MK801 pretreatment reduces kainic acid-induced spontaneous seizures in prepubescent rats

41

Epilepsy Research, 14 (1993) 41-48 0920-121 l/93/$06.00

EPIRES

0

1993 Elsevier Science Publishers

B.V. All rights reserved

00534

MK80 1 pretreatment reduces kainic acid-induced spontaneous seizures in prepubescent rats

Carl E. Stafstrom,

Gregory

L. Holmes

and James L. Thompson

Department of Neurology, Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA (Received

10 April

1992; revision

Key words; Immature

MK801 is a noncompetitive pretreatment epilepsy, With

in immature

intermittent

MK801

blocker of N-methyl-D-aspartate

video monitoring,

MKSOl treated

llurothyl;

These results show that MK801 seizure susceptibility,

KA caused

was significantly

rats (43%) developed

using the volatile convulsant

receptors

which has antiepileptic

recurrent

i.p.) or saline was administered

pretreatment,

1992; accepted

prolonged

lower in MK801

at both doses of MK801,

while not substantially

to prepubescent

MK80 1 [( + )-5-methyl- 10,ll -dihydro-SH-dibenzo[a,dcyclo-hepten-5, lo-imine maleate] is a noncompetitive blocker of the N-methyl-D-aspartate (NMDA) receptor38. Accumulating evidence implicates NMDA receptors in the pathogenesis of epilepsy and seizure related brain damage6. In several animal models of epilepsy, MK801 has antiepileptogenic properties, and this compound has been suggested as a potentially useful therapeutic agent for humans2’. Kainic acid (KA), a potent gluta-

Correspondence to: Carl E. Stafstrom, MD, PhD, Division of Pediatric Neurology, Box 3533, Duke University Medical Center, Durham, NC 27710, USA. Tel.: 919-684-3219; Fax: 919-681-8943.

properties.

To evaluate

whether

MK801

in a model of limbic

rats 30 min prior to kainic acid (KA; 10 mg/kg,

epilepticus.

treated

rats than in those which received KA alone. In addition,

flurothyl

SRS rate over the next 4 weeks, to generalized

seizure latency was significantly

status epilepticus

the acute epileptogenic

Introduction

Flurothyl

status

prior to KA induced altering

1992)

seizure (SRS) rate or seizure susceptibility

SRS than those which got KA alone (88%). Susceptibility

pretreatment

1 October

MKSOI; Kainic acid; Seizures; Status epilepticus;

rats affects the future spontaneous

MK801 (0.2 or 1.0 mg/kg,

or without

brain;

received 28 September

reduces

subsequent

greater

i.p.).

as assessed

by

fewer

seizures was then tested in pretreated

SRS frequency

animals.

and flurothyl

effects of KA.

mate analog with neuroexcitant and neurotoxic properties, causes seizures and brain damage when injected systemically or intracerebrally, and KA seizures simulate many features of human temporal lobe epilepsy2322. KA causes acute limbic-onset partial seizures which secondarily generalize and progress to status epilepticus (SE). Weeks to months later, spontaneous recurrent seizures (SRS) develop3327, with interictal behavioral and cognitive abnormalities’07’3333. KA also causes prominent neuronal necrosis in limbic structures22330. It was of interest to determine whether these chronic sequelae of KA can be prevented by pharmacological pretreatment, especially in KA treated immature rats, which have previously been shown to exhibit enhanced susceptibility to kindled seizures as adults12. Although the predominant action of KA is at non-NMDA receptors, there is

42

some evidence that NMDA fy KA seizures4*‘,‘s.

antagonists

can modi-

To assess whether MK801 could protect the developing brain from long-term KA induced epileptic abnormalities, we pretreated with either MK801 or saline,

prepubescent rats then administered

KA 30 min later. During the 4 weeks following status epilepticus, we assessed SRS frequency with video monitoring, then tested susceptibility to generalized tonic-clonic seizures using the volatile convulsant flurothyl. Methods Animals Male Sprague-Dawley rats (n = 30) of postnatal age 25 days (P25) (Charles River Laboratories, Cambridge, MA) were used in these experiments (PO defined as the day of birth). Rats were housed in pairs in plastic cages with a 12jl2-h light/dark cycle. Animals had free access to food and water. On P23, rats were anesthetized with a mixture of intraperitoneal (i.p.) ketamine hydrochloride (50 mg/kg~ and xylazine (2 mg/kg). Bipolar electrodes (Plastic Products, Roanoke, VA) were then stereotaxically implanted into the left ventral hippocampus (coordinates from bregma in mm: AP - 1.6, DV - 6.0, ML 4.6). Electrodes consisted of insulated 0.25 mm diameter steel wires twisted together except at the tips. The electrode was anchored to the skull using dental acrylic and two stainless screws.

steel

Kainic acid injection and recording On P25, rats were divided into three pretreatment groups of 10 rats each: control (phosphate buffered saline i.p.), 0.2 mg/kg MK801 i.p. or 1.0 mg/kg MK801 i.p. Thirty minutes after pretreatment, all rats were administered KA, 10 mg/kg i.p. Electroencephalographic (EEG) activity was recorded from the hippocampal electrode for 5510 min prior to pretreatment, for at least two 5-min epochs following pretreatment, and intermittently for 3-6 h following KA. Clinical behavior and seizure activity were continuously monitored during this phase of the experiment. Status epilepticus was defined as continuous ictal activity for greater than 20 min.

SRS occurrence was evaluated using intermittent closed circuit video monitoring. Each animal was videotaped for > 24 h, in 6-h sessions, regularly spaced over the 4 weeks following ISA treatment. An equal number evening recording sessions trol for diurnal variablility wide angle ing of 69

KA or MK801/ of daytime and

were included to conin SRS frequency. A

lens permitted simultaneous videotapanimals. Observers were blind to the

treatment status of each rat. SRS were categorized according to seizure stage: stage 1 (agitation or immobility), 2 (wet dog shakes or scratching). 3 (myoclonic jerks or facial clonus/chewing), 4 (forelimb clonus), and 5 (forelimb cfonus with rearing or falling). Only stage 3, 4 or 5 seizures were considered in the analysis of SRS.

On about P70, seizure susceptibility was tested using flurothyl ether (Indoklon), a volatile convulsant that causes a stereotyped progression of generalized seizures when inhaled: myoclonic jerks (MJ) followed by bilateral forelimb clonus (FC), loss of posture (LP) and wild running (WR). Seizure susceptibility was defined as the latency to myoclonic jerks. Rats were placed in an airtight clear plastic chamber (12 x 12 x 5.25 inches) under a ventilation hood. Within the chamber were four com~rtments of equal size, separated by a wire mesh screen, thus accommodating four rats (experimentals and controls) in each trial. Liquid flurothyl (bis-2,2,2-trifluoroethyl) was delivered onto a 2-inch piece of filter paper in the center of the chamber at constant rate of 38 pl/min via an infusion pump (Harvard Apparatus). Observers blind to the treatment status of each rat manually timed the onset of each seizure stage. Pathology After flurothyl testing, rats were killed and their brains prepared for histology. Animals were injected with a lethal dose of pentobarbital, then their hearts were perfused with Ringer’s lactate followed by 10% formalin phosphate. Brains were removed and stored in formalin for about 2 months. Sections of 20 pm were cut and stained with hematoxylin & eosin (H & E). Electrode placement was verified in all animals. Sections were analyzed for

43

necrosis

and gliosis, but cell counting

was not per-

formed. Data analysis A two-way analysis

a-of variance

(ANOVA)

was

used to compare latencies to MJ, FC, LP, and WR during flurothyl exposure between the three treatment groups. A one-way ANOVA with post hoc Dunnett’s multiple comparison procedure was used to compare means of the three treatment groups within a given flurothyl seizure stage and SRS frequency. The significance level was defined as 0.05 for all tests.

Fig. 1. MK801 seizures. mg/kg,

does not ameliorate

EEG traces i.p.). Thirty

was pretreated

before minutes

KA induced

electrographic

(a) and 30 min after (b) KA (10 prior

to trace (a), the control

with i.p. saline and the experimental MK801

rat

rat with i.p.

(0.2 mg/kg).

Results Acute response to MK801 and KA Rats which received 0.2 mg/kg MK801 developed mild wet dog shakes (WDS), slight hypotonia with hindlimb splay, and some displayed increased motor activity interspersed with periods of hypoactivity. Righting responses were slightly reduced. Rats which got 1.0 mg/kg MK801 were more severely affected, with pronounced WDS, hyperactivity alternating with immobility, tremulousness, ataxia, restlessness and hypotonia. At both doses of MK801, the EEG became slightly slower with some higher voltage waveforms, as has been reported by others’. After KA administration, all rats developed SE. In all treatment groups, seizures began with immobility (freezing), followed by WDS and scratching, forelimb and facial clonus with salivation, rearing, and falling. During SE, eight of the 30 rats died (two from the KA only group, and three from each of the MK801 groups), for a mortality rate of 27%. Seizure intensity and duration were simi-

TABLE

lar in the control and 0.2 mg/kg MK801 groups. In the 1.0 mg/kg MK801 group, behavioral seizures were sometimes less severe, with less forceful clonic movements, although all animals developed stage 5 seizures acutely after KA administration. Electrographic seizures were not diminished by either dose of MK801, and ictal EEG changes included high voltage rapid spikes in all groups. The duration of electrical SE (minutes f SD) was 164.4 f 55.9 in the control group, 167.0 f 48.3 in MK-0.2, and 130.5 f 30.7 in MK-1.0 (NS, one-way ANOVA, P = 0.10). As seen in Fig. 1, ictal discharges were similar in control and MK801

pretreated

animals.

SRS After recovery from SE, surviving rats underwent video monitoring for SRS. Table I describes some of the features of SRS in the three treatment groups. A smaller percentage of rats pretreated with MK801 developed SRS, and SRS among MK801 pretreated rats were less severe (no stage

I

Spontaneous recurrent seizures n

% of rats

Stage 3

Stage 4

Stage 5

with SRS

SRS frequency (SRS/24

h & SEM)

8

88

15

7

1

3.3

KA + MK801

(0.2 mg/kg)

I

43

5

0

0

0.74 * 0.38’

KA + MK801

(1.0 mg/kg)

I

43

8

0

0

1.18 k 0.62’

KA only

*Significantly

different

from KA only group,

P ~0.05.

f 0.98

44

stage (F= 13.57; P=O.OOOO), but not their interaction (F=0.74; P=O.617). Post hoc Dunnett’s tests

TIMING OF SRS OCCURRENCE

showed that animals pretreated with either dose of MK801 demonstrated a significantly increased la-

7.

6

tency to the first two stages (MJ, FC) (P~0.05; Fig. 3).

5

of flurothyl

seizures

4’ 3-

I

2. II Oi

1

2

3

WEEK KA Fig.

L_mI1l 0.2 mg/kg MKSOl

2. SRS occurrence

during

AFTER

KA

KA

m

l

4

1.0 mglkg

MK601

* KA

the 4 weeks of video monitoring.

Fewer SRS were seen with MKSOI pretreatment

Histology No major hippocampal or cortical lesions at the light microscopic level were noted in either control or MK801 pretreated animals (Fig. 4). One control and one MK801 (0.2 mg/kg) pretreated brain had slight disorganization of the CA3 pyramidal layer, which probably represent nonspecific findings.

in each week.

Discussion 4 or 5 seizures were observed). Both MK801 pretreated groups had a significantly lower SRS frequency than did rats treated with KA only. Fig. 2 illustrates the timing of SRS occurrence. There was no particular pattern to SRS occurrence over time, with a similar number of SRS within each group occurring in each of the 4 weeks of video recording. Seizure susceptibility

to jlurothyl

When tested on about P70, all rats developed typical seizures in response to flurothyl: myoclonic jerks, forelimb clonus, loss of posture and wild running. Two-way ANOVA was significant for treatment

group

MJ

(F= 3.14; P = 0.047) and

FC

Seizure

Fig. 3. Latency

to the various

LP

seizure

WR

Stage

stages of flurothyl

seizures. Com-

pared to KA (IO mg/kg, i.p.) alone, rats pretreated with either 0.2 or 1.0 mg/kg i.p. MK801 had significantly longer latencies to the first two stages of flurothyl ANOVA

seizures (asterisks,

with post hoc Dunnett’s

test, PcO.05).

two-way

The main findings of this study are that in the KA model of epilepsy in the prepubescent rat, MK801 pretreatment reduces the number of chronic spontaneous seizures and increases the latency to flurothyl seizures. Therefore, this NMDA receptor antagonist ameliorates two of the longterm sequelae of KA seizures in prepubescent rats, although it does not substantially alter the acute seizure stage (SE). We have previously shown that KA administered to developing rats causes SE followed by an age dependent increase in SRS frequency; no SRS were seen in rats given KA on PlO or younger, whereas there were progressively more SRS in rats given KA from P20 to P6032. Among rats given KA as prepubescents (P20, P30) in that study, only those which developed SRS had a significantly reduced latency to flurothyl seizures. We also previously reported that prepubescent rats given KA on P27 kindle to stage 5 seizures faster than controls when tested either 3 days later or as adults12. Therefore, in prepubescent rats, KA causes both short- and long-term enhanced seizure susceptibility. We did not detect pathological damage after KA in either saline or MK801 pretreated animals, and thus could not compare the effect of MK801 pretreatment on KA induced neurodegenerative changes. Intraperitoneal KA can produce CA1 and CA3 damage (mostly to hilar glia and nonpyramida1 cells of stratum oriens and stratum radiatum) in P24 rats killed l-2 weeks later23. Others have

45

Fig. 4. Photomicrographs

of H & E stained

(A) KA alone. (B) Pretreated

hippocampal

with 1.0 mg/kg

sections from rats treated

i.p. MK801,

with KA (10 mg/kg,

30 min prior to KA. No major

i.p.) on P25 and killed on P70. Bar = 200 pm.

lesions are noted.

46

also not noted histological changes when KA was administered at similar ages and animals were kil-

cling movements3’. NMDA receptor

led months later, although detailed neuropathology was not performed’2.‘4. In rats given KA at

activity in a wide variety of experimental seizure models20*26,36, and this agent clearly protects certain neuronal populations from damage caused by

younger

ages (Pl5-18)

histological

damage

and killed 5 days later, no

was seen’. In rats given KA at

P20 or P30 and killed as adults, about 50% of the animals showed hippocampal lesions, with more extensive damage in those rats undergoing SRS’* (Stafstrom et al., unpublished data). These observations corroborate those of Nitecka and Tremblay24, who noted greater damage in adult KA treated rats with SRS than those without overt spontaneous seizures, and raise the intriguing possibility that seizure induced damage with subsequent synaptic rearrangement may predispose to SRS following KA administration’. The methodology of this study differs somewhat from our previous work. P25 animals were used, and the KA dose was slightly higher (10 mg/kg here, compared to 8 and 10 mg/kg for P20 and P30 rats, respectively, in the previous studys2). The higher dose was chosen in order to produce a higher SRS frequency. Since the mortality rate is dependent on the KA dose, there was a slightly greater mortality here (27%). In addition, here we included stage 3 SRS (chewing, facial clonus, repetitive myoclonic jerks) and monitored SRS for only 1 month post KA. It is possible that longer video monitoring would have increased the number of stage 4 and 5 SRS, but the finding of a statistically significant difference in SRS between treatment groups even in the first month after KA suggests that MK801 exerts a protective effect against spontaneous seizures. Acute, dose dependent behavioral effects of MK801 in adult animals have been noted by several investigators4979’5’26’35. At doses of less than about 0.1 mg/kg, few if any behavioral changes are apparent; in the range of 0.1-0.2 mg/kg, head weaving, body rolling, increased locomotion, and ataxia are seen. At higher doses, animals become increasingly ataxic, hypotonic, and sedated. Observations of MK801 effects in immature animals have been limited2993’936, but similar signs are noted: hypotonia, intermittent bursts of increased activity, loss of posture, abnormal movements such as wet dog shakes and (in P7 pups) rhythmic cy-

antagonists

exhibit antiepileptic

excitatory amino acids or the seizures they produce49’9. Although such noncompetitive NMDA receptor antagonists as MK801 are quite specific for NMDA sites39, there is some evidence of functional overlap between compounds active at NMDA and KA receptors34. Several studies have now shown that by use of NMDA antagonists, KA induced brain damage and electrical seizure activity can be dissociated. Pretreatment with competitive (APV) or noncompetitive (MK801, TCP) NMDA antagonists, followed by systemic4,7,‘8 or intracerebra189’6,28 KA leads to selective protection of various neuronal populations. NMDA blockers generally spare CA1 but not CA3 from the degenerative effects of KA, in accordance with the predominant distribution of NMDA receptors in CA 1 and KA receptors in CA3. One report, however, also cites MK801 protection of CA3 following KA7. Despite amelioration of neurodegeneration, hippocampal electrical seizure activity is not eliminated (and may even _be worsened7,31) by MK801 pretreament. This suggests that KA may be exerting part of its neurodegenerative effect through NMDA receptors, whereas KA receptors may be more responsible for actual seizure generation. Similar information is lacking in immature animals. Schoepp et al.29 found that in P7-11 rats, neither MK801 nor 6,7-dinitroquinoxaline-2,3dione - (DNQX, a selective non-NMDA receptor blocker) prevented KA seizures, although histological changes were not examined in that study. Although we detected no major KA induced histologic damage in these prepubescent rats, we cannot exclude the possibility that KA has caused damage at the cellular or subcellular level below detection by methods used here. The mechanisms by which seizures early in life might cause later epilepsy yet produce no detectable histologic lesion must remain speculative. Some possibilities might include genetic alteration of neurotransmitter receptor structure or function, such as expression of novel receptor properties4’ or immediate early gene expression17. These possibilities remain to be inves-

47

tigated. Whether or not early seizures in humans lead to later epilepsy is a complex and unresolved question’ ‘. Until now, the chronic effects of MK801 pretreatment on KA induced seizures have not been well studied. This issue is important, since MK801 is a potential clinically useful antiepileptic drug2’325. Since we show here that MK801 reduces spontaneous seizure occurrence in the 4 weeks following KA and increases the latency to subsequent generalized seizures, this agent may have some usefulness in reducing chronic epileptic sequelae. The side effects of MK801 (sedation, hypotonia) and its inability to suppress established seizures*’ may limit its potential clinical benefits. However, it may be possible to reduce side effects by concurrent anti-

cholinergic agents, diazepam, or barbiturates25,37. at least in immature animals, Furthermore, MK801 can suppress established kindled seizures as well as prevent their development36. Therefore, MK801 may yet find a role as an adjunctive medication. Acknowledgements

This work was sponsored by the American Epilepsy Society with support from the Milken Family Medical Foundation (C.E.S., G.L.H.), an Epilepsy Foundation of American Medical Student Summer Research Stipend (J.L.T.) and the Steven Linn Research Fund (G.L.H.).

References 1 Albala,

B.J., Moshi,

duced

seizures:

S.L. and Okada,

a developmental

R., Kainic

acid-in-

Dev. Brain Res., 13

study,

kainic

Y., Limbic

seizure and brain damage

acid: mechanisms

lobe epilepsy,

E.A.,

Long-term

and relevance

Neuroscience,

3 Cavalheiro,

Riche,

produced

to human

by

temporal

14 (1985) 375403. D.A.

and

for inducing

La Salle, G.,

kainic acid injection

spontaneous

recurrent

sei-

zures, Electroenceph. Clin. Neurophysiol., 53 (1982) 581-589. D.B., Olney,

Zorumski,

J.W.,

C.F., Ketamine,

tect against

kainic

Benz, A.M., phencyclidine,

acid-induced

Fuller,

T.A. and

and MK801

seizure-related

brain

prodam-

age, Epilepsiu, 31 (1990) 382-390. 5 Cronin,

of dentate

tory amino

Potentiation

of kainic damage

J.O., Excita-

Trends Neurosci.,

in epilepsy,

11

G.T., Smith, G.G.

and Reyes, P.F.,

epileptogenicity

by an NMDA

and

receptor

sparing

antagonist,

Epilepsy Rex, 3 (1989) 206213. 8 Foster, effects

G.N.,

in vivo: selectivity

Neuroprotective

and evidence

layed degeneration mediated by NMDA tion, J. Neurosci., 8 (1988) 47454754.

receptor

for deactiva-

9 French, J. and Domino, E.F., Comparative effects of phencyclidine, ketamine and MK801 on the rat electroencephalogram.

In: E.F. Domino

and Phencyclidine-Like

and J.-M.

10 Griffith,

Kamenka

disturbances

Sigma

MI, 1988, pp. 463472.

N., Engel Jr., J. and Bandler,

ing interictal

(Eds.),

Compounds as Molecular Probes in

Biology, NPP Books, Ann Arbor,

Thompson,

14 Holmes,

effects

in emotional

G.L., Thompson,

Hoy, J. and McLaughlin,

Marchi,

T. and Feldman,

acid

administration

J.L., Carl, G.F.,

Gallagher,

W., Woods,

B.S.,

in the pre-

rat, Epilepsy Res., 5 (1990) 125-130.

J.H. and Winger,

noncompetitive

antagonist produces

effects in pigeons,

on

M., Effect of 2-amino-7-phospho-

acid (APH) on seizure susceptibility and mature

G.D.,

MK801,

of excitatory

phencyclidine-like

rats and rhesus

a pro-

amino

acid

behavioral J. Pharmacol.

monkeys,

Exp. Ther., 245 (1988) 969-974. W., Simpson,

J.N. and McGinty,

J.F., Effects of

D-

(-)aminophosphonovalerate

on behavioral

changes

kainic acid, Neurosci. Len., 87

induced

by systemic

and histological

(1988) 23-28. c-fos oncoprotein

expression

and sequential

in kainic

increase

acid-induced

of

status

Neurosci. Left., 88 (1988) 127-130.

epilepticus,

18 Lerner-Natoh, M., Rondouin, G., Belaidi, M., Baldy-Moulinier, M. and Kamenka, J.M., N-[1-(2-Thienyl)cyclohexyl]piperidine

(TCP) does not block kainic

epilepticus

but

reduces

secondary

acid-induced

hippocampal

status damage,

Neurosci. Lett., 122 (1991) 174178. 19 McDonald,

J.W.,

Neuroprotective

R., Ictal and endur-

against

behavior

vivo perinatal

in an ani-

Dev. Bruin

brain,

Epilepsia, 29 (1988) 721-730.

brain,

noheptanoic

J.L.,

of kainic

17 Le Gal La Salle, G., Long-lasting

A.C., Gill, R. and Woodruff, of MK801

J.L., Effects of kainic acid on

in the developing

neurotransmission,

C.J. and McNamara,

acid

G.L.,

Behavioral

the immature

16 Lason,

R.G., Golden,

from neuronal

D.S.,

posed

(1990) 334338. 7 Fariello,

13 Holmes,

15 Koek,

R., McBain,

of seizures in (1990) 7-13.

Res., 39 (1988) 51-59.

seizures and collateral

F.E., Chronic

acid receptors

G.L. and Thompson, susceptibility

pubescent

in rats, Brain Rex, 474 (1988) 181-184. 6 Dingledine,

12 Holmes,

mossy fibers after kainic acid treatment

J. and Dudek,

sprouting

brain, J. Epilepsy, 3 (Suppl.)

the developing seizure

Le Gal

effects of intrahippocampal

in rats: a method 4 Clifford,

Brain Res., 400 (1987)

lobe epilepsy,

360-364.

II Holmes, G.L. and Moshe, S.L., Consequences

(1990) 139-148. 2 Ben-Ari,

ma1 model of temporal

Silverstein, effects

N-methyl-o-aspartate

F.S.

of MK801, induced

and TCP,

Johnston, PCP

neurotoxicity

M.V., and

CPP

in an in

rat model, Brain Res., 490 (1989) 3340.

48

20 McNamara, D.W.,

J.O.,

Russell,

Anticonvulsant

MK80l

in

the

R.D.,

and

Rigsbee,

L. and Bonhaus,

antiepileptogenic

kindling

and

actions

electroshock

of

models,

Neuropharmacology, 27 (I 988) 5633568. 21 Meldrum,

B., Possible

nists of excitatory

therapeutic

amino

applications

of antago-

acid neurotransmitters,

Clin. Sri..

23 Nitecka,

L., Tremblay, damage

sequelae,

E., Charton,

syndrome

Ben-Ari

J.P., Ber-

of kainic

acid sei-

E.. Long-term

of kainic

acid.

sequelae

of paren-

In: R. Schwartz

and Y.

26 Peeters,

Science. 254 (1991) 1515 1518.

and prevention, B.W.M.M..

Van

E.L.J.M.

and Coenen.

A.M.L.,

al actions

of MK80l

absence

C.M.,

Van

Antiepileptic

in an animal

model

Luijtelaar.

and behaviour-

27 Pisa, M., Sanberg,

P.R., Corcoran,

recurrent

seizures

after

tions of kainic acid in rat: a possible poral lobe epilepsy,

H.C.,

intracerebral

injec-

model of human

tem-

Brain Res., 200 (1980) 481487.

28 Rogers,

B.C. and Tilson,

H.A.,

deficits

are not blocked

by MK801,

Kainate-induced Neurosci.

and Ornstein,

A.Y., Salhoff,

P.L., Excitatory

sions in neonatal

rats

amino

mediated

convul-

receptor

sub-

types, Eur. J. Pharmacol., I82 (1990) 421427. 30 Schwab, spread

intracerebral

of neuronal

injections

damage

following

systemic

of kainic acid: A histological

or

study,

C.E.,

Holmes.

G.L.

and Thompson,

kainic

acid

J.L.,

Age-

and behavEpilepsia, in

seizures,

E. and Lipton, prevent

kainate

S.A., N-Methyl-oneurotoxicity

in rat

cells in vitro, J. Neurosci., II (1991) 966

ganglion

971. 35 Tricklebank, Iverson.

M.D.,

SD.,

Singh,

L., Oles, R.J.,

The behavioural

Preston,

effects of MK801:

acting non-competitively

tively at the NMDA

C. and

a compar-

and competi-

Eur. J. Pharmacol., I67 (I 989)

receptor,

127-135. 36 Trommcr,

B.L. and

tagonists

J.F..

NMDA

epileptogenesis

N.Y. and Treiman, of refractory

rats to treatment

and

E.H.F.,

D.M.. Motor experimental

with MK801,

and electrograph-

status

diazepam,

Kemp,

J.A.,

Priestly,

and

Iversen,

L.L.,

G.N. is a potent G.N.,

J.O..

receptors

T.,

in plus

Knight,

A.R.,

anticonvulsant

antagonist,

Proc.

A.C., Gill, R., Kemp, J.A., Wong,

L.L., The interaction

for N-methyl-D-aspartate:

between

MKSOI

functional

conse-

Neuropharmacology, 26 (1987) 903-909. Bonhaus,

D.W.,

N-Methyl-D-aspartate

quantitative aspartate

epilepticus

or MK801

The

N-methyl-D-aspartate

Foster.

and Iverson,

quences,

an-

Brain Res., 553 (1991) 97 104.

diazepam,

E.H.F.

receptor

and seizure expres-

rats, Dev. Brain Res., 53 (1990) 2488252.

sion in developing

38 Wong,

Pasternak,

inhibit kindling

and qualitative receptor-channel

USA, 86 (1989) 8157-8160.

Neuroscience, 5 ( 1980) 99 1-l 0 14. 31 Stafstrom.

antagonists

40 Yeh, G.-C.,

J.E., Fuller, T., Price, J.L. and Olney, J.W., Widepatterns

following

Natl. Acad. Sci. USA, 83 (1986) 7104-7108.

B.C.

and

S., Thompson,

cognitive

MK80l

acid-induced

by distinct

A., Thurber,

functional

C.R., Johnson.

Kainic

Dev. Brain Res., 65 (1992)

G.L., Age-dependent

N.J., Aizenman,

39 Woodruff,

D.D., Gamble,

G.L.,

status epilepticus

Let/.,

109

sei-

press. 34 Sucher.

Woodruff,

(1990) 335340. 29 Schoepp,

deficits

ic response

M.E. and Fibiger,

brain:

C.E., Chronopoulos,

J.L. and Holmes,

37 Walton,

of spontaneous

Epilepsy Res., 3 (I 989) 178&l8 I.

epilepsy,

Spontaneously

Rijn,

acid-induced

J.L. and Holmes,

seizures,

ison with antagonists

num. New York, NY. 1986, pp. 1477155. 25 Olney, J.W.. Labruyere, J., Wang, G., Wozniak, D.F., Price, M.T. and Sesma. M.A.. NMDA antagonist neurotoxicity: mechanism

on kainic

2377246.

retinal

Excitatory Amino Acids and Epilepsy, Ple-

(Eds.),

recurrent

aspartate

in the rat. II. Histopathologic

I3 (1984) 107331094.

L. and Tremblay,

tal administration

of MK80l

C.E., Thompson,

spontaneous

ioral

G., Bouillot,

Y.. Maturation

Neuroscience,

24 Nitecka,

(I 98 I) 203 I-2042.

Lifr Sci., 29

ger, M.L. and Ben-Ari. zure-brain

32 Stafstrom,

33 Stafstrom,

J.V., Kainic acid as a tool for the study of temporal

lobe epilepsy,

effects

zures, Epilepsia, 32 (I 991) 3 I acid seizures in the developing

68 (1985) ll3m-122. 22 Nadler,

dependent

Nadler, receptor alterations

complex,

J.V. and McNamara, plasticity

in kindling:

in the N-methyl-oProc. Nafl. Acad. Sri.