Low Glycolysis is Neuroprotective During Anoxic Spreading Depolarization (SD) and Reoxygenation in Locusts.

Migratory locusts enter a reversible hypometabolic coma to survive environmental anoxia, wherein the cessation of central nervous system (CNS) activity is driven by spreading depolarization (SD). While glycolysis is recognized as a crucial anaerobic energy source contributing to animal anoxia tolerance, its influence on the anoxic SD trajectory and recovery outcomes remains poorly understood. We investigated the effects of varying glycolytic capacity on adult female locust anoxic SD parameters, using glucose or the glycolytic inhibitors 2-deoxy-D-glucose (2DG) or monosodium iodoacetate (MIA). Surprisingly, 2DG treatment shared similarities with glucose yet had opposite effects compared to MIA. Specifically, though SD onset was not affected, both glucose and 2DG expedited the recovery of CNS electrical activity during reoxygenation, whereas MIA delayed it. Additionally, glucose and MIA, but not 2DG, increased tissue damage and neural cell death following anoxia-reoxygenation. Notably, glucose-induced injuries were associated with heightened CO 2 output during the early phase of reoxygenation. Conversely, 2DG resulted in a bimodal response, initially dampening CO 2 output and gradually increasing it throughout the recovery period. Given the discrepancies between effects of 2DG and MIA, the current results require cautious interpretations. Nonetheless, our findings present evidence that glycolysis is not a critical metabolic component in either anoxic SD onset or recovery, and that heightened glycolysis during reoxygenation may exacerbate CNS injuries. Furthermore, we suggest that locust anoxic recovery is not solely dependent on energy availability, and the regulation of metabolic flux during early reoxygenation may constitute a strategy to mitigate damage. Significance Statement The central nervous system (CNS) in insects can reversibly shutdown under extreme conditions like anoxia, through a process known as spreading depolarization (SD). Despite the central importance of glycolysis in CNS functioning, its precise involvement during anoxic SD remains poorly understood. Using the locust ( L. migratoria ) SD model, we show that glycolysis is not a critical energy source for the CNS to recover from anoxic SD, and that it could exacerbate anoxic injuries during reoxygenation. These findings identify the CNS glycolytic pathways as a potential target to mitigate detrimental effects of anoxia.