神经元激活期间慢性癫痫大鼠和人类离体海马中的代谢异常

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Metabolic dysfunction has been implicated in the pathogenesis of temporal lobe epilepsy (TLE), but its manifestation during neuronal activation in the ex vivo hippocampus from TLE patients has not been shown. We characterized metabolic and mitochondrial functions in acute hippocampal slices from pilocarpine-treated, chronic epileptic rats and from pharmacoresistant TLE patients. Recordings of NAD(P)H fluorescence indicated the status of cellular en- ergy metabolism, and simultaneous monitoring of extracellular potassium concentration ([K+]o) allowed us to control the induction of neuronal activation. In control rats, electrical stimulation elicited biphasic NAD(P)H fluorescence transients that were characterized by a brief initial ‘drop’and a subsequent prolonged ‘overshoot’correlating to enhanced NAD(P)+reduction. In chronic epileptic rats, overshoots were significantly smaller in area CA1, but not in the subiculum as compared to controls. In TLE patients, who were histopathologically classified in groups with and without Ammon’s horn sclerosis (AHS, non-AHS), large drops and very small overshoots of NAD(P)H transients were observed in dentate gyrus, CA3, CA1 and subiculum. Nevertheless, monitoring mitochondrial membrane potential (ΔΨm) by mitochondria-specific, voltage-sensitive dye (rhodamine-123) revealed similar mitochondrial responses during neuronal activation with glutamate and protonophore application in area CA1 of control and chronic-epileptic rats. Applying confocal laser scanning microscopy, these findings were confirmed in individual neurons of AHS tissue, indicating a negative ΔΨm and activatio n-dependent mitochondrial depolarization. Our data demonstrate severe metabolic dysfunction during neuronal activation in the hippocampus from chronic epileptic rats and humans, although mitochondria maintain negative ΔΨm. Thus, our findings provide a cellular correlate for ‘hypometabolism’as described for epileps y patients and suggest mitochondrial enzyme defects in TLE. Metabolic dysfunction has been implicated in the pathogenesis of temporal lobe epilepsy (TLE), but its manifestation during neuronal activation in the ex vivo hippocampus from TLE patients has not been shown. We characterized metabolic and mitochondrial functions in acute hippocampal slices from pilocarpine-treated, chronic epileptic rats and from pharmacoresistant TLE patients. Recordings of NAD (P) H fluorescence indicate the status of cellular en- ergy metabolism, and simultaneous monitoring of extracellular potassium concentration ([K +] o) allowed us to control the induction of neuronal activation. In control rats, electrical stimulation elicited biphasic NAD (P) H fluorescence transients that were characterized by a brief initial ’drop’and a subsequent prolonged’ overshoot’correlating to enhanced NAD (P) + reduction. In chronic epileptic rats, overshoots were significantly smaller in area CA1, but not in the subiculum as compared to controls. In TLE patients, who were histopathologic Nevertheless, there was no evidence of a significant increase in NAD (P) H transients were observed in dentate gyrus, CA3, CA1 and subiculum. Nevertheless, monitoring mitochondrial membrane potential (AHS, non-AHS), large drops and very small overshoots of NAD ΔΨm) by mitochondria-specific, voltage-sensitive dye (rhodamine-123) were similar mitochondrial responses during neuronal activation with glutamate and protonophore application in area CA1 of control and chronic-epileptic rats. Applying confocal laser scanning microscopy, these findings were confirmed in individual data of severe metabolic dysfunction during neuronal activation in the hippocampus from chronic epileptic rats and humans, although mitochondria maintain negative ΔΨm. Thus, our findings provide a cellular correlate for ’hypometabolism’as described for epileps y patients and suggest mitochondria l enzyme defects in TLE.
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