Metabolic abnormalities found in epileptogenic tissue provide considerable evidence of brain hypometabolism, while major risk factors for acquired epilepsy all share brain hypometabolism as one common outcome, suggesting that a breakdown of brain energy homeostasis may actually precede epileptogenesis. However, a causal link between deficient brain energy metabolism and epilepsy initiation has not been yet established. To address this issue we developed an in vivo model of chronic energy hypometabolism by daily intracerebroventricular (i.c.v.) injection of the nonmetabolizable glucose analog 2-deoxy-D-glucose (2-DG) and also investigated acute effects of 2-DG on the cellular level. In hippocampal slices, acute glycolysis inhibition by 2-DG (by about 35%) led to contrasting effects on the network: a downregulation of excitatory synaptic transmission together with a depolarization of neuronal resting potential and a decreased drive of inhibitory transmission. Therefore, the potential acute effect of 2-DG on network excitability depends on the balance between these opposing preand postsynaptic changes. In vivo, we found that chronic 2-DG i.c.v. application (estimated transient inhibition of brain glycolysis under 14%) for a period of 4 weeks induced epileptiform activity in initially healthy male rats. Our results suggest that chronic inhibition of brain energy metabolism, characteristics of the well-established risk factors of acquired epilepsy, and specifically a reduction in glucose utilization (typically observed in epileptic patients) can initiate epileptogenesis.V C 2017 Wiley Periodicals, Inc.

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A predominant trigger and driver of sporadic Alzheimer’s disease (AD) is the synergy of brain oxidative stress and glucose hypometabolism starting at early preclinical stages. Oxidative stress damages macromolecules, while glucose hypometabolism impairs cellular energy supply and antioxidant defense. However, the exact cause of AD-associated glucose hypometabolism and its network consequences have remained unknown. Here we report NADPH oxidase 2 (NOX2) activation as the main initiating mechanism behind Aβ1-42-related glucose hypometabolism and network dysfunction. We utilize a combination of electrophysiology with real-time recordings of metabolic transients both ex- and in-vivo to show that Aβ1-42 induces oxidative stress and acutely reduces cellular glucose consumption followed by long-lasting network hyperactivity and abnormalities in the animal behavioral profile. Critically, all of these pathological changes were prevented by the novel bioavailable NOX2 antagonist GSK2795039. Our data provide direct experimental evidence for causes and consequences of AD-related brain glucose hypometabolism, and suggest that targeting NOX2-mediated oxidative stress is a promising approach to both the prevention and treatment of AD.

A paramount driver of sporadic Alzheimer's disease (AD) is the synergy of oxidative stress and glucose hypometabolism in the brain. Oxidative stress damages cellular macromolecules such as DNA, lipids and proteins, whereas glucose hypometabolism impairs cellular energy supply and antioxidant defence; Together, these cellular and functional alterations may be primary triggers of AD. However, the exact molecular basis of AD-associated glucose hypometabolism has remained unknown, hampering the search for effective interventions. Here, we identify NADPH oxidase 2 (NOX2) activation by beta-amyloid peptide (Aβ1-42) as the main molecular source of oxidative stress driving brain glucose hypometabolism and network hyperactivity. Using a combination of electrophysiology with dynamic recordings of autofluorescence and metabolic biosensors, we show that in hippocampal brain slices, Aβ1-42 application reduced network activity-driven glucose consumption and glycolysis by half, while NOX2 antagonism prevented this effect. In vivo, intracerebroventricular injection of Aβ1-42 exerted a profound inhibitory effect on brain glucose consumption, resulting in long-lasting network hyperactivity and changes in animal behavioral profile. Critically, the novel bioavailable NOX2 antagonist GSK2795039 prevented all of the observed Aβ-related detrimental effects. These data suggest that targeting NOX2-induced oxidative stress is a promising approach to both the prevention and treatment of AD.