N,N-dimethyltryptamine reduces infarct size and improves functional recovery following transient focal brain ischemia in rats

A single intraperitoneal dose of DMT (1 mg/kg) followed by a 24-hour infusion (2 mg/kg/h) reduced ischemic brain lesion volume and improved functional recovery in male Wistar rats after 60 minutes of transient middle cerebral artery occlusion. The neuroprotective effect was blocked by a Sigma-1 receptor antagonist, indicating a Sigma-1 receptor-dependent mechanism. DMT treatment lowered expression of the pro-apoptotic protein APAF1, increased brain-derived neurotrophic factor (BDNF), and shifted the inflammatory cytokine profile toward an anti-inflammatory state (decreased TNF-α, IL-1β, IL-6; increased IL-10). The findings suggest DMT protects against ischemic injury through combined anti-apoptotic, pro-neurotrophic, and anti-inflammatory actions.

Study at a glance

Abstract

Background and purposeN,N-dimethyltryptamine (DMT) is an endogenous ligand of the Sigma 1 receptor (Sig-1R) with documented in vitro cytoprotective properties against hypoxia. Our aim was to demonstrate the in vivo neuroprotective effect of DMT following ischemia-reperfusion injury in the rat brain.MethodsTransient middle cerebral occlusion (MCAO) was induced for 60 min in male Wistar rats using the filament occlusion model under general anaesthesia. Before the removal of the filament the treatment group (n = 10) received an intra-peritoneal (IP) bolus of 1 mg/kg-body weight (bw) DMT dissolved in 1 ml 7% ethanol/saline vehicle, followed by a maintenance dose of 2 mg/Kg-bw/h delivered over 24 h via osmotic minipumps. Controls (n = 10) received a vehicle bolus only. A third group (n = 10) received a Sig-1R antagonist (BD1063, 1 mg/kg-bw bolus +2 mg/kg-bw/h maintenance) in parallel with the DMT. Lesion volume was measured by MRI 24 h following the MCAO. Shortly after imaging the animals were terminated, and the native brains and sera were removed. Four rats were perfusion fixed. Functional recovery was studied in two separate group of pre-trained animals (n = 8-8) using the staircase method for 30 days. The expression levels of proteins involved in apoptosis, neuroplasticity and inflammatory regulation were assessed by real-time qPCR and ELISA.ResultsDMT treated rats were characterized by lower ischemic lesion volume (p = .0373), and better functional recovery (p = .0084) compared to the controls. Sig-1R was expressed both in neurons and in microglia in the peri-infarct cortex, and the DMT induced change in the lesion volume was hindered by BD1063. Lower APAF1 expression (mRNA and protein) and higher BNDF levels were documented on DTM, while decreased TNF-α, IL1-β, IL-6 and increased IL-10 expressions indicated the compound's anti-inflammatory potential.ConclusionOur results indicate a Sig-1R dependent reduction of the ischemic brain injury following exogenous DMT administration in rats, presumably through a combined anti-apoptotic, pro-neurotrophic and anti-inflammatory treatment effect.