Chronic neuronal activation leads to elevated lactate dehydrogenase A through the AMP-activated protein kinase/hypoxia-inducible factor-1α hypoxia pathway

Abstract

Recent studies suggest that changes in neuronal metabolism are associated with epilepsy. High rates of ATP depletion, lactate dehydrogenase A and lactate production have all been found in epilepsy patients, animal and tissue culture models. As such, it can be hypothesized that chronic seizures lead to continuing elevations in neuronal energy demand which may lead to an adapted metabolic response and elevations of lactate dehydrogenase A. In this study, we examine elevations in the lactate dehydrogenase A protein as a long-term cellular adaptation to elevated metabolic demand from chronic neuronal activation. We investigate this cellular adaptation in human tissue samples and explore the mechanisms of lactate dehydrogenase A upregulation using cultured neurons treated with low Mg2+, a manipulation that leads to NMDA-mediated neuronal activation. We demonstrate that human epileptic tissue preferentially upregulates neuronal lactate dehydrogenase A, and that in neuronal cultures chronic and repeated elevations in neural activity lead to upregulation of neuronal lactate dehydrogenase A. Similar to states of hypoxia, this metabolic change occurs through the AMP-activated protein kinase/hypoxia-inducible factor-1α pathway. Our data therefore reveal a novel long-term bioenergetic adaptation that occurs in chronically activated neurons and provide a basis for understanding the interplay between metabolism and neural activity during epilepsy.

Glycolytic lactate production supports status epilepticus in experimental animals

“…During seizures, extracellular lactate concentration increases (Fig. 1), indicating increased LDH activity 23,27 . After oxamate treatment, we detected fewer high‐frequency discharges and an overall decrease in extracellular lactate concentration.…”

“…1), indicating increased LDH activity. 23,27 After oxamate treatment, we detected fewer high-frequency discharges and an overall decrease in extracellular lactate concentration. Lack of energy would stop the development of the ATP-demanding, fast discharges in the early stage of SE (Fig.…”

“…21 LDH has recently attracted attention as a potential regulator of energy metabolism in several brain conditions, including cancer 22 and epilepsy. [23][24][25][26][27] LDH-catalyzed reduction of pyruvate to lactate regenerates NAD + from NADH. NAD + is an obligatory substrate for one of the steps in the glycolytic pathway, the conversion of glyceraldehyde-3-phosphate to 1,3-diphosphoglycerate.…”

“…LDH has recently attracted attention as a potential regulator of energy metabolism in several brain conditions, including cancer 22 and epilepsy 23–27 . LDH‐catalyzed reduction of pyruvate to lactate regenerates NAD + from NADH.…”

Differential metabolic alterations in IDH1 mutant vs. wildtype glioma cells promote epileptogenesis through distinctive mechanisms

“…Lactate's role in causing hyperexcitability is indicated by mechanisms also found in epilepsy (Angamo et al, 2017). In both tumoral cells and epileptic neurons, metabolic reprogramming mediated by HIF-1α leads to increased LDHA levels, boosting lactate production and release into the extracellular environment (Sada et al, 2020;Ksendzovsky et al, 2023). Furthermore, although still an area of active investigation, there is literature to suggest that LDHA inhibition may reduce seizure susceptibility (Sada et al, 2015).…”