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

Abstract

Glioma-related epilepsy (GRE) is a hallmark clinical presentation of gliomas with significant impacts on patient quality of life. The current standard of care for seizure management is comprised of anti-seizure medications (ASMs) and surgical resection. Seizures in glioma patients are often drug-resistant and can often recur after surgery despite total tumor resection. Therefore, current research is focused on the pro-epileptic pathological changes occurring in tumor cells and the peritumoral environment. One important contribution to seizures in GRE patients is metabolic reprogramming in tumor and surrounding cells. This is most evident by the significantly heightened seizure rate in patients with isocitrate dehydrogenase mutated (IDH^mut) tumors compared to patients with IDH wildtype (IDH^wt) gliomas. To gain further insight into glioma metabolism in epileptogenesis, this review compares the metabolic changes inherent to IDH^mut vs. IDH^wt tumors and describes the pro-epileptic effects these changes have on both the tumor cells and the peritumoral environment. Understanding alterations in glioma metabolism can help to uncover novel therapeutic interventions for seizure management in GRE patients.

Keywords: brain; glioma; peritumoral excitability; seizure development; tumor-related epilepsy; tumoral metabolism.

Figure 1

Comparison of the changes in IDH^wt glioma cells and IDH1^mut glioma cells energy metabolism to normal glia. IDH^wt glioma cells have an upregulation of aerobic glycolysis through increased glucose consumption and LDHA expression. IDH1^mut glioma cells demonstrate suppression of glycolysis and subsequent reliance on oxidative phosphorylation through glutaminolysis for anaplerosis.

Figure 2

Metabolic reprogramming in IDH^wt glioma cells and their pro-convulsive effects. IDH^wt cells upregulate aerobic glycolysis and increase extracellular lactate through increased LDHA activity, leading to local acidosis and peritumoral neuronal depolarization of local cortical neurons. In addition, increased glutamate production and release induces local activation of excitatory receptors AMPA and NMDA.

Figure 3

Metabolic reprogramming in IDH1^mut glioma cells and their pro-convulsive effects. IDH^mut cells have reduction in glucose consumption and downregulation of glycolytic factors, such as LDHA, which decreases carboxylic entry into the TCA cycle. Thus, IDH1^mut cells rely on intracellular glutamate breakdown to aKG to sustain oxidative phosphorylation. At the same time, IDH1 mutations significantly overproduce D-2HG which exerts its pro-excitatory effects through activation of NMDA receptors and the mTOR pathway of local cortical neurons.

Figure 4

Molecular Similarity between glutamate and 2-hydroxyglutarate. Glutamate and 2 Hydroxyglutarate follow a similar molecular structure. The only difference is a hydroxyl group instead of an amine group on carbon-2 in 2-hydroxyglutarate.