PURPOSE: 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.
PURPOSE: 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 pilocarpinerat 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 epilepticrats. 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.
Authors: Kong Y Chen; Robert J Brychta; Zahraa Abdul Sater; Thomas M Cassimatis; Cheryl Cero; Laura A Fletcher; Nikita S Israni; James W Johnson; Hannah J Lea; Joyce D Linderman; Alana E O'Mara; Kenneth Y Zhu; Aaron M Cypess Journal: J Biol Chem Date: 2019-12-30 Impact factor: 5.157