Neurones are the most vulnerable brain cells to excess reactive oxygen species. Their survival is thought to exclusively rely on the antioxidant protection promoted by neighbouring astrocytes. Indeed, these glial cells are not only self-protected by a robust antioxidant equipment -coordinated by Nrf2; they also provide neurones with both energy substrates and antioxidant glutathione (GSH) precursors (1). However, whilst astrocytes are necessary for neuronal protection, recent data suggest that they may not be sufficient; neurones would be intrinsically equipped with a biochemical mechanism that couples glucose metabolism to antioxidant defence for full protection (2). Here, we would like to review recent data from our and other laboratories suggesting that this neuroprotective coupling is connected with neuronal activity. Increasing body of evidence is now consolidating the antioxidant and antiapoptotic functions of glucose oxidation through the pentose phosphate pathway (PPP). In essence, PPP oxidatively decarboxylates glucose-6-phosphate (G6P) to ribulose-5-phosphate (R5P), conserving the redox equivalents as NADPH(H+). Constantly maintaining this redox coenzyme in its reduced status is essential for cellular GSH regeneration from its oxidized form (GSSG). Neurones are deficient in total glutathione and in their capacity to de novo synthesize it. Accordingly, the antioxidant status and survival of these cells are particularly dependent on a very efficient PPP (3). How is this metabolic route constitutively up-regulated in neurones? Glycolysis and PPP are two interconnected metabolic pathways that exist in equilibrium. Thus, the rate of G6P conversion into pyruvate through glycolysis, and that into R5P through PPP, are reciprocally influenced. In neurones, the rate of glycolysis is normally very low due to continuous destabilization of PFKFB3 (6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase-3), a key glycolytic-promoting enzyme (4). Our laboratory identified APC/CCdh1 (anaphase-promoting complex/cyclosome-Cdh1) as the E3 ubiquitin ligase responsible for PFKFB3 destabilization (4). The high APC/CCdh1 activity in neurones hence accounts for their low glycolysis and high PPP rates; in contrast, astrocytes express very low APC/CCdh1 activity (4), hence PFKFB3 is stable. By keeping PFKFB3 unstable in neurones, APC/CCdh1 accounts for efficient PPP-mediated NADPH(H+) regeneration and high GSH/GSSG redox status (4). Thus, neurones maintain their antioxidant status by consuming G6P through the PPP at the expense of lowering its use through glycolysis for energy purposes. How, then, neurones obtain their energy from? The most plausible -but not the only- explanation to this apparent paradox is the astrocyte-neurone lactate shuttle (ANLS) (5). In essence, following neuronal activity, astrocytes remove excess glutamate from the synaptic cleft by an energy-dependent glutamate transport that stimulates glycolysis to lactate. Astrocytic-released lactate would then be taken up by neurones, which utilize it for oxidative mitochondrial metabolism (5). Our results demonstrating that APC/CCdh1, by promoting PFKFB3 degradation, continuously inhibits glycolysis in neurones (4) would favour lactate to pyruvate conversion, thus contributing to explain how neuronal activity is coupled to brain glucose utilization. Furthermore, the coordination of APC/CCdh1 activity with ANLS supports the notion that the coupling of energy metabolism between astrocytes and neurones is necessary to maintain neuronal antioxidant redox status and survival. However, how is this bioenergetic-antioxidant axis physiologically regulated? Previously, it was found that following NMDA receptor (NMDAR) activity, the APC/C protein adaptor, Cdh1, becomes hyper-phosphorylated, and inhibited, via a Ca2+-dependent activation of cyclin-dependent kinase 5 (Cdk5) in neurones (6). Recent results from our laboratory show that NMDAR stimulation, by inhibiting APC/CCdh1, stabilizes PFKFB3 leading neurones to an increased rate of glycolysis and a decreased rate of PPP (7). These results indicate that the control of the bioenergetic and antioxidant status of neurones by APC/CCdh1 is amenable to regulation, at least in a glutamatergic in vitro setting. Further studies would be required to more precisely identify and characterize the molecular players involved in the tuning of glycolysis and antioxidant status under different physiological conditions. This would also provide a boost to our understanding of the molecular mechanisms underlying neurological disorders, as well as in our search for novel therapeutic strategies.