Dimethyltryptamine (DMT): a biochemical Swiss Army knife in neuroinflammation and neuroprotection?

The biochemical background of this extensive ability lies in the possible cross-talk of the GPCR-coupled downstream signaling of 5-HTRs/Sig-1R and other inflammatory pathways in immune cells, as well as the fine-tuning of cytokine feedback loops in peripheral tissues. [...]in neuroinflammation, two major scenarios are possible: i) the modulation of cytokine production by brain resident microglia that implies a negative feedback regulation of inflammation via the induction of the release of anti-inflammatory IL-10 and TGFβ occurring subsequent of both 5-HTR and Sig-1R activation; ii) the direct/indirect control of NF-κB signaling and possibly other pathways (e.g., MAPKs) involved in inflammation through intracellular kinases, adaptor proteins, etc (reviewed by Szabo, 2015). The Gq family of α subunits couple a large number of GPCRs to PLC-β, and many of these have been shown to activate NF-κB. This mechanism is based on the activity of the IκB kinases IKKα and IKKβ, as well as the PI3K pathway involving the serine/threonine protein kinase Akt (Xie et al., 2000). The neuroregenerative potential of DMT through the Sig-1R has been suggested earlier as multiple biochemical and physiological mechanisms exist, which facilitate the transportation and binding of DMT to the Sig-1R in the mammalian brain (Frecska et al., 2013). [...]DMT - as a natural, endogenous agonist at both the Sig-1R and 5-HTRs - is hypothesized to be an unique, many-faced pharmacological entity, which has many important roles in the immunoregulatory processes of peripheral and brain tissues, as well as involved in the promotion and induction of neuroregeneration in the mammalian nervous system[19].