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. 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. Tryptaminergic trace amines (e.g., N,N-dimethyltryptamine; DMT) as well as neurosteroids (e.g., dehydroepiandrosterone) are endogenous ligands of the Sig-1R. DMT was shown to be endogenously present in the human brain and in other tissues of the body, however the exact physiological role of this tryptamine has not been identified yet. This wide-spectrum agonist activity may allow DMT to modulate several physiological processes and regulate inflammation through the Sig-1R and 5-HTRs. Protective and neuroregenerative effects of Sig-1R agonists have been reported in several in vitro and in vivo studies. The selective Sig-1R agonists 2-(4-morpholinethyl)1 phenylcyclohexanecarboxylate (PRE084) and cutamesine have been shown to strongly promote neuroprotective mechanisms and significantly increase neuronal cell survival and regeneration under various conditions, such as traumas, autoimmunity, and neurodegenerative disorders. Specific Sig-1R stimulation has also been found to greatly increase the levels of the glial cell-derived neurotrophic factor (GDNF) that promotes neuronal cell survival and differentiation. 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. Thus DMT – as a natural, endogenous agonist atboth 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.