Axons in the mature central nervous system (CNS) fail to regenerate after axotomy, partly due to the inhibitory environment constituted by reactive glial cells producing astrocytic scars, chondroitin sulfate proteoglycans, and myelin debris. We investigated this inhibitory milieu, showing that it is reversible and depends on glial metabolic status. We show that glia can be reprogrammed to promote morphological and functional regeneration after CNS injury in Drosophila via increased glycolysis. This enhancement is mediated by the glia derived metabolites: L-lactate and L-2-hydroxyglutarate (L-2HG). Genetically/pharmacologically increasing or reducing their bioactivity promoted or impeded CNS axon regeneration. L-lactate and L-2HG from glia acted on neuronal metabotropic GABA_B receptors to boost cAMP signaling. Local application of L-lactate to injured spinal cord promoted corticospinal tract axon regeneration, leading to behavioral recovery in adult mice. Our findings revealed a metabolic switch to circumvent the inhibition of glia while amplifying their beneficial effects for treating CNS injuries.

成熟的中枢神经系统 (CNS) 中的轴突在轴突切断后无法再生，部分原因是由产生星形胶质细胞疤痕的反应性神经胶质细胞、硫酸软骨素蛋白聚糖和髓鞘碎片构成的抑制环境。我们研究了这种抑制环境，表明它是可逆的并且取决于神经胶质代谢状态。我们表明，在果蝇中枢神经系统损伤后，胶质细胞可以通过增加糖酵解进行重新编程，以促进形态和功能再生。这种增强是由胶质细胞衍生的代谢物介导的：L-乳酸和 L-2-羟基戊二酸 (L-2HG)。遗传/药理学增加或减少其生物活性促进或阻碍中枢神经系统轴突再生。来自胶质细胞的 L-乳酸和 L-2HG 作用于神经元代谢型 GABA _B受体以增强 cAMP 信号。L-乳酸对受伤脊髓的局部应用促进了皮质脊髓束轴突再生，导致成年小鼠的行为恢复。我们的研究结果揭示了一种代谢开关，可以绕过对神经胶质的抑制，同时放大它们对治疗中枢神经系统损伤的有益作用。