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

ABSTRACT: 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.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE287518 | GEO | 2025/07/01

REPOSITORIES: GEO

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Project description:Cerebral ischemia/reperfusion injury (CI/RI), including neurological behavior deficits, cerebral infarction, blood-brain barrier (BBB) dysfunction, and neuroinflammation, et al. is a severe challenge in treatment of ischemic stroke. Traditional Chinese medicine (TCM) with the characteristics of multi-components and multi-functions for multiple targets/pathways has been historically used in the treatment of stroke and post stroke recovery in China. QiShenYiQi (QSYQ), a representative component-based Chinese medicine, is capable of reducing organ injury caused by ischemia/reperfusion via multiple mechanisms. Recently, we have previously reported that the positive action of QSYQ against the acute phase of CI/RI is partly via modulation of neuroinflammatory response. However, the effects and underlying mechanisms of QSYQ on subacute phase of CI/RI remain unknown, which are aimed to investigate in present study. The pharmacological action of QSYQ treatment on brain damage was estimated in the experimental stroke rats underwent 90 min ischemia and 8 days reperfusion by assessing the neurological and locomotor deficits, cerebral infarction, brain edema, and BBB integrity. Furthermore, we used TMT-based quantitative proteomics technology to identify significantly differentially expressed proteins following QSYQ treatment, which could give important clues for revealing the possible mechanism underlying the positive role of QSYQ in CI/RI. Besides, immunohistochemistry, western blot analysis, RT-qPCR, and rat ELISA kits were executed to further verify the accuracy of proteomics analysis results. As a consequence, we found that treatment with QSYQ (600mg/kg) for 7 days obviously improved neurological and behavioral impairment, attenuated infarct volume and brain edema, and alleviated BBB breakdown in stroke rats. Bioinformatics analysis suggested that differentially expressed protein galectin-3 mediated inflammatory response was closely related to the beneficial effect of QSYQ. Results of immunohistochemistry, western blot analysis and RT-qPCR showed that the model rats treated with QSYQ (600mg/kg) markedly downregulated the mRNA and protein expression level of galectin-3 in brain tissues compared to the untreated stroke rats. In addition, the decrease of mRNA level in brain tissues and contents in serum of TNF-α and IL-6 following QSYQ treatment were also observed. These interesting finding manifested that the effective action of QSYQ against subacute phase of CI/RI was partly via regulating galectin-3 mediated inflammatory reaction.

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

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