Rewiring Brain Recovery: Astrocyte–Neuron Metabolic Cooperation in Stroke

SIGNIFICANCE: The high level of metabolism in the central nervous system (CNS) induces the production of large amounts of free radicals following stroke, thereby resulting in oxidative stress. The brain is particularly vulnerable to oxidative stress-induced damage due to its high oxygen consumption. Astrocytes, as key regulators of CNS homeostasis, play a critical role in modulating oxidative stress and maintaining CNS function. RECENT ADVANCES: Accumulating evidence has shown that astrocytes undergo polarization into two distinct states: A1 (neurotoxic and pro-inflammatory) and A2 (neuroprotective and anti-inflammatory) phenotypes following ischemic stroke, which, respectively, exhibit harmful and beneficial roles in oxidative stress-induced brain injury. In addition, metabolic crosstalk between astrocytes and neurons during the acute phase of ischemic stroke, involving lactate, amino acids, healthy mitochondria, and fatty acids, is crucial in maintaining neuronal morphology and function. CRITICAL ISSUES: A2 astrocytes possess significant antioxidative capabilities by expressing high levels of antioxidative stress genes. Notably, the polarization of astrocytes toward the A2 subtype appears to enhance their beneficial and supportive role in metabolic crosstalk with neurons. A deeper understanding of astrocytic roles, particularly those of A2 astrocytes, in redox regulation and astrocyte-neuron metabolic crosstalk may provide novel therapeutic strategies for ischemic stroke. Therefore, in this review, we mainly discuss the roles of astrocytes, particularly A2 astrocytic polarization, in redox regulation and metabolic crosstalk with neurons following ischemic stroke. FUTURE DIRECTION: 44, 410-435.