Aarhus Universitets segl

Differential role of oxidative stress in synaptic and nonsynaptic in vitro ictogenesis

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It is well established that dysfunctional glucose metabolism and in particular hypoglycemia can lead to hyperexcitability and exacerbate epileptic seizures. The precise mechanisms behind this form of hyperexcitability are still unresolved. The present study investigates to what extent oxidative stress can account for the acute proconvulsant effect of hypoglycemia. We used the glucose derivative 2-deoxy-d-glucose (2-DG) to mimic glucose deprivation in hippocampal slices during the extracellular recording of interictal-like (IED) and seizure-like (SLE) epileptic discharge in areas CA3 and CA1. After induction of IED in area CA3 by perfusion of Cs+ (3 mM), MK801 (10 µM), and bicuculline (10 µM), subsequent application of 2-DG (10 mM) resulted in the appearance of SLE in 78.3% of experiments. This effect was only observed in area CA3 and was reversibly blocked by tempol (2 mM), a scavenger of reactive oxygen species, in 60% of experiments. Preincubation with tempol reduced the incidence of 2-DG-induced SLE to 40%. Low-Mg2+-induced SLE in area CA3 and in the entorhinal cortex (EC) was also reduced by tempol. In contrast, to the above models, which depend on synaptic transmission, nonsynaptic epileptiform field bursts induced in area CA3 by a combination of Cs+ (5 mM) and Cd2+ (200 µM), or in area CA1 using the "low-Ca2+ model," was unaffected or even enhanced by tempol. These results indicate that oxidative stress significantly contributes to 2-DG-induced seizures in area CA3 and that the impact of oxidative stress differs between synaptic and nonsynaptic ictogenesis.NEW & NOTEWORTHY The main findings of the current study are that area CA3 but not area CA1 can support 2-DG-induced seizure activity, that oxidative stress significantly contributes to 2-DG-induced seizure activity in area CA3, and that the impact of oxidative stress differs between synaptic and nonsynaptic epileptiform activity. In in vitro models where ictogenesis depends on synaptic interactions, oxidative stress lowers the seizure threshold, whereas in nonsynaptic models seizure threshold is unchanged or even increased.

TidsskriftJournal of Neurophysiology
Sider (fra-til)999 - 1009
Antal sider11
StatusUdgivet - apr. 2023

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