Developmental neurotoxicity of ketamine in pediatric clinical use

Toxicology

Letters

220 (2013) 53–

60

Contents

lists

available

at

SciVerse

ScienceDirect

Toxicology

Letters

jou

rn

al

hom

epage:

www.elsevier.com/locate/toxlet

Mini

review

Developmental

neurotoxicity

of

ketamine

in

pediatric

clinical

use

Chaoxuan

Dong

a,b,∗

,

K.J.S.

Anand

b,c

a

Department

of

Chemical

Biology

and

Therapeutics,

St.

Jude

Children’s

Research

Hospital,

Memphis,

TN

38105,

United

States

b

Departments

of

Pediatrics,

Anesthesiology,

Anatomy

and

Neurobiology,

University

of

Tennessee

Health

Science

Center,

Memphis,

TN

38103,

United

States

c

Pediatric

Intensive

Care

Unit,

Department

of

Pediatrics,

Le

Bonheur

Children’s

Hospital,

Memphis,

TN

38105,

United

States

h

i

g

h

l

i

g

h

t

s

•

History

and

pharmacology

of

ketamine.

•

Ketamine

induces

neuronal

cell

death

in

developing

brains.

•

Ketamine

alters

the

neurogenesis

of

early

developing

brains.

•

Current

studies

on

the

developmental

neurotoxicity

of

ketamine

in

pediatric

clinical

use.

a

r

t

i

c

l

e

i

n

f

o

Article

history:

Received

2

January

2013

Received

in

revised

form

21

March

2013

Accepted

22

March

2013

Available online xxx

Keywords:

Ketamine

NMDA

receptors

Neural

stem

progenitor

cells

Cell

death

Neurogenesis

Proliferation

Differentiation

a

b

s

t

r

a

c

t

Ketamine

is

widely

used

as

an

anesthetic,

analgesic,

and

sedative

in

pediatric

clinical

practice

and

it

is

also

listed

as

an

illicit

drug

by

most

countries.

Recent

in

vivo

and

in

vitro

animal

studies

have

conﬁrmed

that

ketamine

can

induce

neuronal

cell

death

in

the

immature

brain,

resulting

from

widespread

neuronal

apoptosis.

These

effects

can

disturb

normal

development

further

altering

the

structure

and

functions

of

the

brain.

Our

recent

studies

further

indicate

that

ketamine

can

alter

neurogenesis

from

neural

stem

progenitor

cells

in

the

developing

brain.

Taken

together,

these

ﬁndings

identify

a

novel

complication

associated

with

ketamine

use

in

premature

infants,

term

newborns,

and

pregnant

women.

Recent

data

on

the

developmental

neurotoxicity

of

ketamine

are

reviewed

with

proposed

future

directions

for

evaluating

the

safety

of

ketamine

in

these

patient

populations.

Contents

1.

Ketamine

.

. 54

2.

Pharmacology

.

. 54

3.

Clinical

use

and

complications

.

. 54

4.

Ketamine

induces

cell

death

in

developing

brains

.

. 55

5.

Ketamine

alters

the

neurogenesis

of

early

developing

brains

.

. 55

5.1.

Proliferation

.

. 56

5.2.

Differentiation

.

. 57

6.

Conclusions

.

. 57

7.

Future

directions

.

. 57

Conﬂict

of

interest

statement

.

. 58

References

.

. 58

∗

Corresponding

author

at:

262

Danny

Thomas

Pl.

MS

1000,

Memphis,

TN

38105,

United

States.

Tel.:

+1

901

834

6612;

fax:

+1

901

595

5715.

E-mail

address:

[email protected]

(C.

Dong).

0378-4274/$

–

see

front

matter ©

http://dx.doi.org/10.1016/j.toxlet.2013.03.030

54 C.

Dong,

K.J.S.

Anand

/

Toxicology

Letters

220 (2013) 53–

60

1.

Ketamine

was

synthesized

as

a

substitute

for

phencyclidine

(PCP)

in

1962,

and

found

to

produce

excellent

anesthesia

with

rapid

onset

(Domino,

2010).

In

1964,

this

newly-synthesized

drug

was

introduced

into

clinical

human

studies

and

produced

remarkable

anesthesia

with

minimal

side

effects.

Soon

thereafter,

physicians

extended

the

application

of

ketamine

to

many

clinical

practices:

ophthalmic

surgery

(Harris

et

al.,

1968)

pediatric

surgery

(Del

Prete

et

al.,

1968),

neurosurgical

procedures

(Corssen

et

al.,

1969),

pedi-

atric

cardiac

catheterization

and

other

procedures

(Ginsberg

and

Gerber,

1969;

Szappanyos

et

al.,

1969;

Wilson

et

al.,

1969).

A

wider

usage

of

ketamine

in

humans

occurred

during

the

Vietnam

War

with

documented

safety

in

resource-poor

settings

(Mercer,

2009).

Ketamine

has

been

widely

accepted

in

clinical

settings

because

of

its

profound

analgesic,

sedative,

dissociative

and

amnestic

effects,

while

maintaining

protective

airway

reﬂexes,

spontaneous

respi-

rations,

and

cardiopulmonary

stability.

With

the

increasing

popularity

of

ketamine

use

in

clinics,

the

psychotropic

effects

of

ketamine

attracted

more

and

more

people

to

consume

it

as

a

recreational

drug,

or

use

it

as

a

date

rape

drug

(

Graeme,

2000;

Jansen,

2000).

Considering

the

increased

abuse

of

ketamine

and

criminal

offences

relating

to

ketamine,

the

DEA

(Drug

Enforcement

Administration)

listed

ketamine

as

a

Sched-

ule

III

non-narcotic

substance

under

the

Controlled

Substances

Act

in

1999.

Coincidentally,

in

the

same

year,

ketamine

was

found

to

induce

neurodegeneration

in

the

developing

brain

(Ikonomidou

et

al.,

1999),

which

led

to

heated

discussions

on

the

neurotox-

icity

of

ketamine

use

in

children.

Further

studies

have

indicated

that

high

doses

or

repeated

ketamine

doses

can

induce

cell

death,

especially

apoptosis,

in

many

kinds

of

in

vivo

and

in

vitro

mod-

els

from

mice,

rats,

and

monkeys

(Amr,

2010;

Fredriksson

et

al.,

2004;

Scallet

et

al.,

2004;

Takadera

et

al.,

2006;

Wang

et

al.,

2005,

2006;

Zou

et

al.,

2009a,

2009b).

Also,

ketamine

was

found

to

dis-

turb

normal

neurogenesis

of

neural

stem

progenitor

cells

(NSPCs)

in

the

developing

brain

(Dong

et

al.,

2012).

These

ﬁndings

forced

scientists

and

physicians

to

reconsider

the

safety

and

toxic

effects

of

ketamine

in

pediatric

settings.

Developmental

neurotoxicity

is

being

explored

and

clariﬁed

as

a

new

complication

of

ketamine

following

its

clinical

use

in

Pediatrics.

2.

Pharmacology

Major

pharmacological

effects

of

ketamine

are

the

antagonism

of

NMDA

receptors,

a

tetrameric

protein

complex

that

forms

a

ligand-gated

calcium

ion

channel

(Duchen

et

al.,

1985;

Harrison

and

Simmonds,

1985;

Honey

et

al.,

1985;

Martin

and

Lodge,

1985;

Snell

and

Johnson,

1985;

Thomson

and

Lodge,

1985;

Thomson

et

al.,

1985).

Ketamine

non-competitively

binds

to

the

phencyclidine

site

inside

the

NMDA

receptor

and

blocks

the

inﬂux

of

calcium

(Bolger

et

al.,

1986;

Ffrench-Mullen

and

Rogawski,

1992;

O‘Shaughnessy

and

Lodge,

1988).

Ketamine-produced

blockade

of

NMDA

receptors

depends

on

the

opening

state

of

the

calcium

ion

channel

in

the

NMDA

receptor.

Varying

composition

of

NMDA

receptor

subunits

determines

temporal

and

regional

speciﬁcity

and

unique

functional

properties

(Monyer

et

al.,

1992;

Paoletti

and

Neyton,

2007).

Ketamine

also

acts

on

other

receptors.

S(+)-ketamine

can

reduce

opioid

consumption

after

surgery

(Lahtinen

et

al.,

2004),

and

reverse

opioid

tolerance

in

pain

management

(Mercadante

et

al.,

2003

)

indicating

that

it

may

interact

with

opioid

receptors

to

some

extent.

Recent

publications

also

indicate

ketamine

may

stim-

ulate

dopaminergic

receptors

(D2)

in

vitro

(Seeman

and

Guan,

2008;

Seeman

et

al.,

2005)

with

even

higher

afﬁnities

than

the

NMDA

receptors

(Kapur

and

Seeman,

2002;

Seeman

and

Guan,

2009;

Seeman

et

al.,

2009;

Seeman

and

Lasaga,

2005).

Effects

of

ketamine

on

dopaminergic

receptors

may

support

the

theory

of

glutamatergic

contributions

to

schizophrenia

(Gilmour

et

al.,

2012).

Ketamine

and

PCP

can

directly

act

on

dopaminergic

receptors

or

block

NMDA

receptors

to

increase

the

release

of

dopamine;

and

dopamine

dysfunction

in

brains

may

trigger

the

underlying

mech-

anisms

of

schizophrenia

(Javitt,

2010).

Ketamine

hydrochloride

is

water

soluble

and

lipid

permeable.

It

is

readily

absorbed

via

intra-

venous,

intramuscular,

subcutaneous,

epidural,

oral,

rectal,

and

transnasal

routes

of

administration,

as

well

as

intraperitoneal

injec-

tion

in

laboratory

animals

(Aroni

et

al.,

2009;

Flecknell,

1998).

Brain

uptake

and

redistribution

occur

rapidly

due

to

its

low

binding

to

plasma

proteins.

Thus,

uptake

and

distribution

of

ketamine

to

chil-

dren’s

brains

occurs

rapidly

in

pediatric

settings

or

to

fetal

brains

via

the

placental

barrier

in

obstetric

settings.

Ketamine

is

metabo-

lized

by

N-demethylation

and

oxidation

in

the

hepatic

cytochrome

P450

system

(by

CYP2B6

and

CYP3A4),

and

its

primary

metabo-

lite,

norketamine,

is

one

third

to

one

ﬁfth

as

potent

as

the

original

compound

(White

et

al.,

1982).

3.

Clinical

use

and

complications

Ketamine

is

widely

used

for

four

major

clinical

indica-

tions:

anesthesia,

analgesia,

sedation,

and

antidepressant

effects

(

Domino,

2010).

Ketamine-induced

anesthesia

is

described

as

a

dissociative

anesthesia,

characterized

by

profound

analgesia

and

amnesia

with

retention

of

protective

airway

reﬂexes,

sponta-

neous

respirations,

and

cardiopulmonary

stability

(Green

et

al.,

2011

).

Under

ketamine

anesthesia,

blood

pressure

is

well

main-

tained

even

in

the

presence

of

hypovolemia.

Spontaneous

breathing

occurs

and

laryngeal

reﬂexes

are

preserved.

This

makes

ketamine

the

‘ﬁrst

choice’

anesthetic

for

pre-hospital

anesthesia/analgesia.

Also,

ketamine

can

be

used

for

premedication,

sedation,

induc-

tion

and

maintenance

of

general

anesthesia.

In

pediatric

practices

combinations

of

ketamine

with

other

anesthetics

like

propofol

or

midazolam,

are

utilized

in

pediatric

plastic

surgery

(Zook

et

al.,

1971

),

oral

surgery

(Birkhan

et

al.,

1971),

neurosurgery

(Chadduck

and

Manheim,

1973),

cardiac

anesthesia

(Koruk

et

al.,

2010;

Radnay

et

al.,

1976),

ophthalmic

surgery

(Raju,

1980),

gastrointestinal

procedures

(Shemesh

et

al.,

1982),

and

for

diagnostic

and

inter-

ventional

cardiac

procedures

(Singh

et

al.,

2000).

Subanesthetic

doses

of

ketamine

can

produce

analgesic

effects

as

an

‘anti-hyperalgesic’,

‘anti-allodynic’

or

‘tolerance-protective’

agent

(Visser

and

Schug,

2006).

Ketamine

is

also

suitable

for

acute

and

chronic

pain

management

(Amr,

2010;

Blonk

et

al.,

2010;

Noppers

et

al.,

2010;

Visser

and

Schug,

2006).

Ketamine

can

induce

excellent

analgesic

effects

in

patients

with

chronic

cancer

pain

and

chronic

neuropathic

pain

(Bell,

2009;

Ben-Ari

et

al.,

2007;

Elsewaisy

et

al.,

2010;

Holtman

et

al.,

2008;

Kalina

et

al.,

2008).

Studies

on

chronic

phencyclidine

and

later

ketamine

abusers,

found

that

ketamine

had

antidepressant

effects

in

depressed

patients

(Berman

et

al.,

2000;

Hashimoto,

2010;

Kudoh

et

al.,

2002;

Valentine

et

al.,

2011

).

The

study

of

the

basic

mechanisms

of

ketamine’s

antidepres-

sant

effects

may

provide

new

lead

targets

to

develop

better

agents

to

treat

psychiatric

patients

with

major

depressive

disorder

and

other

forms

of

depression.

In

children,

ketamine

produces

potent

analgesia

(Da

Conceic¸

ão

et

al.,

2006;

Dal

et

al.,

2007).

Although

ketamine

was

under

reevaluation

because

of

its

neurotoxicity

in

the

developing

brain,

in

pediatric

clinical

settings,

it

is

being

used

increasingly

to

supplement

opioids

for

pain

after

major

surgery

(

Anderson

and

Palmer,

2006).

In

the

emergency

department

(ED),

intensive

care

unit

(ICU),

and

during

invasive

examination

proce-

dures,

when

conscious

sedation

is

necessary

for

pediatric

patients,

ketamine

is

a

popular

choice.

A

large

number

of

clinical

studies

indicate

that

combinations

of

ketamine

and

midazolam

(McGlone,

C.

Dong,

K.J.S.

Anand

/

Toxicology

Letters

220 (2013) 53–

60 55

2009;

Sener

et

al.,

2011),

ketamine

and

dexmedetomidine

(McVey

and

Tobias,

2010),

or

ketamine

and

propofol

(Weatherall

and

Venclovas,

2010)

are

very

useful

and

safe

for

sedation

and

pain

relief

in

ED

or

ICU

patients,

especially

during

ventilator

manage-

ment.

Long-term

ketamine

use

results

in

impaired

cognition,

mem-

ory

and

mood.

Prolonged

exposure

to

ketamine

can

up-regulate

D1

receptor

activity

in

the

dorsal–lateral

prefrontal

cortex,

which

impairs

the

memory

and

judgment

of

chronic

recreational

ketamine

abusers

(Narendran

et

al.,

2005).

Subanesthetic

doses

of

ketamine

in

healthy

volunteers

(Malhotra

et

al.,

1996)

leads

to

signiﬁcant

decrease

in

attention

and

semantic

memory.

In

pharma-

cological

model

of

acute

schizophrenia,

short

and

long-term

use

of

ketamine

impaired

semantic

control

and

memory,

mimicking

schizophrenia

(Morgan

et

al.,

2006).

Recent

reports

show

that

ketamine

use

in

newborn

animals

results

in

long

lasting

cognitive

deﬁcits

in

rats

and

rhesus

monkeys

(

Paule

et

al.,

2011;

Young

et

al.,

2005).

Ketamine

is

listed

as

an

illicit

club

drug

and

is

mainly

abused

among

the

teenagers

and

young

adults

at

bars,

nightclubs,

and

parties.

Low-dose

intoxi-

cation

impairs

attention,

learning

ability,

and

memory

(Morgan

and

Curran,

2006;

Morgan

et

al.,

2009,

2010).

At

higher

doses,

ketamine

can

cause

dreamlike

states

and

hallucinations

and

even

lead

to

delirium

and

amnesia.

Ketamine

is

used

recreationally

as

a

club

drug

because

it

decreases

social

inhibitions

and

is

thought

to

heighten

the

sexual

experience

(Parks

and

Kennedy,

2004),

which

can

increase

the

incidence

of

unintended

pregnancy

(Romanelli

et

al.,

2003;

Semple

et

al.,

2009).

These

pregnant

mothers

may

have

other

opportunities

to

abuse

large

doses

of

ketamine

long

term.

Ketamine

can

easily

cross

the

placenta,

enter

the

fetal

circulation

(

Craven,

2007),

and

rapidly

distribute

to

the

embryonic/fetal

brain.

This

situation

results

in

greater

chances

for

ketamine

to

alter

the

development

of

embryonic

brains.

Thus,

it

is

necessary

to

deﬁne

the

dose-

and

time-dependent

effects

of

ketamine

on

neural

stem

pro-

genitor

cells

for

a

reevaluation

of

the

risk

of

ketamine

as

an

abuse

drug.

4.

Ketamine

induces

cell

death

in

developing

brains

During

the

brain

growth

spurt

period

of

the

developing

brain,

neuronal

apoptosis

can

be

triggered

by

the

blockade

of

NMDA

receptors.

Experimental

evidence

has

conﬁrmed

the

fact

that

high

doses

of

ketamine

trigger

cell

death

in

the

developing

brain.

In

1999,

a

classic

study

by

Ikonomidow

et

al.

reported

that

prolonged

ketamine

anesthesia

enhanced

neuronal

cell

death

in

neonatal

rats

(

Ikonomidou

et

al.,

1999).

Scallet

et

al.

reported

that

repeated

doses

of

20

mg/kg

ketamine

increased

the

number

of

degenerating

neu-

rons

in

neonatal

rats

at

postnatal

day

(PND)

7

(Scallet

et

al.,

2004).

In

neonatal

mice,

high

doses

of

ketamine

induced

severe

degeneration

of

cells

in

the

parietal

cortex,

with

apparent

deﬁcits

in

habituation,

acquisition

learning,

and

retention

memory

at

the

age

of

2

months

(

Fredriksson

and

Archer,

2004;

Fredriksson

et

al.,

2004).

Rudin

et

al.

reported

that

a

clinically

relevant

single

dose

of

ketamine

can

produce

long-lasting

neuronal

apoptosis

in

certain

brain

areas

of

neonatal

mice

at

PND7

(Rudin

et

al.,

2005).

Slikker

et

al.

showed

that

monkeys

at

the

earlier

developmental

stage

are

more

sen-

sitive

to

ketamine-induced

cell

death.

Small

doses

of

ketamine

with

short

term

exposure

did

not

lead

to

cell

death

in

the

new-

born

monkey

at

PND5

(Slikker

et

al.,

2007),

but

long

term

ketamine

exposure

produced

extensive

increases

in

the

number

of

caspase-

3

positive

neurons

in

infant

monkey

brains

(Zou

et

al.,

2009a).

Furthermore,

a

recent

study

has

indicated

that

ketamine-induced

neuronal

cell

death

in

the

developing

brain

may

be

associated

with

very

long-lasting

deﬁcits

in

brain

function

in

primates

(Paule

et

al.,

2011

).

In

vitro

studies

with

neuronal

cultures

also

conﬁrmed

that

ketamine

induced

apoptosis

in

developing

brains.

In

rat

forebrain

cultures,

10

and

20

␮M

ketamine

exposure

for

12

h

induced

a

sub-

stantial

increase

of

TUNEL

positive

cells

relating

to

the

upregulation

of

NR1-subunit

of

the

NMDA

receptor

following

ketamine

adminis-

tration

(Takadera

et

al.,

2006;

Wang

et

al.,

2005).

The

same

doses

of

ketamine

also

alleviate

apoptotic

level

in

cultured

frontal

cortical

neurons

isolated

from

a

monkey

at

PND

3

(Wang

et

al.,

2006).

Addi-

tionally,

although

low,

subanesthetic

concentrations

of

ketamine

do

not

affect

cell

survival,

it

can

impair

neuronal

morphology

and

dendritic

arbor

development

in

immature

GABAergic

neurons.

This

indicates

that

even

low

doses

of

ketamine

can

interfere

with

the

build-up

of

neural

networks

in

the

developing

brain

(Vutskits

et

al.,

2007,

2006).

In

a

long

run,

the

developmental

complications

of

ketamine

neurotoxicity

create

important

issues

for

both

clinician

and

scien-

tists.

Based

on

present

proposed

mechanisms

of

ketamine-induced

apoptosis,

ketamine

can

upregulate

NMDA

receptor

expression

in

cultured

neurons

(Wang

et

al.,

2005).

Increased

NMDA

receptors

can

promote

calcium

inﬂux

under

normal

amounts

of

gluta-

mate,

which

may

trigger

both

apoptotic

and

excitotoxic

cell

death

(

Anand

and

Scalzo,

2000).

Up-regulated

NR1

may

directly

mediate

ketamine-induced

cell

death

via

some

unknown

pathways

and

not

via

calcium

inﬂux

(Fig.

1).

Although

there

is

a

heated

controversy

on

the

neurotoxic

role

of

ketamine,

multiple

lines

of

evidence

sug-

gest

that

ketamine

can

affect

the

expression

of

NMDAR

as

well

as

the

neuronal

fate

during

normal

development.

5.

Ketamine

alters

the

neurogenesis

of

early

developing

brains

Neurogenesis

is

deﬁned

as

the

process

generating

new

nerve

cells.

Neurogenesis

initiated

from

neural

stem

cells

and

resulting

in

functional

new

neurons,

is

a

fundamental

process

for

both

embry-

onic

neurodevelopment

and

adult

brain

plasticity

(Shi

et

al.,

2010).

In

a

wider

concept,

neurogenesis

is

a

process

of

creating

properly

functional

neurons,

including

neural

stem

cell

proliferation

and

fate

speciﬁcation,

neuronal

migration,

maturation,

and

integration

into

neural

networks.

Neurogenesis

from

undifferentiated

neural

stem

progenitor

cells

(NSPCs)

determines

the

cellular

quantity

in

the

developing

brain

and

the

formation

of

neurons,

astrocytes,

oligo-

dendroglia,

and

other

neural

lineages.

Meanwhile,

NSPCs

replenish

the

undifferentiated

cell

pool

via

continued

proliferation.

Thus,

any

chemicals

or

drugs

interfering

in

the

neurogenesis

of

NSPCs

in

the

developing

brain

can

alter

normal

development

of

the

brain.

In

developmental

neurotoxicological

studies,

NSPCs

can

serve

as

an

ideal

tool

to

clarify

and

evaluate

potential

risks

of

various

toxic

factors

in

the

developing

brain

(Breier

et

al.,

2010).

The

NMDA

receptor

is

one

type

of

inotropic

calcium

chan-

nel

receptor,

composed

of

obligatory

NR1

and

regulatory

NR2

(NR2A-D)

and/or

NR3

(NR3A-B)

subunits

(Furukawa

et

al.,

2005).

The

expression

of

NMDA

receptor

subunits

presents

developmen-

tal

stage-dependent

and

brain

region-dependent

differences

in

the

developing

brain.

The

expression

patterns

of

NMDA

receptor

subunits

in

different

brain

regions

can

be

regulated

as

develop-

ment

proceeds.

Compared

to

the

wide

distribution

of

NR1-subunit

expression

throughout

the

CNS

at

all

ages,

the

expression

proﬁles

of

the

NR2subunits

in

the

brain

are

developmentally

and

regionally

regulated

(Ishii

et

al.,

1993).

Neural

stem

progenitor

cells

are

con-

sidered

to

have

no

or

little

expression

of

NMDA

receptors

until

they

are

completely

differentiated.

directly

detected

the

expression

of

NMDA

receptor

subunits

in

NSPCs

from

different

sources.

Immunocytochemical

analysis

showed

expression

of

NR1,

NR2A,

and

NR2B

subunits

in

cultured

neurospheres

(Joo

et

al.,

2007;

Kitayama

et

al.,

2004;

Mochizuki

et

al.,

2007;

Ramirez

and

Lamas,

56 C.

Dong,

K.J.S.

Anand

/

Toxicology

Letters

220 (2013) 53–

60

Fig.

1.

Developmental

neurotoxic

effects

of

ketamine

on

NSPCs

and

developing

neurons

in

the

developing

brain.

During

normal

brain

development,

neural

stem

progenitor

cells

including

neural

stem

cells

(NSCs)

and

neural

progenitor

cells

(NPCs),

differentiate

into

neurons

following

a

normal

development

program.

In

this

maturation

process,

the

expression

of

NMDA

receptor

subunits

is

regulated

in

developmental

stage

and

brain

regions

dependent

manners.

Also,

functions

of

NMDA

receptors

turn

into

being

mature

after

a

complete

differentiation.

However,

ketamine

can

disturb

normal

expression

patterns

of

NMDA

receptors,

leading

to

pre-maturation

of

functional

NMDA

receptors.

In

this

scenario,

NSPCs

have

lower

proliferative

ability

and

differentiate

into

neurons

at

the

earlier

developmental

stage.

More

functional

NMDA

receptors

expressed

in

these

pre-matured

neurons

can

make

themselves

susceptible

to

ketamine-induced

cell

death.

As

a

result,

normal

developmental

patterns

of

a

brain

is

reset

to

an

earlier

developmental

stage

and

further

brain

structure

and

functions

could

be

disordered,

under

the

exposure

to

ketamine.

2009).

The

expression

of

NMDA

receptors

containing

NR1

and

NR2B

were

found

in

human

neural

progenitor

cells

and

NR2B

was

the

predominant

NR2

subunit

(Hu

et

al.,

2008;

Suzuki

et

al.,

2006;

Wegner

et

al.,

2009;

Zhang

et

al.,

2004).

The

expression

patterns

of

NMDA

receptor

subunits

in

NSPC

cultures

are

also

time-dependent.

NR2A,

NR2B,

and

NR2D

subunit

transcripts

are

present

in

both

non-

differentiated

and

neuronally

differentiated

cultures,

while

NR2C

subunits

were

expressed

only

transiently

during

the

early

period

of

neural

differentiation.

NR1

and

NR2B

can

be

detected

in

rat

fetal

cortical

NSPCs,

but

the

calcium

current

cannot

be

recorded

in

these

cultures

(Yoneyama

et

al.,

2008).

This

ﬁnding

implies

that

NSPCs

have

already

expressed

NMDA

receptors

but

these

receptors

may

be

nonfunctional

(Dong

et

al.,

2012).

Other

studies

also

support

that

functional

NMDA

receptors

are

absent

in

NSPCs

until

a

cer-

tain

stage

of

neuronal

commitment

or

the

appearance

of

synaptic

communication

despite

of

the

expression

of

their

subunits

(Jelitai

et

al.,

2002;

Muth-Kohne

et

al.,

2010;

Varju

et

al.,

2001).

We

found

that

ketamine

does

not

induce

cell

death

in

the

in

vitro

cultured

rat

fetal

cortical

NSPCs

(Dong

et

al.,

2012).

This

ﬁnding

could

be

explained

by

no

expression

of

functional

NMDA

receptors

in

NSPCs.

Some

studies

showed

even

high

levels

of

glutamate,

up

to

1

mM

fail

to

induce

toxic

effects

in

neural

precursor

cultures

until

late

stages

of

neuronal

differentiation

(Brazel

et

al.,

2005;

Buzanska

et

al.,

2009;

Hsieh

et

al.,

2003).

Therefore,

compared

with

primary

neuronal

cells,

NSPCs

appear

to

have

a

high

resistance

to

neurotox-

icity

induced

by

glutamate

or

NMDAR

antagonists

like

ketamine

(

Fig.

1).

The

developmental

patterns

of

NMDA

receptor

subunit

expres-

sion

can

be

regulated

by

NMDA

receptor

antagonists

like

PCP,

MK-801,

and

ketamine.

Acute

exposure

to

PCP

at

PND7

increases

membrane

levels

of

both

NR1

and

NR2B

proteins

in

the

frontal

cortex;

but

decreases

NR1

and

NR2B

levels

in

the

endoplasmic

reti-

culum

fraction

(Anastasio

and

Johnson,

2008).

Remarkable

increase

in

NR1mRNA

signals

appear

in

the

frontal

cortex

under

the

expo-

sure

of

ketamine

in

situ

hybridization

assay

(Zou

et

al.,

2009b).

NMDA

receptor

subunits

mRNA

in

the

developing

brain

are

rapidly

altered

under

the

exposure

to

MK-801.

The

increase

of

NR2A

mRNA

is

greater

than

NR1,

NR2B

or

NR2D

(Wilson

et

al.,

1998).

Chronic

PCP

administration

in

postnatal

rats

produces

signiﬁcant

reduction

in

NR2B

subunits

in

the

cerebral

cortex,

whereas

the

expression

of

the

other

NMDA

receptor

subunits

does

not

change

in

the

cere-

bral

cortex

following

drug

treatment

(Sircar

et

al.,

1996).

For

NSPCs,

our

unpublished

data

showed

that

ketamine

can

dose-dependently

upregulate

NR1

expression

in

rat

fetal

cortical

NSPCs.

The

upre-

gulated

NR1

expression

may

increase

the

proportion

of

functional

NMDA

receptors

in

differentiating

NSPCs

and

enhance

the

suscep-

tibility

of

neural

progenitor

cells

at

the

late

differentiation

stage

to

ketamine

(Fig.

1).

In

the

mammalian

brain,

amino

acid

neurotransmitters,

gluta-

mate

and

aspartate,

mediate

mainly

excitatory

neurotransmission.

High

levels

of

glutamate

are

found

during

neurogenesis

in

several

CNS

developing

areas

(Benitez-Diaz

et

al.,

2003;

Miranda-Contreras

et

al.,

1999,

1998,

2000).

Therefore,

the

antagonism

of

NMDA

receptors

is

possibly

involved

in

disturbing

the

normal

process

of

neurogenesis,

proliferation

and

differentiation

of

NSPCs

during

the

CNS

development.

5.1.

Proliferation

of

neural

stem

progenitor

cells

is

changed

under

the

exposure

to

glutamate

or

glutamate

receptor

antagonists.

Proliferation

and

neuronal

differentiation

of

hippocampal

neu-

ral

progenitor

cells

were

increased

by

the

activation

of

NDMA

receptors

(Joo

et

al.,

2007).

Proliferative

state

of

rat

hippocampal

progenitor

cells

is

associated

with

low

level

NMDA-induced

cur-

rent

(

Sah

et

al.,

1997).

Sustained

exposure

to

NMDAR

antagonist

decreases

the

diameter

and

number

of

neurospheres

formed

by

hippocampal

neural

progenitor

cells

(Mochizuki

et

al.,

2007).

The

proliferation

of

striatal

neuronal

progenitors

also

is

enhanced

by

glutamate

exposure

in

vivo

and

in

vitro

by

an

NMDA

receptor-

mediated

mechanism

(Luk

et

al.,

2003;

Luk

and

Sadikot,

2001;

Sadikot

et

al.,

1998).

In

the

models

of

human

and

rat

NSPCs

from

the

fetal

cortex,

the

activation

of

glutamate

receptors

also

stimulates

the

increase

of

cell

division

(Luk

and

Sadikot,

2004;

Suzuki

et

al.,

2006

).

Another

in

vivo

study

reported

that

the

glutamate

release

following

perinatal

hypoxia/ischemia

may

act

to

acutely

promote

the

proliferation

of

multipotent

precursors

in

the

subventricular

zone

(Brazel

et

al.,

2005).

NMDA

receptor

activation

also

induces

postnatal

Müller

glia-derived

retinal

cell

progenitor

proliferation

both

in

culture

and

in

vivo

(Ramirez

and

Lamas,

2009).

C.

Dong,

K.J.S.

Anand

/

Toxicology

Letters

220 (2013) 53–

60 57

In

contrast,

a

couple

of

studies

using

hippocampal

progeni-

tor

cells

show

an

opposite

effect

that

NMDA

exposure

reduces

the

proliferation

ability

and

inhibits

the

formation

of

neuro-

spheres

(Yoneyama

et

al.,

2008).

The

inhibition

of

the

proliferation

in

hippocampal

NPCs

(neural

progenitor

cells)

is

mediated

by

NMDA

receptors

and

is

regulated

by

the

transient

expression

of

NMDA

receptors

(Kitayama

et

al.,

2004,

2003).

Another

NMDA

receptor

antagonist,

memantine

can

increase

the

proliferation

of

hippocampal

progenitor

cells

by

inducing

up-regulation

of

Pigment

Epithelium

Derived

Factor

(PEDF)

(Namba

et

al.,

2010).

Addition-

ally,

in

the

mouse

hippocampal

slice

cultures,

NMDA

triggers

delayed

neuroblast

proliferation

in

the

dentate

gyrus

(Bunk

et

al.,

2010

).

Obviously,

the

effects

of

NMDAR

activities

on

the

proliferation

of

NSPCs

are

different

in

the

NSPCs

isolated

from

different

brain

regions.

This

difference

may

be

associated

with

the

temporal

and

brain

regional

speciﬁc

characteristics

of

the

expression

patterns

of

NMDAR

subunits.

NSPCs

in

different

brain

regions

at

certain

devel-

opment

stage

have

a

different

composition

of

NMDAR

subunits,

resulting

in

different

responses

of

NMDAR

activity

on

proliferation.

Additionally,

NMDAR

activity

induced

proliferation

changes

may

not

be

directly

mediated

by

functional

NMDAR,

but

by

growth

fac-

tors

generated

by

NSPCs

under

the

exposure

of

NMDAR

agonists

or

antagonists

(Namba

et

al.,

2010).

The

expression

of

functional

channels

and

receptors

in

primary

cultures

of

progenitor

cells

is

regulated

by

growth

factors

such

as

BDNF,

and

NT-3

from

NSPCs

(

Sah

et

al.,

1997).

Proliferation

changes

in

the

developing

brain,

resulting

from

ketamine

exposure

may

be

ketamine-

altered

growth

factors

levels

secreted

from

NSPCs.

5.2.

Differentiation

Glutamate

is

currently

recognized

as

a

regulator

in

the

neu-

ral

differentiation

of

NSPCs

(Bading

et

al.,

1995).

Its

application

to

postnatal

rat

whole-brain

dissociated

cell

cultures

promotes

neuronal

growth

and

differentiation

(Aruffo

et

al.,

1987).

NMDAR

activation

promotes

neurite

outgrowth

from

cerebellar

granule

cells

(Pearce

et

al.,

1987)

and

dendritic

outgrowth

and

branch-

ing

of

hippocampal

cells

(Brewer

and

Cotman,

1989;

Huerta

et

al.,

2000;

Mattson

and

Kater,

1988).

Additionally,

activation

of

NMDAR

transiently

expressed

in

undifferentiated

NPCs

in

fetal

rat

neo-

cortex

promotes

neuronal

differentiation

(Yoneyama

et

al.,

2008).

Excitatory

stimuli

act

directly

on

adult

hippocampal

NPCs,

which

can

increase

neuronal

production.

The

excitation

mediated

via

l-

type

Ca

2+

channels

and

NMDAR

on

the

proliferating

precursors

can

inhibit

expression

of

the

glial

fate

genes

Hes1

and

Id2

and

increase

the

expression

of

NeuroD,

a

positive

regulator

of

neuronal

differen-

tiation

(Deisseroth

et

al.,

2004).

Enhanced

neuronal

differentiation

in

NPCs

is

regulated

by

complex

interactions

between

Ca

2+

inﬂux

and

excitation-releasable

cytokines,

even

at

mild

levels

of

excita-

tion

(Joo

et

al.,

2007).

The

precise

cellular

role

of

NMDAR

in

the

neuronal

differentia-

tion

of

NSPCs

remains

unclear

due

to

quite

a

few

opposing

opinions.

In

hippocampal

slice

cultures,

the

exposure

to

IGF-I

and

EGF

and

NMDA

receptor

antagonists

MK-801

or

APV

increases

granule

cell

neurogenesis

from

preexisting

neural

precursors

(Poulsen

et

al.,

2005

).

The

increase

of

Ca

2+

inﬂux

mediated

by

NMDA

receptors

is

accompanied

with

decreased

neuronal

marker-microtubules-

associated

protein-2

(MAP2)

expression

in

hippocampal

neurons

cultured

under

static

magnetism

without

cell

death

(Nakamichi

et

al.,

2009).

Moreover,

in

human

neuroblastoma,

cells

having

stem

cell-like

qualities,

a

signaling

cascade,

including

Ca

2+

inﬂux

and

NMDA

receptor

activity,

is

identiﬁed

as

playing

a

role

in

the

regu-

lation

of

neurogenesis.

This

pathway

functions

to

maintain

BE(2)C

cells

in

an

undifferentiated,

proliferative

state.

Therefore,

it

is

still

necessary

to

clarify

whether

NMDA

receptor

antagonist

can

inhibit

the

proliferation

as

well

as

promote

differentiation

in

progenitor

cells.

NMDA

receptors

also

appear

to

be

involved

in

determining

the

differentiation

direction

in

NSPCs.

Astrocytic

nestin

expression

in

less

differentiated

CNS

cells

is

mediated

by

NMDA

receptors.

MK-

801

treatment

can

inhibit

NMDA

receptor

dependent

astrocytic

nestin

expression,

suggesting

the

antagonism

of

NMDA

recep-

tors

may

inhibit

the

commitment

of

NSPCs

to

glial

differentiation

(

Holmin

et

al.,

2001).

In

NMDA-treated

retinas,

the

differentia-

tion

of

NPCs

preferred

the

glial

lineage

through

gp130

signaling

(

Mawatari

et

al.,

2005).

A

recent

study

also

reported

that

functional

NMDA

receptor

subunits

are

expressed

in

glia

(Schipke

et

al.,

2001).

Glutamate

may

stimulate

the

phosphorylation

of

glial

ﬁbrillary

acidic

protein

(GFAP)

via

NMDA

receptors

in

cortical

microslices

and

in

mixed

neuronal/glial

cell

cultures

prepared

from

the

cerebel-

lum

(Kommers

et

al.,

2002).

These

data

present

us

some

clues

for

the

involvement

of

NMDA

receptors

in

determining

the

differentiation

direction

of

NSPCs.

Calcium

inﬂux

may

play

a

role

in

the

neuronal

differentiation

of

NPSCs.

On

examining

the

expression

of

NMDAR

in

NSPCs,

it

is

evident

that

there

are

few,

if

any,

functional

NMDA

receptors

on

NSPCs,

which

explains

the

resistance

of

NSPCs

to

ketamine-induced

neurotoxic

effects.

show

that

ketamine

can

induce

the

expression

of

NR1

in

mature

neurons

(Wang

et

al.,

2005)

and

in

NSPCs(

Dong

et

al.,

2012).

Ketamine

exposure

induces

the

expres-

sion

of

NMDAR

subunits

to

build

up

more

functional

NMDAR

as

the

differentiation

proceeds.

These

newly-induced

NMDA

recep-

tors

can

trigger

calcium

inﬂux

to

promote

neuronal

differentiation

(

Fig.

1).

This

may

indicate

a

potential

mechanism

for

ketamine-

enhanced

neuronal

differentiation

in

NSPCs.

6.

Conclusions

Ketamine

is

widely

used

as

an

anesthetic,

analgesic,

and

seda-

tive

in

obstetric

and

pediatric

settings

and

also

as

an

illicit

club

drug

consumed

by

pregnant

drug

abusers.

Also,

extrapolating

from

adult

studies,

the

off-label

use

of

ketamine

has

been

explored

as

an

antidepressant

in

the

treatment

of

pediatric

bipolar

disorders

(

Papolos

et

al.,

2012).

Despite

this

widespread

use,

many

lines

of

evidence

indicate

that

ketamine

can

induce

neuronal

cell

death

of

and

disturb

the

normal

neurogenesis

of

NSPCs

in

the

developing

brain,

via

effects

on

both

proliferation

and

differentiation.

Recent

studies

have

already

indicated

that

ketamine

can

result

in

long-

lasting

cognitive

deﬁcits

in

a

primate

model

(Paule

et

al.,

2011).

Developmental

neurotoxic

effects

of

ketamine

should

be

investi-

gated

as

a

new

clinical

complication

resulting

from

ketamine

use

in

large

doses

and/or

for

prolonged

periods

of

time,

in

obstetric

and

pediatric

clinical

practices

and

in

the

setting

of

drug

abuse.

7.

Future

directions

Current

ﬁndings

that

ketamine

induces

neuronal

cell

death

and

alters

neurogenesis

in

the

developing

brain

are

based

on

animal

studies,

mostly

in

rodents

and

primates.

Clearly,

future

ketamine

studies

must

clarify

whether

ketamine

can

induce

the

same

toxic

effects

in

the

developing

human

brain.

Well-designed

studies

are

needed

to

systematically

evaluate

the

potential

developmental

neurotoxic

proﬁle

of

current

ketamine

use

protocols

in

pediatric

and

obstetric

practice.

Furthermore,

it

is

critical

to

further

elucidate

the

mechanisms

by

which

ketamine-induced

NMDA

receptor

antagonism

leads

to

cell

death

in

mature

neurons

and

altered

neurogenesis

in

neural

stem

progenitor

cells.

Once

the

speciﬁc

NMDA

receptor

subunits

or

cell

signaling

pathways

are

identiﬁed

that

result

in

those

toxic

effects,

novel

compounds

or

derivatives

of

ketamine

that

are

more

selective

58 C.

Dong,

K.J.S.

Anand

/

Toxicology

Letters

220 (2013) 53–

60

for

NMDA

receptor

subunits

or

activate

other

cell

signaling

path-

ways

can

be

developed.

As

for

other

clinically

used

NMDA

receptor

antagonists

like

dextromethorphan,

amantadine,

and

memantine,

the

potential

developmental

neurotoxic

proﬁles

in

their

clinical

use

also

need

to

be

evaluated

further.

A

wider

collaboration

among

lab-

oratory

investigators,

clinician-scientists,

and

pediatric

physicians

will

explicate

the

developmental

neurotoxic

effects

of

ketamine

and

promote

safe

and

effective

clinical

use

of

ketamine

in

the

future.

Conﬂict

of

interest

statement

The

authors

declare

that

there

are

no

conﬂicts

of

interest.

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