The Endogenous Hallucinogen and Trace Amine N,N-Dimethyltryptamine (DMT) Displays Potent Protective Effects against Hypoxia via Sigma-1 Receptor Activation in Human Primary iPSC-Derived Cortical Neurons and Microglia-Like Immune Cells.
N,N-dimethyltryptamine (DMT) is a potent endogenous hallucinogen present in the brain of humans and other mammals. Despite extensive research, its physiological role remains largely unknown. Recently, DMT has been found to activate the sigma-1 receptor (Sig-1R), an intracellular chaperone fulfilling an interface role between the endoplasmic reticulum (ER) and mitochondria. It ensures the correct transmission of ER stress into the nucleus resulting in the enhanced production of antistress and antioxidant proteins. Due to this function, the activation of Sig-1R can mitigate the outcome of hypoxia or oxidative stress. In this paper, we aimed to test the hypothesis that DMT plays a neuroprotective role in the brain by activating the Sig-1R. We tested whether DMT can mitigate hypoxic stress in in vitro cultured human cortical neurons (derived from induced pluripotent stem cells, iPSCs), monocyte-derived macrophages (moMACs), and dendritic cells (moDCs). Results showed that DMT robustly increases the survival of these cell types in severe hypoxia (0.5% O2) through the Sig-1R. Furthermore, this phenomenon is associated with the decreased expression and function of the alpha subunit of the hypoxia-inducible factor 1 (HIF-1) suggesting that DMT-mediated Sig-1R activation may alleviate hypoxia-induced cellular stress and increase survival in a HIF-1-independent manner. Our results reveal a novel and important role of DMT in human cellular physiology. We postulate that this compound may be endogenously generated in situations of stress, ameliorating the adverse effects of hypoxic/ischemic insult to the brain.
NORMENT, KG Jebsen Centre for Psychosis Research, Institute of Clinical Medicine, University of OsloOslo, Norway; Division of Mental Health and Addiction, Oslo University HospitalOslo, Norway; Department of Immunology, Faculty of Medicine, University of DebrecenDebrecen, Hungary.
Attila
A
Szabo
Department of Psychiatry, Faculty of Medicine, University of Debrecen Debrecen, Hungary.
Attila
A
Kovacs
Human Neuropsychopharmacology Research Group, Sant Pau Institute of Biomedical ResearchBarcelona, Spain; Centro de Investigación Biomédica en Red de Salud MentalBarcelona, Spain.
Jordi
J
Riba
NORMENT, KG Jebsen Centre for Psychosis Research, Department of Clinical Science, University of BergenBergen, Norway; Department of Medical Genetics, Oslo University HospitalOslo, Norway.
Srdjan
S
Djurovic
Department of Immunology, Faculty of Medicine, University of Debrecen Debrecen, Hungary.
Eva
E
Rajnavolgyi
Department of Psychiatry, Faculty of Medicine, University of Debrecen Debrecen, Hungary.
Ede
E
Frecska
cellular stress; cellular survival; dimethyltryptamine; hypoxia; sigma-1 receptor
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