This commentary (2016) reviews the role of DMT as an endogenous ligand of the Sigma-1 receptor, and although the exact physiological role of endogenous DMT is yet to be identified, there is evidence that suggests that it can modulate immune responses through the suppression of inflammatory cytokines. These neuroprotective and neuroregenerative effects may render DMT a potentially useful therapeutic tool in a broad range of chronic inflammatory and autoimmune diseases.
Abstract
“The inflammatory theory of many neuropsychiatric illnesses has become an emerging trend in modern medicine. Various immune mechanisms – mainly via the activity of microglia – may contribute to the etiology and symptomatology of diseases, such as schizophrenia, bipolar disorder, depression, or Alzheimer’s disease (Deleidi et al., 2015; Khandaker et al., 2015). Unwanted and excess inflammation is most typically the result of dysregulated innate immune responses. Recognition of self-derived damage-associated molecular patterns (DAMPs) or pathogen-associated molecular pattern molecules (PAMPs) is usually leading to the activation of tissue resident immune cells including macrophages (microglia) and dendritic cells. They act as ‘gatekeepers’ continuously monitoring the tissue microenvironment for potential ‘danger signals’ by means of their pattern recognition receptors, such as Toll-like receptors or RIG-I-like receptors. Once a DAMP or PAMP has been recognized by a pattern recognition receptor various downstream signaling pathways are initiated, which eventually leads to the secretion of inflammatory cytokines and many other soluble factors important in the elimination of e.g. invading microbes. Pattern recognition receptors couple to nuclear factor kappaB (NF-κB), the master transcription regulator of inflammatory cytokines (e.g., IL-1β, IL-6, TNFα) and chemokines (e.g., IL-8/CXCL8) (Szabo and Rajnavolgyi, 2013). Macrophages and dendritic cells are also capable of antigen-presentation so they can initiate adaptive immune responses by priming naive T-cells. During inflammation of the central nervous system, polarization towards the T helper 1 and 17 (Th1, Th17) subsets is especially important as these T cells play a major role in the development of chronic inflammation and brain tissue damage in infectious diseases and autoimmunity (Kothur et al., 2016).”
Authors: Atilla Szabó & Ede Frecska
Summary
Dimethyltryptamine (DMT): a biochemical Swiss Army knife in neuroinflammation and neuroprotection?
The inflammatory theory of many neuropsychiatric illnesses is an emerging trend in modern medicine. Microglia are cells that are involved in the immune response to self- and pathogen-derived damage-associated molecular patterns (DAMPs) and pathogen-associated molecular pattern molecules (PAMPs). Pattern recognition receptors couple to nuclear factor kappaB (NF-B), the master transcription regulator of inflammatory cytokines and chemokines. Macrophages and dendritic cells can also present antigens to T-cells, which can initiate adaptive immune responses.
The sigma-1 receptor (Sig-1R) is located at the endoplasmic reticulum-mitochondrion interface and plays an important role in the regulation of cellular metabolism and energetics under stressful conditions. It also plays an important role in neuronal differentiation, neuronal signaling, cellular survival in hypoxia, resistance against oxidative stress, and mitigating unfolded protein response.
DMT is an endogenous ligand of the Sig-1R and also acts as an agonist at numerous serotonin receptors, including 5-HT1A, 5-HT2A, and 5-HT2C. DMT can regulate several physiological processes, including inflammation, through the Sig-1R and 5-HTRs. The biochemical background of the extensive ability of DMT to modulate inflammatory responses lies in the possible cross-talk between 5-HTR/Sig-1R GPCR-coupled downstream signaling and other inflammatory pathways in immune cells, as well as the fine-tuning of cytokine feedback loops in peripheral tissues.
DMT regulates NF-B and MAPKs via G (Gi and Gq families), and G proteins, and a large number of GPCRs have been shown to activate NF-B. The Sig-1R receptor can also couple to NF-B and MAPKs and regulate inflammation and apoptosis through this mechanism. DMT may be a useful therapeutic tool in a broad range of chronic inflammatory and autoimmune diseases, but its powerful hallucinogenic property poses an important problem.
DMT has been shown to have neuroprotective and neuroregenerative effects in several in vitro and in vivo studies. DMT is also a natural agonist at both the Sig-1R and 5-HTRs, and is involved in the promotion and induction of neuroregeneration in the mammalian nervous system.