Metabolic Reprogramming by Andrographolide: Enhanced Pentose Phosphate Pathway and Antioxidant Capacity in Cortical Astrocytes

TL;DR

This study shows that andrographolide boosts antioxidant capacity and alters glucose metabolism in brain astrocytes, potentially offering neuroprotection.

Contribution

The study reveals andrographolide's novel effect on astrocytic metabolic reprogramming via the pentose phosphate pathway and Wnt signaling.

Findings

Andrographolide increases glucose uptake and antioxidant capacity in astrocytes.

It enhances glucose-6-phosphate dehydrogenase activity and NADPH availability.

The compound promotes redox maintenance over energy production in astrocytes.

Abstract

Background/Objectives: Astrocytes are key regulators of brain energy homeostasis, integrating glucose metabolism with antioxidant support for neuronal function. Dysregulation of these processes contributes to neurodegenerative diseases, including Alzheimer’s disease. Andrographolide, a bioactive diterpenoid from Andrographis paniculata, has been reported to exert neuroprotective effects through the modulation of Wnt/β–catenin signaling and neuronal metabolism; however, its actions on astrocytic metabolic pathways remain insufficiently characterized. Methods: Here, we investigated the effects of andrographolide on metabolic and redox parameters in primary mouse cortical astrocytes. Results: Andrographolide increased glucose uptake and antioxidant capacity without affecting AMPK activation or the activity of core glycolytic enzymes. Instead, it selectively enhanced glucose-6-phosphate dehydrogenase activity, promoting glucose flux through the pentose phosphate pathway in a partially Wnt-dependent manner. This metabolic reprogramming was associated with increased NADPH availability and glutathione levels, together with a reduced ATP/ADP ratio, consistent with a shift toward redox maintenance rather than maximal energy production. Conclusions: Collectively, these findings highlight astrocytic metabolic plasticity as a relevant and underexplored target of andrographolide and support the concept that natural compounds can enhance brain resilience by modulating glial redox metabolism.

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