Caloric Restriction Mimetic 2-Deoxyglucose Reduces Inflammatory Signaling in Human Astrocytes: Implications for Therapeutic Strategies Targeting Neurodegenerative Diseases

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.

Complement component 3 and complement factor H protein levels are altered in brain tissues from people with human immunodeficiency virus: A pilot study

“…Our findings are consistent with a finding that C3 is positively associated with metabolic alterations in aged PWH (Bryant et al, 2016) and a significant role for complement in AD (Morgan, 2018). Elevated C3 levels in HAND and Aβ + brains are also consistent with studies showing that reactive astrocytes produce C3 (Liddelow et al, 2017;Nitkiewicz et al, 2017;Clarke et al, 2018;Vallee and 2022) and may contribute to metabolic deficiencies in neurons in HAND and AD (Jiang and Cadenas, 2014;Yin et al, 2016;Fields et al, 2019;Swinton et al, 2019). However, the relationship between C3 and AD neuropathogenesis is not clear.…”

Modulation of Cellular Levels of Adenosine Phosphates and Creatine Phosphate in Cultured Primary Astrocytes

“…ATP is regenerated in astrocytes mainly by glycolysis and mitochondrial respiration [ 15 ]. To test how the absence or the presence of glucose and/or the inactivation of glycolysis and/or mitochondrial respiration may affect cellular ATP and CrP contents, astrocyte cultures were incubated for up to 30 min with or without glucose or with the glycolysis inhibitor 2DG [ 50 , 51 ] in the absence or the presence of 10 µM of the respiratory chain inhibitor antimycin A [ 52 ]. None of the conditions used compromised the cell viability as demonstrated by the absence of any significant increase in extracellular LDH activity (Table 2 ).…”

Inhibition of HDAC6 alleviates cancer‑induced bone pain by reducing the activation of NLRP3 inflammasome

“…GFAP is the hallmark intermediate filament protein that is found in astrocytes ( 42 ). CFB rapidly amplifies C3 activation ( 43 ), which is linked to astrocyte reactivity and the promotion of the neuroinflammatory phenotype ( 44 ). GFAP, C3 and CFB expression levels were detected in the present study.…”