Preventive and curative effects of etifoxine in a rat model of brain oedema.
1. The aim of the present study was to test the hypothesis that increasing GABAergic neurotransmission is involved in the prevention or treatment of brain oedema. The study was conducted in the well-established rat triethyltin (TET) model of brain oedema and examined the effects of etifoxine, a compound that increases GABAergic neurotransmission through multiple mechanisms, including neurosteroid synthesis. 2. Daily oral administration of 3 mg/kg per day TET for 5 consecutive days strongly perturbed rat behaviour and induced reproducible cerebral oedema. Coadministration of etifoxine (2 x 25 or 2 x 50 mg/kg per day, p.o.) over the 5 days of TET treatment blocked the development of brain oedema and the increase in brain sodium content induced by TET, as well as reducing the increase in brain chloride content. Moreover, etifoxine inhibited the decrease in bodyweight, the neurological deficit and the altered locomotor activity induced by TET. At a lower dose (2 <--> 10 mg/kg per day, p.o.), etifoxine did not have any preventive effects. 3. To examine the curative effects of etifoxine, it was administered from the 4th day of TET treatment for 5 consecutive days, when brain oedema was already established. In these experiments, etifoxine (2 <--> 50 mg/kg per day, p.o.) significantly reduced cerebral oedema and the outcomes induced by TET treatment. Moreover, etifoxine reduced the mortality in response to TET treatment. 4. In conclusion, because etifoxine has a good safety profile as an anxiolytic, the results of the present study suggest that it is worth further clinical investigation as a neuroprotectant.
Girard
Philippe
P
Biocodex, Pharmacology Department, Zac de Mercières, Compiègne, France. p.girard@biocodex.fr
Pansart
Yannick
Y
Gillardin
Jean-Marie
JM
D000818:Animals; D001929:Brain Edema / Q000188:drug therapy* / Q000378:metabolism / Q000517:prevention & control*; D004195:Disease Models, Animal; D008297:Male; D010078:Oxazines / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar
D010078:Oxazines; C002125:etifoxine