Glycolytic lactate production supports status epilepticus in experimental animals

Abstract

ObjectiveStatus epilepticus (SE) requires rapid intervention to prevent cerebral injury and mortality. The ketogenic diet, which bypasses glycolysis, is a promising remedy for patients with refractory SE. We tested the role of glycolytic lactate production in sustaining SE.MethodsExtracellular lactate and glucose concentration during a seizure and SE in vivo was measured using lactate and glucose biosensors. A lactate dehydrogenase inhibitor, oxamate, blocked pyruvate to lactate conversion during SE. Video‐EEG recordings evaluated seizure duration, severity, and immunohistochemistry was used to determine neuronal loss. Genetically encoded calcium indicator GCaMP7 was used to study the effect of oxamate on CA1 pyramidal neurons in vitro. Spontaneous excitatory postsynaptic currents (sEPSCs) were recorded from CA1 neurons to study oxamate's impact on neurotransmission.ResultsThe extracellular glucose concentration dropped rapidly during seizures, and lactate accumulated in the extracellular space. Inhibition of pyruvate to lactate conversion with oxamate terminated SE in mice. There was less neuronal loss in treated compared to control mice. Oxamate perfusion decreased tonic and phasic neuronal activity of GCaMP7‐expressing CA1 pyramidal neurons in vitro. Oxamate application reduced the frequency, but not amplitude of sEPSCs recorded from CA1 neurons, suggesting an effect on the presynaptic glutamatergic neurotransmission.InterpretationA single seizure and SE stimulate lactate production. Diminishing pyruvate to lactate conversion with oxamate terminated SE and reduced associated neuronal death. Oxamate reduced neuronal excitability and excitatory neurotransmission at the presynaptic terminal. Glycolytic lactate production sustains SE and is an attractive therapeutic target.

The Benefits of “Spoilt Milk”: Lactic Acid Can Limit Excitability via HCAR1

“…Other notable aspects that were not discussed here are that lactate has been reported to fuel seizure activity 11 and contribute to vasodilation (cited in studies by Bergersen and Gjedde 2 and Dienel 6 ). HCAR1 activation at the blood-brain barrier can also increase angiogenesis.…”