N,N-Dimethyltryptamine attenuates spreading depolarization and restrains neurodegeneration by sigma-1 receptor activation in the ischemic rat brain.
Írisz Szabó, Viktória É Varga, Szabolcs Dvorácskó, Attila E Farkas, Tímea Körmöczi, Róbert Berkecz, Szilvia Kecskés, Ákos Menyhárt, Rita Frank, Dóra Hantosi, Nicholas V. Cozzi, Ede Frecska, Csaba Tömböly, István A Krizbai, Ferenc Bari, Eszter Farkas
Neuropharmacology July 1, 2021 DOI: 10.1016/j.neuropharm.2021.108612 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Controlled laboratory study Peer reviewed |
|---|---|
| Population | Anesthetized rats |
| Interventions | DMT PRE-084 NE-100 asenapine |
| Topics | 5-MeO-DMT DMT |
| Keywords | Cerebral ischemia N,N-Dimethyltryptamine Sigma-1 receptor Spreading depolarization Stroke neuroprotection |
| Citations | 67 |
| Key points | DMT and the sigma-1 receptor agonist PRE-084 mitigated spreading depolarizations and reduced cell death in a rat model of cerebral ischemia, effects counteracted by a sigma-1 receptor antagonist. |
Abstract
Dimethyltryptamine (DMT), an endogenous ligand of sigma-1 receptors (Sig-1Rs), acts against systemic hypoxia, but whether DMT may prevent cerebral ischemic injury is unexplored. Here global forebrain ischemia was created in anesthetized rats and aggravated with the induction of spreading depolarizations (SDs) and subsequent short hypoxia before reperfusion. Drugs (DMT, the selective Sig-1R agonist PRE-084, the Sig-1R antagonist NE-100, or the serotonin receptor antagonist asenapine) were administered intravenously alone or in combination while physiological variables and local field potential from the cerebral cortex was recorded. Neuroprotection and the cellular localization of Sig-1R were evaluated with immunocytochemistry. Plasma and brain DMT content was measured by 2D-LC-HRMS/MS. The affinity of drugs for cerebral Sig-1R was evaluated with a radioligand binding assay. Both DMT and PRE-084 mitigated SDs, counteracted with NE-100. Further, DMT attenuated SD when co-administered with asenapine, compared to asenapine alone. DMT reduced the number of apoptotic and ferroptotic cells and supported astrocyte survival. The binding affinity of DMT to Sig-1R matched previously reported values. Sig-1Rs were associated with the perinuclear cytoplasm of neurons, astrocytes and microglia, and with glial processes. According to these data, DMT may be considered as adjuvant pharmacological therapy in the management of acute cerebral ischemia.
Comparable studies
Other preclinical and animal studies on 5-MeO-DMT, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Psychedelic N,N-dimethyltryptamine and 5-methoxy-N,N-dimethyltryptamine modulate innate and adaptive inflammatory responses through the sigma-1 receptor of human monocyte-derived dendritic cells. Human primary monocyte-derived dendritic cells | 2014 | In vitro study | |
| Effects of N,N-Dimethyltryptamine on Rat Behaviors Relevant to Anxiety and Depression Adult male Sprague-Dawley rats | 2018 | Experimental study | |
| Hallucinogen-like actions of 5-methoxy-N,N-diisopropyltryptamine in mice and rats. Mice and rats | 2006 | Preclinical study | |
| Agonist Properties of N,N-Dimethyltryptamine at Serotonin 5-HT2A and 5-HT2C Receptors Rats and transfected fibroblasts | 1998 | Experimental study | |
| Subtypes of the 5-HT receptor mediating the behavioural responses to 5-methoxy-N,N-dimethyltryptamine in the rat Intact rats and rats depleted of monoamines with reserpine | 1985 | Experimental study |
Citations in the library
Cited by 49
- Towards an understanding of psychedelic-induced neuroplasticity. Neuropsychopharmacology 2023
- From psychiatry to neurology: Psychedelics as prospective therapeutics for neurodegenerative disorders Journal of Neurochemistry September 14, 2021
- Therapeutic mechanisms of psychedelics and entactogens. Neuropsychopharmacology July 24, 2023
- Psychedelic-inspired approaches for treating neurodegenerative disorders. Journal of Neurochemistry July 1, 2022
- Administration of N,N-dimethyltryptamine (DMT) in psychedelic therapeutics and research and the study of endogenous DMT Psychopharmacology January 22, 2022
and 44 more in the library
Cites 19
- Amphetamine, 3,4-Methylenedioxymethamphetamine, Lysergic Acid Diethylamide, and Metabolites of the Catecholamine Neurotransmitters Are Agonists of a Rat Trace Amine Receptor Molecular Pharmacology December 1, 2001
- The Hallucinogen N,N -Dimethyltryptamine (DMT) Is an Endogenous Sigma-1 Receptor Regulator Science February 13, 2009
- Psychedelics and the Human Receptorome PLoS One 2010
- Neuropharmacology of N,N-dimethyltryptamine Brain Research Bulletin April 30, 2016
- Psychedelic N,N-dimethyltryptamine and 5-methoxy-N,N-dimethyltryptamine modulate innate and adaptive inflammatory responses through the sigma-1 receptor of human monocyte-derived dendritic cells. PLoS One 2014
and 14 more in the library