THE ANTICONVULSANT, FLUOROFELBAMATE PROVIDES PROTECTION AGAINST DEPOLARIZATION-INDUCED CA1 NEURONAL INJURY
Abstract number :
1.310
Submission category :
Year :
2003
Submission ID :
4006
Source :
www.aesnet.org
Presentation date :
12/6/2003 12:00:00 AM
Published date :
Dec 1, 2003, 06:00 AM
Authors :
Kimberly L. Panizzon, Roi Ann Wallis, Duane Sofia Neurology, VA Greater Los Angeles Healthcare System, North Hills, CA; Neurology, UCLA, Los Angeles, CA; Carter-Wallace Inc., Cranbury, NJ
Felbamate is a dicarbamate anticonvulsant showing high efficacy in reducing seizures, particularly for Lennox-Gastaut syndrome. Felbamate also exhibits neuroprotective properties. However, hematotoxicity and hepatotoxicity have limited the use of Felbamate. This toxicity is likely related to the formation of oxidative metabolites. Fluorofelbamate is a newly developed anticonvulsant structurally related to felbamate that exhibits similar anticonvulsant efficacy. However, fluorofelbamate is less likely to produce oxidative metabolites, due to its fluoridated structure. We have previously found that felbamate provides excellent protection against CA1 depolarization-induced injury. Therefore, we assessed whether fluorofelbamate would also be neuroprotective against depolarization-induced injury.
Using paired rat hippocampal slices, we monitored the CA1 orthodromic and antidromic population spike (PS) amplitude during depolarization injury with and without fluorofelbamate treatment. To induce depolarization injury, slices were exposed to 25 mM KCl for 8 mins. Treatment with fluorofelbamate was begun 30 minutes prior to KCl exposure and continued for the first 15 mins. of recovery. Final recovery was assessed 60 mins. following exposure to KCl.
Fluorofelbamate supplied dose-dependent neuroprotection of CA1 PS amplitude in hippocampal slices at concentrations of 25 mg/l and greater ([italic]p[/italic][lt]0.05). At a fluorofelbamate concentration of 100 mg/l CA1 orthodromic and antidromic PS amplitude recovered to 94% [plusmn] 2 and 96% [plusmn] 2, compared to unmedicated slices which recovered to 13% [plusmn] 3 and 14% [plusmn] 1, respectively. The EC50 for fluorofelbamate was 54 mg/l and 53 mg/l for strong neuroprotection against CA1 depolarization injury. By comparison, the EC50 for felbamate against this injury was 138 mg/l and 132 mg/l.
These results demonstrate that the anticonvulsant fluorofelbamate provides protection against CA1depolarization-induced neuronal injury. This neuroprotection appears to be more potent than that seen for felbamate in this model. These data also suggest that fluorofelbamate may be a useful in the preventing or limiting brain injury from status epilepticus.
[Supported by: VA Research Services.]