Memantine restores impaired synaptic plasticity by reducing synaptic noise

s242

Poster

ANTI-AMYLOIDOGENIC VITRO STUDIES

111051

ACTIVITY

OF TETRACYCLINES:

IN

Presentation:

WITH ALZHEIMER’S

Alzheimer’s

of olanzapine

Aims A multicenter

tangles and cortical

atrophy.

deposited in cortical

Beta-amyloid

and meningeal

characterized

(bA)

is the major component

of bA peptide

in AD

genetic,

studies pointing

of bA

aggregates

approach

anthracycline

numerous

with

or their

to the disesase.

chemical

anti-tumoral

the possibility

analogies

the antibiotic derivatives

activity,

inhibited

with anthracyclines,

tetracycline,

(i.e. doxycycline)

formed

fluorescent

co-incubated formation. trypsin

with

T

digestion.

with a well-known

clinical

microscopy

not

profile,

tetracycline

in dose-dependent

only

including

the

fib&.

amyloid

Alzheimer‘s

years)

study was conducted

in treating psychotic

with

disease. Methods

dementia

study entered

(dose range:

Agifation/A,~gression, as the primary olanzapine.

Elderly

(n= 137) who

an open-label 5,

patients

mensure

(Core

SCOTCSimproved

p<.oOl),

Total

(mean,

p<.OOl).

included There

changed.

double-blind

which

change

they received

in the sum of the

wtal

(26W),

treatment

on the Core

scores

Total

improved

Simpson Angw

with

(meaw7.55:

injury

symptoms

wow

in patient

ECGs,

including symptom!,

and rash (22%).

generally

from

were not

Treatment-emergent

(2X%),

is an effective,

significantly

and AIMS

changes occurred

sign or in weight.

accidental

war used

treatment

p<.OOl), and IO of the 13 Owupational Disruptivmrss (mean,

Akathisia

for psychotic

Alzheimer’y

Following

SD=23.72;

including

No significant

nor in any

somnolence

long-term

(mean age: 83.1

a 6-week

during

Results

significantly

p=.C02).

data suggest that olanzapine

patients with

aaaociatrd

home patients

Mean

Total).

17.85;

Barner

haaehne (mean, 0.22; SD=O.SO; interval,

and safety

completed

15 mglday).

item score5 of the NPVNH,

significantly

successfully

10, or

individual

QTc

nursing

efficacy

disturbances

Delusions, and Hallucinations items of the NPVNH

efficacy

SD=3.24;

long-term

and behaworal

phase of up to 18 weeks

SD=8.53: 2.84;

to determine

symptoms

Beth E. Juliur. Peter D.

Conclusion?

safe, and well-tolerated

and behaworal

disturbances

in elderly

dementw

and quantified doxycycline the amyloid

amyloid

fibrils

beta-amylold

in CNS,

fibrils

nmnner

The rewlts

activity

We investi-

and

of beta l-42

inhibited

of

whose

depoaits and ha\

by electron

the pre-formed

capacity

using beta l-42

Beta l-42

also the resistance

Tetracyclines

but also diaawzmbled

Based on some

in the CNS.

in AD amyloid

Both

aggre-

profile.

formation.

assay.

an

barrier pasaagr

and doxycycline

represented

for amyloid

reduduced

The drugs attenuated

formation

of amyloid

toxicological

distribution

of tetracycline

binding

the peptide

is a potential

iodo-doxorubucin,

the formation

a safer

in vitro were analyzed

thioflavine with

that

and low blood-brain

have a favorable capacity

peptide, this peptide is highly

spontaneously

Thus. prevention

we tested the anti-amyloidogenic

a molecule

been proposed as a seed molecule

by

toxicity

of AD.

with

olanzapine

and neuropathological

once formed,

have found

of

is an early event

of a direct we of this drug m AD therapy.

gated the anti-amyloidogenic synthetic

and l-42,

biochemical

elimination

We

gates in vitro and in viva. The intrmsic has inhibited

l-40

to a causal role of bA in the pathogenesis

the formation therapeutic

are now

of SP and i\

blood vessels of the AD brain. The formation

bA deposits, which are insoluble fibrils and there

by senile plaques (SP)

II

DEMENTIA

Jarnie S. Street, W. Scott Clurk. Eli Lilly and Cornpam: Feldmun, Deborah L. Kadam, Alan Breier

is neuropathologically

Studies

LONG-TERM EFFICACY OF OLANZAPINE IN THE CONTROL 111071 OF PSYCHOTIC AND BEHAVlORAL SYMPTOMS IN PATIENTS

Gianluigi Forlnm. Laura Colombo, Lam Girola, lnsr di Ricerchr Farrnacologiche Mano Negri, Milano Italy; Fabririo Taglinvini, lnst Nazionalr Neurologico Carlo Bwtu, Milano Italy; Mm-w Salmona, lnst di Ricerche Farmacologichr Mario Negri. Milano ltul, disease (AD)

IIrug

MEMANTINE RESTORES IMPAIRED BY REDUCING SYNAPTIC NOISE

to

SYNAPTIC

PLASTICITY

aggregate?

indicate that drug\

are potentially

useful

for AD therapy. In the accompanying wxcral

MEMANTINE 111061 MODELS AT

PROVIDES NEUROPROTECTION IN ANIMAL THERAPEUTICALLY RELEVANT DOSES

models

abstracts we have shown that memantine

of

lneuroprotectlve

chronic

agent in dementia.

symptomatological contrast

with

neurodegenerative

effects

the effects

expected

function

of these receptors

indicate that memantine

of NMDA

disease.

has been suggested to be involved Hence,

NMDA

disease progression. actwity

receptor

However,

can be achwed

therapeutically therapeutic

relevant dose in animals

either

NMDA

relevent.

receptor

to the brain (i.c.v.)

for cognition.

Memantine

animals ally.

doses of NMDA

In the wne

quinolinic

acid

minipump

previously

microinjection NBM

infused

while

to the clinical

acid (3.NP)

different

nucleus

protection

by Memantine.

factors contributing

role m the neurodegeneration

NMDA

are preclinical

basah\

of Meynert

lesion

receptors

(NBM

of this structure

qyntheaising

2.8 @kg. toxin

might

to the neuronill insult and memantine diseae

studies

provided

the high

kinetics

&es

activation

propertie?

synaptic

NMDA

and MgZt

increased synaptic cholinesterase

where energy deficit5

inhibitors.

Again

synaptic noise.

receptor

data provide

antagonist kinetics

upport

for our

supporting

it’s promising

the physiological

in blocking

isn t quite

to act like a somewhat

noise. Memantine

strategy to treat Al/heimrr’s

by lowering noise.

slow unblocking

in determining allow

is more effective

memantine

Mg’ ’ under condition,

These

(I OpM)

and associated rapid strongly voltage-dependent

as its voltage-dependency

allow

in (25

of memantine

also be induced

increasing

uncompetitive

are important

memantine

function learning

by NMDA

concentration

could

thereby

voltage-dependency.

receptors but memantine

receptor The%

affinity

of memantine

Both

preclinical

dose\ of NMDA

reversed this deficit by reducing

that the moderate affinity

profile.

recent

their combined

of

tonic low level NMDA

so pronounced

as Mg”.

more potent surrogate for

cause tonic relief

shows no negative

thera-

activation

’block

of Mg’

interactions

and

with reversible

use as a potential.

rynergiatic

disease.

enzyme,

given i.p. before NMDA

with an EDSOof

blocking

a decrease in chohne

addition-

model,

wzem to

(2.5 and 5 mg/kp i.p.). Similarly,

slices was impaired

was unable to restore LTP due to its extremely

hypothesis peutic

Memantme

m hippocampal

completely

and far less pronounced

S.C. with

In all cases, no side-effects

of Allheimer’s

acid alone

for learning and affected in

of mitochondrial

NMDA

weeks

was seen in the cortex of

NMDA-induced

injection

doses. Hence,

to slow down the progression

quinolinic

Similarly,

in target cortical areas. Memantine

was inhiblted

at the neuroprotective

with

decrease in levels of the acetylcholine

by a direct

two

those infused in parallel

use of’Memantine

in rats).

for

a second pump delivered

acid but not in those recewing

produced a clear-cut

lesion produced

was infused

while

such as the cholinergic

caused a considerable

(I to IO bM)

dizocilpine

Alzheimer’s

choline acetyltransferase

memantme

may

as the normal

synaptic noise. Thus, passive avoidance

(I FM). Deficit? in LTP in hippocampal Mg* ’ concentration (to IOIJ.M) and

of this agent, the

the task normally.

magnocellularls

A

in rats maximum

in structures known to be impofiant

diseae

antagonists.

This

antagonist

of low, non-toxic

in

use as a

shows clear positive

However.

and this effect was reversed by a therapeutically-relevant

Hence,

of the density of ACh terminals)

treated with quinolinic

baaalla

down

activity

on neurodegeneration

nucleus

slow

p,M for Memantine).

Animals

relevance

should

To test neuroprotective

agonist

were able to acquire

Of particular

relevant

deficits in the T-maze

uptake sites (an indicator

Memantine)

(LTP)

it’s

is also able to restore normal physiological

by systemic administration

long term potentmtion

IS one that leads to plasma levels close to the

via an ALZET

saline or Memantine.

showed clear learning

(like

of Alrheimer’s

one of the major concerns is, whether neuroprotective

range in humans (0.2-1.0

endogenous directly

antagonista

at therapeutically

5 mg/kg is therapeutically

m the pathomechanism

al\o

patients.

receptor

mglkg i.p.) and this deficit was reversed memantine Glutamate

is neuroprotective

supporting

memantine

in demented

for a NMDA

ia essential

receptors by reducing

rats was impaired

However,

on cognition

findings

diseases

Similarly.

3-nitropropionic

12 MONTH DECLINE IN COGNITIVE AND DAILY FUNCTION 11109(IN PATIENTS WITH MILD-TO-MODERATE ALZHEIMER’S DISEASE: STUDIES

were observed

be a link

TWO

RANDOMIZED,

PLACEBO-CONTROLLED

between

should be expected

that glutamate

plays a

in this disorder. Background: cognitive of decline

dwase

and activities

in these domains

Objectives: data from

Alzheimer’s

function

(AD)

is characterized

of daily living (ADL).

is ersential

to the evaluation

To measure the rate? of change in cognitive two

double-blind.

12.month

AD

placebo-controlled

clinlcal

trial‘;.

ctudia

by a progressive

Characterizing

Methods:

of sabelurole

decline

long-term

of treatment

and functional Two

12.month,

were

undertaken

in

rates

intervention. ability,

using

randomixd. in wbjcct?