EFFECT OF TOPIRAMATE ON MITOCHONDRIAL FUNCTION AND DYSFUNCTION IN A CHRONIC MODEL OF EPILEPSY
Abstract number :
1.275
Submission category :
Year :
2002
Submission ID :
1871
Source :
www.aesnet.org
Presentation date :
12/7/2002 12:00:00 AM
Published date :
Dec 1, 2002, 06:00 AM
Authors :
Wolfram S. Kunz, Alexei Kudin, Tatiana Kudina, Stefan Vielhaber, Christian E. Elger. Epileptology, University Bonn Medical Center, Bonn, Germany; Neurology, University Magdeburg Medical Center, Magdeburg, Germany
RATIONALE: Topiramate showed in several studies a neuroprotective effect on the survival of pyramidal neurons by a yet unknown mechanism. Since mitochondria are intimately involved in pathways leading to pyramidal cell death in epilepsy we evaluated putative effects of topiramate on mitochondrial function in the rat hippocampus in vitro and in vivo using the pilocarpine model of chronic epilepsy.
METHODS: We investigated the in vitro action of topiramate on the oxygen consumption of digitonin-treated rat homogenates and 400 [mu]m thick rat hippocampal slices with different mitochondrial substrates. To evaluate the in vivo action of topiramate 30-days-old Wistar-rats were injected with pilocarpine and received 40 min after onset of status epilepticus different doses of the drug (20, 40 and 100 mg/kg). The status epilepticus was terminated by diazepam (4 mg/kg; injected 3 hours and 40 min after onset of status epilepticus). Neuronal cell counts and mitochondrial enzyme activities in hippocampal subfields were determined in the chronic epileptic state 30 days after pilocarpine injection.
RESULTS: Topiramate (2.5 mM) inhibited in digitonin-treated rat hippocampal homogenates 20% of pyruvate-dependent respiration while the succinate-dependent respiration was unaffected indicating mild inhibition of respiratory chain complex I. In hippocampal slices a comparable inhibitory effect on respiration with NAD-dependent substrates was observed at 1 mM topiramate. In our in vivo experiments topiramate protected rat hippocampal CA1 and CA3 neurons against seizure activity related cell damage and rescued mitochondrial function after status epilepticus showing effects above 40 mg/kg.
CONCLUSIONS: Our findings confirm the neuroprotective action of topiramate on the survival of hippocampal pyramidal cells in pilocarpine-treated epileptic rats. Assuming a possible in vivo accumulation of the drug we suggest that the observed mild inhibitory action of mitochondrial respiratory chain complex I by topiramate might precondition the rat hippocampal pyramidal cells against seizure activity related cell damage.
[Supported by: a grant from Johnson and Johnson Pharmaceutical Research and Development, LLC.]; (Disclosure: Salary - Tatiana Kudina, Grant - Supported by a grant from Johnson and Johnson Pharmaceutical Research and Development, LLC.)