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COMPARATIVE ANTICONVULSANT ACTIVITY OF CARBAMAZEPINE,

LAMOTRIGINE AND VALPROATE IN THE MOUSE AND IN THE RAT


Elise Esneault, Guillaume Peyon, David Virley and Vincent Castagné

„ INTRODUCTION
Three well-known antiepileptic drugs, carbamazepine, lamotrigine and valproate, were evaluated in different tests of epilepsy in the mouse and in the
rat. These substances were compared in two models used to assess generalized tonic-clonic seizures, the audiogenic seizure test in the DBA/2 mouse
and the maximal electroshock (MES) test in the rat as well as in the amygdala kindling test in the rat considered as a model of partial seizures with
secondary generalization.

„ MATERIAL & METHODS


• Treatments:
ΠValproate was administered i.p. 30 minutes before the test. Carbamazepine and Lamotrigine were administered p.o. 60 or 120 minutes before the test.
• Maximal Electroconvulsive Shock (MES) in the rat:
ΠRats were administered MES (50 mA, rectangular current: 0.6 ms pulse width, 1.5 s duration, 200 Hz) via earclip electrodes connected to a constant current shock generator (Ugo Basile: Type 7801). The
number of tonic convulsions was recorded.

• Audiogenic Seizure Test:


ΠMice (DBA/2, 3-4 weeks old) were placed in a Plexiglas jar mounted with an electric bell (110-120 dB). Upon activating the bell, the number of wild runnings, clonic and tonic seizures and deaths were
measured. The bell was activated until death was observed or for a maximum of 60 seconds.

• Amygdala Kindling Test:


ΠRats were implanted with 2 depth electrodes into the amygdala. Following recovery, rats were stimulated twice daily. Rats showing behaviorally at least 4 consecutive stage 5 seizures were included in the drug
study phase. A control stimulation was applied approximately 24 hours prior to administration, serving as a baseline measurement. The following day, stimulation was applied at different time points. For each
stimulation, the behavior was observed and the seizure severity scored on a 6 point scale (0: no response, 1: mouth and facial movements, 2: head nodding, 3: forelimb clonus, 4: rearing and 5: rearing and
falling).

„ RESULTS
Audiogenic Seizure Test in the mouse MES Test in the rat Amygdala Kindling Test in the rat

Vehicle
Numberr of tonic convulsions

Wild Running Clonic convulsions Tonic convulsions Death 6 Valproate (150 mg/kg)
12
10 Valproate (300 mg/kg)
9 5
10
Number of rats

Seizure score
4
7 8
6
6 3
5
*

4 2
4 ***
3 *
***
N

2 2 1 *
***

1
***

**
0 0 0
Vehicle Valproate Valproate Valproate Vehicle Valproate Valproate Valproate -24 h + 30 min + 90 min +180 min +6h
(20 mg/kg) (60 mg/kg) (180 mg/kg) (75 mg/kg) (150 mg/kg) 300 (mg/kg)

Vehicle
Number of tonic convulsions

Wild running Clonic convulsions Tonic convulsions Death 6 Carbamazepine (250 mg/kg)
10 12 Carbamazepine (500 mg/kg)
9 5
10
Number of rats

Seizure score
8
4
7 8
6
3
*

5 6 **

**
4

**

**
2
***

3 4
2 *** 1
2 ***
1
**

**
*

0 0 0
Vehicle Carbamazepine Carbamazepine Carbamazepine Vehicle Carbamazepine Carbamazepine Carbamazepine -24 h +1h +2h + 24 h
(6.25 mg/kg) (12.5 mg/kg) (25 mg/kg) (12.5 mg/kg) (25 mg/kg) (50 mg/kg)

Vehicle
6 Lamotrigine (4 mg/kg)
Number of tonic convulsions

Wild Running Clonic convulsions Tonic convulsions Death 12 Lamotrigine (16 mg/kg)
10 5
9 10
Number of rats

Seizure score

8 4
7 8
6 3
6 **
5
4 4 2
3
***

***

2 2 *** *** 1
***

1 * *
0 0 0
Vehicle Lamotrigine Lamotrigine Lamotrigine Vehicle Lamotrigine Lamotrigine Lamotrigine -24 h +1h +2h + 24 h
(4 mg/kg) (8 mg/kg) (16 mg/kg) (4 mg/kg) (8 mg/kg) (16 mg/kg)
Fisher’s Exact Test: *, p < 0.05, **, p < 0.01 and ***: p < 0.001. Fisher’s Exact Test: **, p < 0.01 and ***: p < 0.001. Wilcoxon Test: *, p < 0.05 and **: p < 0.01.

Valproate (180 mg/kg), Carbamazepine (12.5-25 mg/kg) Valproate (150-300 mg/kg), Carbamazepine (12.5-50 Valproate (300 mg/kg) decreased the seizure score at 30
and Lamotrigine (4-16 mg/kg) suppressed tonic convulsions mg/kg) and Lamotrigine (4-16 mg/kg) dose- and 90 minutes. Similar effects were observed with
and protected from death. Clonic convulsions were also dependently decreased tonic convulsions. Carbamazepine (500 mg/kg) at 1, 2 and 24 hours. No
decreased. significant effects were observed with Lamotrigine at 4 or 16
mg/kg. © Porsolt – All rights reserved.

„ CONCLUSION
The results show that the active doses of carbamazepine, lamotrigine and valproate vary depending on the epilepsy model. Partial
seizures with secondary generalization are antagonized after administration of these substances at higher dose strengths as compared
with generalized seizures, confirming the importance of testing the same compound across several tests to assess anti-convulsant
efficacy.

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