxiracetam, SPIGNOLI, G. and PEPEU, G. aniracetam and scopolamine on behavior and brain acetylcholine. Pharmacol. Biochem. Behav. 27: 491-495. (1985) Effects of TOBE, A., YAMAGUCHI, T., NAGAI, R. and EGAWA, M. bifemelane (MCI-2016) on experimental amnesia (passive avoidance failure) in rodents. Japan. J. Pharmacol. 2: 153-161. (1978) Possible ccnseguences of VAN RIEZEN, H. and RIGTER, H. Drug Res. ACTH-like peptides for human mental performance. a: 1294-1296.

Eur.

Pharmacology

WHITEHOUSE, P.J., VALE, W.W., KUliAR, M.J., PRICE, D.L.

of cognition

ZWEIG,

enhancing

R.M.,

drugs

SINGER,

315

H.S.,

MAYEUX,

R.,

and DESOUZA, E.B. (1987) Reductions in corticotropin releasing factor-like immunoreactivity in cerebral cortex in Alzheimer's disease, Parkinson's disease, and prgressive supranuclear palsy. Neurology 37: 905-909.

WIEMER, G., GERHARDS, H.J., HOCK, F-J., USINGER, P., VON RECHENBERG, W. and GEIGER, R. (1988) Neurochemical effects of the synthetic ACTH4-9 analogue Hoe 427 (Ebiratide) in rat brain. Peptides 2: 1081-1087. YAMADA, K., INOUE, T., TANAKA, M. and FURUKAWA, T. (1985) Prolongation of latencies for passive avoidance reponses in rats treated with aniracetam or piracetam. Pharmacol. Biochem. Behav. 2: 645-648. YAMAMOTO, M. and SHIMIZU, M. indeloxazine hydrochloride. 761-770.

(1987) Cerebral activating properties of Neuropharmacology z:

YAMAZAKI, N., TAKE, Y., NAGAOKA, A. and NAGAWA, Y. (1984) Beneficial effect of idebenone (CV-2619) on cerebral ischemia-induced amnesia in rats. Japan. J. Pharmacol. 36: 349-356. YOSHIZAKI, H. and OKADA, T. (1986) Pharmacological study of aniracetam (V). Inhibitory effect of aniracetam on scopolamine induced increase of sodium dependent high affinity choline uptake into rat hippocampus. Japan. Phannacol. Ther. u Suppl.4: 75-84. Inquiries and reprint requests should be adressed to: Dr. Ursula Schindler Department of CNS-Pharmacology Cassella AG Hanauerlandstr. 526 D-6000 Frankfurt am Main 61 Federal Republic of Germany