N,N-Dimethyltryptamine attenuates spreading depolarization and restrains neurodegeneration by sigma-1 receptor activation in the ischemic rat brain

Introduction

N,N-Dimethyltryptamine (DMT) is an endogenous indole alkaloid with recognised activity at multiple receptor systems, including the sigma-1 receptor (Sig-1R). Earlier work has suggested that DMT concentrations rise in mammalian brain under severe stress, and that exogenous DMT can protect cultured human cortical neurons from hypoxia and reduce infarct size and inflammation in rodent focal ischemia models. Sig-1Rs are intracellular chaperone-like proteins at the mitochondria-associated endoplasmic reticulum membrane that regulate calcium trafficking, reactive oxygen species, and cell survival pathways; prior studies indicate Sig-1R activation can be neuroprotective in ischemia. Szabó and colleagues designed an in vivo study to test whether intravenous DMT given during acute, transient global forebrain ischemia can limit pathological events that promote lesion progression and thereby reduce early neurodegeneration, and whether such effects are mediated by Sig-1R activation. To increase metabolic stress and create a model relevant to penumbral injury, the investigators superimposed three induced spreading depolarizations (SDs) and a brief episode of hypoxia onto two-vessel occlusion (2VO). They compared DMT with a selective Sig-1R agonist and antagonist, and probed potential contributions of serotonin receptors using a broad-spectrum 5-HT receptor antagonist; outcomes included electrophysiological indices of SD, cerebral blood flow (CBF), histological markers of cell death and glial integrity, Sig-1R binding, tissue DMT levels, and cellular localisation of Sig-1R.