N,N-dimethyltryptamine protects against experimental stroke via blood-brain barrier stabilization and reduction of neuroinflammation

N,N-Dimethyltryptamine (DMT) is a psychoactive molecule naturally present in the brains of mammals, including humans. Due to its neuroprotective effect in experimental stroke, DMT is under clinical evaluation, yet its mechanism of action remains poorly understood. Here we show that DMT protects against stroke by stabilizing the blood-brain barrier (BBB) and by mitigating neuroinflammation. In a transient middle cerebral artery occlusion (tMCAO) model of stroke in rats, treatment with DMT reduced infarct volume, and restored tight junction integrity and BBB function in vitro and in vivo. DMT also reduced cerebral edema, attenuated astrocyte dysfunction and shifted serum protein composition towards an anti-inflammatory, neuroprotective state. Finally, DMT suppressed the release of proinflammatory cytokines and chemokines in brain endothelial cells and peripheral immune cells, and reduced microglial activation, all in a sigma-1 receptor-dependent manner. Together, our findings demonstrate that the protective effect of DMT relies on its interaction with the vascular and immune systems, which can be harnessed to complement current stroke therapy.N,N-二甲基色胺（N,N-Dimethyltryptamine，DMT）是一种具有精神活性的分子，天然存在于包括人类在内的哺乳动物大脑中。鉴于其在实验性脑卒中中的神经保护作用，DMT目前正处于临床评估阶段，但其具体作用机制仍不甚明晰。本研究表明，DMT可通过稳定血脑屏障（blood-brain barrier，BBB）并减轻神经炎症发挥脑卒中保护作用。在大鼠短暂性大脑中动脉阻塞（transient middle cerebral artery occlusion，tMCAO）脑卒中模型中，DMT治疗可减小脑梗死体积，并在体内外恢复紧密连接完整性与血脑屏障功能。此外，DMT还可减轻脑水肿、缓解星形胶质细胞功能障碍，并使血清蛋白组成向抗炎、神经保护状态转变。最后，DMT可通过σ1受体（sigma-1 receptor）依赖的方式，抑制脑内皮细胞与外周免疫细胞释放促炎细胞因子及趋化因子，并减少小胶质细胞激活。综上，本研究结果证实，DMT的保护作用依赖于其与血管系统及免疫系统的相互作用，这一机制可用于补充当前的脑卒中治疗方案。