BACKGROUND AND PURPOSE N,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. METHODS Transient 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. RESULTS DMT 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. CONCLUSION Our 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.

中文翻译：

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N，N-二甲基色胺减少大鼠短暂性局灶性脑缺血后的梗塞面积并改善功能恢复。

背景和目的N，N-二甲基色胺（DMT）是Sigma 1受体（Sig-1R）的内源性配体，具有体外抗缺氧的细胞保护作用。我们的目的是证明大鼠脑缺血再灌注损伤后DMT的体内神经保护作用。方法采用全身麻醉下的灯丝闭塞模型，在雄性Wistar大鼠中诱导短暂中脑闭塞（MCAO）60分钟。在去除细丝之前，治疗组（n = 10）接受溶于1 ml 7％乙醇/盐水载体的1 mg / kg体重（bw）DMT的腹膜内（IP）推注，然后进行维护通过渗透微型泵在24小时内递送2 mg / Kg-bw / h的剂量。对照组（n = 10）仅接受了一次车辆大剂量注射。第三组（n = 10）接受了Sig-1R拮抗剂（BD1063，与DMT平行进行1 mg / kg-bw推注+ 2 mg / kg-bw / h维持）。MCAO后24小时通过MRI测量病变体积。成像后不久，将动物处死，并去除天然脑和血清。固定四只大鼠。使用阶梯法在两组单独训练的动物（n = 8-8）中研究功能恢复30天。通过实时qPCR和ELISA评估参与凋亡，神经可塑性和炎症调节的蛋白质的表达水平。结果与对照组相比，DMT治疗的大鼠的特点是缺血性病变体积较小（p = .0373），功能恢复较好（p = .0084）。Sig-1R在梗死灶周围皮层的神经元和小胶质细胞中都有表达，而BD1063阻碍了DMT诱导的病变体积改变。DTM上记录到较低的APAF1表达（mRNA和蛋白）和较高的BNDF水平，而TNF-α，IL1-β，IL-6和IL-10表达降低表明该化合物具有抗炎作用。结论我们的结果表明，在大鼠中外源性DMT给药后，Sig-1R依赖性缺血性脑损伤的减轻，可能是通过组合的抗凋亡，促神经营养和抗炎作用。