Selective hippocampal cell damage and mossy fiber sprouting induced by chronic intracerebral injections of 2-deoxy-D-glucose

Abstract

A reduction in glucose consumption has been shown in both patients with acquired epilepsy and in animal epilepsy models. However, the question remains whether the disturbance of glucose metabolism is the driving force of epileptogenesis. We have recently reported that a chronic partial inhibition of brain glycolysis by the non-metabolizable glucose analogue 2-deoxy-D-glucose (2-DG) triggers epileptogenesis in initially healthy rats. In this study, we further investigated whether chronic 2-DG treatment caused a cellular loss in the dorsal hippocampus and mossy fiber sprouting in the dentate gyrus. We found that prolonged (four weeks) treatment with 2-DG induced a neuronal loss in the CA1 field and the dentate hilus. We also found mossy fibers reorganization in the 2-DG group. In addition, we showed that pentylenetetrazole-induced convulsions were considerably strengthened and prolonged in 2-DG-treated rats. Our results demonstrate that the chronically impaired brain glucose metabolism likely leads to a structural remodeling resembling epileptogenesis and has a proconvulsive effect.

Glucose-Sparing Action of Ketones Boosts Functions Exclusive to Glucose in the Brain

“…The frequent claim that ketones directly inhibit the process of glycolysis is not supported by experimental evidence and seems theoretically unlikely. Moreover, glycolysis inhibition modifies a number of cellular functions that lead to unpredictable variations of network excitability, and in the long-run has been shown to result in epileptogenesis (Samokhina et al, 2020(Samokhina et al, , 2017. In pathology, ketones are capable of partially taking over the glucose's energy fuel role in mitochondria and presumably spare glucose for its other exclusive functions.…”

The Mathematical Model of Disturbance of Energy Metabolism in Brain during Development of Neurodegenerative Diseases: A Proposed Mechanism of Cell Death

“…Предсказанием нашей модели является то, что клетки, попавшие в аденилатный коллапс, должны прекращать потребление глюкозы и кислорода, что в свою очередь может привести к их гибели. Действительно, в экспериментах in vivo с хроническим введением 2-ДГ в дозе, ингибирующей гликолиз мозга на 14 %, наблюдали гибель порядка 20 % нейронов в поле CA1 гиппокампа и зубчатой фасции [29].…”

Unifying mechanism behind the onset of acquired epilepsy

“…Our in vivo experiments suggest that this is indeed the case. We showed directly that chronic partial inhibition of brain glycolysis by 2-deoxy-D-glycose (2-DG) intracerebroventricular injections in rats led to the initiation of paroxysmal brain activity and, following a latent period of 3-4 weeks, to tonicclonic seizures in some animals [14,15]. Thus, AE is associated with glucose hypometabolism, which triggers network hyperactivity, while oxidative stress, linked with most AE risk factors, has been shown to result from seizures [16,17].…”