Naslov
Prolonged seizure activity impairs mitochondrial bioenergetics and induces cell death

Autori
Kovač, Stjepana ; Domijan, Ana-Marija ; Walker, Matthew ; Abramov, Andrey

Izvornik
Journal of cell science (0021-9533) 125 (2012), 7; 1796-1806

Vrsta, podvrsta i kategorija rada
Radovi u časopisima, članak, znanstveni

Ključne riječi
cell death; seizure; status epilepticus; mitochondria; ATP; neurons

Sažetak
The mechanisms underlying neuronal death following excessive activity such as occurs during prolonged seizures are unclear, but mitochondrial dysfunction has been hypothesised to play a role. Here, we tested this with fluorescence imaging techniques in rat glioneuronal neocortical co-cultures using low Mg2+ levels to induce seizure-like activity. Glutamate activation of NMDA receptors resulted in Ca2+ oscillations in neurons and a sustained depolarisation of the mitochondrial membrane potential, which was cyclosporine A sensitive, indicating mitochondrial permeability and transition pore opening. It was also dependent on glutamate release and NMDA receptor activation, because depolarisation was not observed after depleting vesicular glutamate with vacuolar-type H+-ATPase concanamycin A or blocking NMDA receptors with APV. Neuronal ATP levels in soma and dendrites decreased significantly during prolonged seizures and correlated with the frequency of the oscillatory Ca2+ signal, indicative of activity-dependent ATP consumption. Blocking mitochondrial complex I, complex V or uncoupling mitochondrial oxidative phosphorylation under low-Mg2+ conditions accelerated activity-dependent neuronal ATP consumption. Neuronal death increased after two and 24 hours of low Mg2+ levels compared with control treatment, and was reduced by supplementation with the mitochondrial complex I substrate pyruvate. These findings demonstrate a crucial role for mitochondrial dysfunction in seizure-activity-induced neuronal death, and that strategies aimed at redressing this are neuroprotective.

Izvorni jezik
Engleski

Znanstvena područja
Biologija, Farmacija

POVEZANOST RADA