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. Overall design: Gene expression profiling analysis of primary rat brain endothelial cells from endothelial cell-pericyte-astrocyte co-cultures in vitro. Treatments include normoxia, OGD/R, OGD/R + DMT, and OGD/R + DMT + BD1063, n=5-6 samples (corresponding to endothelial lysates from 5-6 individual culture inserts) per group.