Dexmedetomidine decreases seizure threshold in a rat model of experimental generalized epilepsy.
BACKGROUND
Dexmedetomidine (DEX) is a highly selective alpha 2 agonist with marked sedative and analgesic properties thought to be mediated via reduction of central noradrenergic transmission. Because an anticonvulsant effect is associated with increased noradrenergic activity, we investigated the possible proconvulsant effects of DEX in an experimental model of generalized seizures.


METHODS
Male rats (n = 82) were administered 0.9% saline as placebo (n = 18) or pretreatment drug(s) before initiation of an infusion of pentylenetetrazol (PTZ) at 5.5 mg.kg-1.min-1. The total dose of PTZ required to elicit electroencephalographic (EEG) and behavioral seizure activity was assessed. Blood samples were obtained 15 min after initiation of infusion (82.5 mg/kg) for determination of serum PTZ concentrations by gas chromatography. Pretreatment drug groups included DEX (20 micrograms/kg [n = 11], 100 micrograms/kg [n = 14], and 500 micrograms/kg [n = 10]); L-medetomidine (500 micrograms/kg [n = 7]); the alpha 2 antagonist atipamezole (500 micrograms/kg [n = 9]); and atipamezole (500 micrograms/kg) before DEX (100 micrograms/kg [n = 7] and 500 micrograms/kg [n = 6]).


RESULTS
In control animals, PTZ 25-35 mg/kg induced EEG evidence of epileptiform activity. The mean dose to EEG epileptiform activity and clonic convulsions was 30 +/- 5.8 (SE) and 59 +/- 3.2 mg/kg, respectively. Infusion of DEX at 100 and 500 micrograms/kg resulted in a marked sedative response and reduced the EEG seizure threshold of PTZ to 18 +/- 1.5 and 7 +/- 1.8 mg/kg, respectively (P < 0.05 at both doses). The clonic convulsant threshold also was significantly decreased in both groups, to 37 +/- 3.2 and 28 +/- 2.3 mg/kg (P < 0.01 at each dose). Before clonic convulsion, a significantly greater number of motor seizure manifestations were scored in the DEX-treated animals at all three dose levels compared with the number scored in control animals. The proconvulsant action of DEX was not a result of alteration of PTZ kinetics, because serum concentrations did not differ between control and DEX-treated animals. Animals treated with L-medetomidine demonstrated more paroxysmal motor phenomena before clonic seizures than controls (P < 0.01) although the clonic seizure threshold was not altered. Atipamezole alone did not alter background EEG, nor did it affect the clonic convulsant threshold. Atipamezole did, however, block the proconvulsant behavioral action at both doses of DEX, raising clonic seizure threshold from 37 +/- 3.2 to 59 +/- 5.8 mg/kg (100 micrograms/kg DEX, P < 0.05) and from 28 +/- 2.3 to 59 +/- 6.9 mg/kg (500 micrograms/kg DEX, P < 0.01).


CONCLUSIONS
DEX exerted a significant proconvulsant action in the PTZ experimental seizure model. The pharmacodynamic effect was dose-dependent and stereospecific and was blocked by the selective alpha 2-receptor antagonist atipamezole. These data are consistent with previous data demonstrating that inhibition of central noradrenergic transmission facilitates seizure expression. Further evaluation of DEX for possible clinical proconvulsant effects may be warranted.
Mirski
M A
MA
Department of Anesthesiology, Johns Hopkins Medical Institutions, Baltimore, Maryland 21287-7834.
Rossell
L A
LA
McPherson
R W
RW
Traystman
R J
RJ
D000316:Adrenergic alpha-Agonists / Q000627:therapeutic use*; D000317:Adrenergic alpha-Antagonists / Q000627:therapeutic use; D000818:Animals; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004569:Electroencephalography; D004827:Epilepsy / Q000139:chemically induced / Q000517:prevention & control*; D007093:Imidazoles / Q000627:therapeutic use*; D007260:Infusion Pumps; D008297:Male; D020926:Medetomidine; D009043:Motor Activity / Q000187:drug effects; D010433:Pentylenetetrazole / Q000037:antagonists & inhibitors* / Q000097:blood / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley
D000316:Adrenergic alpha-Agonists; D000317:Adrenergic alpha-Antagonists; D007093:Imidazoles; C050701:atipamezole; D020926:Medetomidine; D010433:Pentylenetetrazole