Metabolic Alterations Underlying the Development of Hypermetabolic Necrosis in the Substantia Nigra in Status Epilepticus

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Abstract
The substantia nigra pars reticulata (SNPR) has previously been shown to undergo tissue necrosis following status epilepticus induced by flurothyl in the rat. Even if the rat is ventilated, the SNPR develops necrosis if the epileptic period lasts more than 30 min. Rat brains were frozen in situ after 20 and 60 min of seizure activity and after 60 min of seizure activity followed by 60 min recovery. Labile energy metabolites were then analyzed in the SNPR and in the periaqueductal grey matter (PAG, control region). In the PAG, the metabolite changes during status epilepticus were similar to those reported for cerebral cortex and hippocampus. Measurements showed an unchanged ATP content and energy charge (97% and 98% of control, respectively) and an accumulation of lactate to 9.2 ± 0.6 μmol/g in the 60-min group. In the PAG, all metabolites measured had returned to control values after 60 min of recovery. In the SNPR, the perturbation of the energy metabolites was much more pronounced during status epilepticus. The concentration of ATP decreased to 75 ± 3%, the energy charge to 91% ± 12% and the adenylate pool to 86.7 ± 5.7% of control. Lactate accumulated to concentrations of 16.1 ± 1.8 μmol/g and 24.9 ± 2.3 μmol/g in the 20-min and 60-min groups, respectively. The concentration of lactate was still increased above control after 60 min recovery, whereas the concentration of ATP and the energy charge were lower than control. The findings demonstrate that sustained and intense neuronal activation can cause metabolic disturbance and thereby lead to necrosis. The very marked accumulation of lactic acid, likely due to mitochondrial failure, yields a very low intracellular pH, possibly explaining why a tissue necrosis, rather than selective neuronal necrosis, develops in the SNPR during status epilepticus.