ERYTHROPOIETIN (EPO) IS ANTICONVULSANT AGAINST KAINIC ACID-INDUCED SEIZURES, BUT NOT PILOCARPINE, PTZ OR ELECTROSHOCK SEIZURES
Abstract number :
1.282
Submission category :
Year :
2002
Submission ID :
1580
Source :
www.aesnet.org
Presentation date :
12/7/2002 12:00:00 AM
Published date :
Dec 1, 2002, 06:00 AM
Authors :
William P. Watson. Neuropharmacology Department, H. Lundbeck A/S, Copenhagen, Denmark
RATIONALE: Brines et al., (1) demonstrated that pre-treatment with erythropoietin (EPO) 24h (but not 30 min) prior to kainic acid administration in mice increased the latency to status epilepticus and decreased their mortality rate. In the present study we aimed to investigate this phenomenon in greater detail and compare the results with another model of status-like seizures (induced by pilocarpine) and two models of seizure threshold.
METHODS: EPO (Eprex [reg])1250, 2500 or 5000 IU/kg, or saline vehicle was administered SC to groups of 10-12 male NMRI (25g) mice either 1h or 24h prior to testing.
Kainic acid seizures: Mice were then injected IP with 30 mg/kg kainic acid and the seizure occurrence observed and rated on a modified rating scale (1 = mild forelimb activity: 5-continuous status epilepticus).
Pilocarpine seizures were induced by 250 mg/kg IP injection and mice observed for clonic convulsions for 30 min.
Maximal electroshock threshold and IV pentylenetetrazole (PTZ) threshold were determined by standard procedures (2).
RESULTS: After 1hour pre-treatment, EPO did not affect the measures in any of the convulsant models used. However, at 24h pre-treatment, EPO significantly reduced the incidence of stage 3 and stage 4 seizures in the kainic acid model (e.g. Stage 4: Incidence of 8/12 in Vehicle group c.f. 1/12 EPO 2500 IU/kg; P[lt]0.05). No other seizure models were significantly affected at this time.
CONCLUSIONS: We conclude that the effect of EPO is selective to kainic acid mediated seizures, and not status models in general, as another model of status like convulsions (the pilocarpine model) was not affected by EPO. This action is only seen when a long pre-treatment time is used, implying that the mechanism of action is likely to involve down-stream signalling pathways after receptor activation.
These results indicate that EPO is unlikely to be of use as an anticonvulsant therapy.
References
(1) Brines ML, et al. (2000) Proc Natl Acad Sci U S A, 97(19):10526-10531.
(2) Klitgaard H, et al., (1998) Eur J Pharmacol, 353(2-3):191-206.
[Supported by: H.Lundbeck A/S]; (Disclosure: Salary - H. Lundbeck A/S)