The mechanism of neuroprotection by topiramate in an animal model of epilepsy.
OBJECTIVE
For the antiepileptic drug (AED) topiramate (TPM), neuroprotective effects have been reported in models of focal cerebral ischemia and experimental status epilepticus, but the putative mechanism of action has remained elusive.


METHODS
We studied the effects of TPM on mitochondrial function in the pilocarpine rat model of chronic epilepsy and in isolated mitochondria from rat brain.


RESULTS
TPM treatment in status epilepticus at doses ranging from 20 to 100 mg/kg considerably improved the survival of rats and improved CA1 and CA3 pyramidal cell survival in a dose-dependent manner. This treatment increased the activity of mitochondrial respiratory chain complex I in the CA1 and CA3 pyramidal subfields and resulted in lower seizure frequencies in chronic epileptic rats. In vitro investigations of the action of TPM on isolated rat brain mitochondria ruled out any direct effects of the drug on mitochondrial oxidative phosphorylation but revealed a protective effect on hippocampal mitochondria against an external calcium challenge. This can explain its observed neuroprotective action in the concentration range tested. The in vitro effects of TPM on the calcium handling of isolated brain mitochondria was found to be comparable to the action of cyclosporin A.


CONCLUSIONS
The neuroprotective action of TPM seems to be directly related to its inhibitory effect on the mitochondrial permeability transition pore.
Kudin
Alexei P
AP
Department of Epileptology, University of Bonn Medical Center, Bonn, Germany.
Debska-Vielhaber
Grazyna
G
Vielhaber
Stefan
S
Elger
Christian E
CE
Kunz
Wolfram S
WS
D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D016572:Cyclosporine / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004827:Epilepsy / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D005632:Fructose / Q000031:analogs & derivatives* / Q000494:pharmacology*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D066298:In Vitro Techniques; D007473:Ion Channels / Q000187:drug effects / Q000378:metabolism; D007696:Kindling, Neurologic / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010085:Oxidative Phosphorylation / Q000187:drug effects; D010862:Pilocarpine; D017966:Pyramidal Cells / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013226:Status Epilepticus / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control; D000077236:Topiramate
D007473:Ion Channels; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D018696:Neuroprotective Agents; D010862:Pilocarpine; D000077236:Topiramate; D005632:Fructose; D016572:Cyclosporine