The Potential Use of Dimethyltryptamine against Ischemia-reperfusion Injury of the Brain

Ischemia-reperfusion injury (IRI) arises from disrupted blood flow and subsequent restoration, causing damage in emergency medicine. Mitochondrial and endoplasmic reticulum dysfunction are key factors. The sigma-1 receptor (Sig1-R), a chaperone between these organelles, regulates signaling and protects against cellular stress. Activating Sig1-R improves mitochondrial respiration and endoplasmic reticulum function. N, N-dimethyltryptamine (DMT), an endogenous Sig1-R agonist, may have therapeutic potential. This article reviews Sig1-R's role in cellular bioenergetics and IRI, summarizing in vitro and in vivo DMT studies. The authors conclude DMT may universally protect cells, suggesting therapies for IRI in brain ischemia after stroke or cardiac arrest.

Study at a glance

Abstract

Ischemia-Reperfusion Injury (IRI) is the outcome of two intertwined pathological processes resulting from the shortage of blood flow to tissues and the subsequent restoration of circulation to a previously ischemic area. IRI (sometimes just one side of the dyad) remains one of the most challenging problems in several branches of emergency medicine. Mitochondrial and endoplasmic reticulum dysfunction is a crucial pathological factor involved in the development of IRI. The sigma-1 receptor (Sig1-R) is an intracellular chaperone molecule located between the mitochondria and endoplasmic reticulum with an apparent physiological role in regulating signaling between these cell organelles and serves as a safety mechanism against cellular stress. Therefore, amelioration of IRI is reasonably expected by the activation of the Sig1-R chaperone. Indeed, under cellular stress, Sig1-R agonists improve mitochondrial respiration and optimize endoplasmic reticulum function by sustaining high-energy phosphate synthesis. The discovery that N, N-dimethyltryptamine (DMT) is an endogenous agonist of the Sig1-R may shed light on yet undiscovered physiological mechanisms and therapeutic potentials of this controversial hallucinogenic compound. In this article, the authors briefly overview the function of Sig1-R in cellular bioenergetics with a focus on the processes involved in IRI and summarize the results of their in vitro and in vivo DMT studies aiming at mitigating IRI. The authors conclude that the effect of DMT may involve a universal role in cellular protective mechanisms suggesting therapeutic potentials against different components and types of IRIs emerging in local and generalized brain ischemia after stroke or cardiac arrest.