Abstract
Therapeutic interventions are greatly needed for age-related neurodegenerative diseases. Astrocytes regulate many aspects of neuronal function including bioenergetics and synaptic transmission. Reactive astrocytes are implicated in neurodegenerative diseases due to their pro-inflammatory phenotype close association with damaged neurons. Thus, strategies to reduce astrocyte reactivity may support brain health. Caloric restriction and a ketogenic diet limit energy production via glycolysis and promote oxidative phosphorylation, which has gained traction as a strategy to improve brain health. However, it is unknown how caloric restriction affects astrocyte reactivity in the context of neuroinflammation. We investigated how a caloric restriction mimetic and glycolysis inhibitor, 2-deoxyglucose (2-DG), affects interleukin 1β-induced inflammatory gene expression in human astrocytes. Human astrocyte cultures were exposed to 2-DG or vehicle for 24 h and then to recombinant IL-1β for 6 or 24 h to analyze mRNA and protein expression, respectively. Gene expression levels of proinflammatory genes (complement component 3, IL-1β, IL6, and TNFα) were analyzed by real-time PCR, immunoblot, and immunohistochemistry. As expected, IL-1β induced elevated levels of proinflammatory genes. 2-DG reversed this effect at the mRNA and protein levels without inducing cytotoxicity. Collectively, these data suggest that inhibiting glycolysis in human astrocytes reduces IL-1β-induced reactivity. This finding may lead to novel therapeutic strategies to limit inflammation and enhance bioenergetics toward the goal of preventing and treating neurodegenerative diseases.
Highlights
We have discovered evidence that reactive astrocytes cause a reduction in the levels of transcription factor at mitochondria (TFAM) in neurons that results in deficient mitochondrial biogenesis [8,9]
We found that the caloric restriction mimetic and glycolytic inhibitor 2-deoxyglucose inhibits IL-1β-induced inflammatory gene expression in a dose-dependent manner
Primary human astrocyte cultures were pretreated with tally inhibit glycolysis
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. The world’s aging population is susceptible to age-related neurodegenerative diseases, for many of which no effective preventive therapies or treatments are available. Neuroinflammation is a hallmark of many neurodegenerative diseases and represents a potential therapeutic target to improve the health and quality of life of aging populations [1,2]. Microglia and astrocytes produce and perpetuate neuroinflammation in the brain and are believed to contribute to neurodegeneration when in a chronically reactive state [3,4,5,6,7]
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