Abstracts

The antiepileptic drug topiramate shows protective effects on the survival of neurons by a yet unknown mechanism. Since mitochondria are intimately involved in pathways leading to neuronal cell death we evaluated the effects of topiramate on mitochondria isolated from rat and human brain.
We investigated the in vitro action of topiramate on the oxygen consumption, on the mitochondrial membrane potential and on calcium transport of mitochondria isolated from rat brain and human brain (using surgical specimens from patients with temporal lobe epilepsy) applying different mitochondrial substrates.
Topiramate up to high doses did not affect the oxygen consumption and the membrane potential of isolated rat and human brain mitochondria in the resting (in the absence of ADP) and active (in the presence of 1 mM ADP) states of mitochondrial respiration. Additionally, we studied the effects of topiramate on calcium transport in rhodamine 123-stained mitochondria applying different external calcium concentrations. Topiramate at the optimal concentration of 100 [micro]M lowered significantly (p [lt] 0.01, n = 11) the fluorescence changes of rhodamine-123 stained mitochondria in response to external calcium additions. This result indicates a stabilizing effect of the drug on mitochondrial membrane potential most probably due to inhibitory effects on mitochondrial calcium transport. Similar mitochondrial membrane potential stabilizing effects were observed with cyclosporine A, an inhibitor of the mitochondrial permeability transition.
Our findings suggest that the neuroprotective action of topiramate might be related to inhibition of mitochondrial calcium transport. This would render neuronal mitochondria more resistant to pathological high cytosolic calcium concentrations which occur as result of increased excitability or ischemic and excitotoxic insults.
[Supported by: Johnson & Johnson Pharmaceutical Research & Development, L.L.C.]