Impact of Two Neuronal Sigma-1 Receptor Modulators, PRE084 and DMT, on Neurogenesis and Neuroinflammation in an Aβ1–42-Injected, Wild-Type Mouse Model of AD
Emőke Borbély, Viktória É Varga, Titanilla Szögi, Ildikó Schuster, Zsolt Bozsó, Botond Penke, Lívia Fülöp
International Journal of Molecular Sciences February 24, 2022 DOI: 10.3390/ijms23052514 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | In vivo experimental study Peer reviewed |
|---|---|
| Population | Aβ-induced in vivo mouse model of Alzheimer's disease |
| Interventions | Dimethyltryptamine (DMT) PRE084 |
| Topics | Neuroplasticity DMT |
| Keywords | Sigma-1 receptor Neuroinflammation Astrogliosis Agonist Pharmacology |
| Citations | 31 |
| Key findings | The selective S1R agonist PRE084 stimulated hippocampal cell proliferation and differentiation, while DMT negatively influenced neurogenesis, and both agonists reduced Aβ-induced astrogliosis. |
Abstract
Alzheimer’s disease (AD) is the most common form of dementia characterized by cognitive dysfunctions. Pharmacological interventions to slow the progression of AD are intensively studied. A potential direction targets neuronal sigma-1 receptors (S1Rs). S1R ligands are recognized as promising therapeutic agents that may alleviate symptom severity of AD, possibly via preventing amyloid-β-(Aβ-) induced neurotoxicity on the endoplasmic reticulum stress-associated pathways. Furthermore, S1Rs may also modulate adult neurogenesis, and the impairment of this process is reported to be associated with AD. We aimed to investigate the effects of two S1R agonists, dimethyltryptamine (DMT) and PRE084, in an Aβ-induced in vivo mouse model characterizing neurogenic and anti-neuroinflammatory symptoms of AD, and the modulatory effects of S1R agonists were analyzed by immunohistochemical methods and western blotting. DMT, binding moderately to S1R but with high affinity to 5-HT receptors, negatively influenced neurogenesis, possibly as a result of activating both receptors differently. In contrast, the highly selective S1R agonist PRE084 stimulated hippocampal cell proliferation and differentiation. Regarding neuroinflammation, DMT and PRE084 significantly reduced Aβ1–42-induced astrogliosis, but neither had remarkable effects on microglial activation. In summary, the highly selective S1R agonist PRE084 may be a promising therapeutic agent for AD. Further studies are required to clarify the multifaceted neurogenic and anti-neuroinflammatory roles of these agonists.
Comparable studies
Other preclinical and animal studies on DMT, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| The Hallucinogen N,N -Dimethyltryptamine (DMT) Is an Endogenous Sigma-1 Receptor Regulator Mice and cell lines | 2009 | Experimental study | |
| Correlation between the potency of hallucinogens in the mouse head-twitch response assay and their behavioral and subjective effects in other species. C57BL/6J mice | 2020 | Experimental study with dose-response experiments | |
| 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 | |
| Inhibitory effect of chlorpromazine on the syndrome of hyperactivity produced by l‐tryptophan or 5‐methoxy‐N,N‐dimethyltryptamine in rats treated with a monoamine oxidase inhibitor Rats | 1971 | Experimental study | |
| Effects of N,N-Dimethyltryptamine on Rat Behaviors Relevant to Anxiety and Depression Adult male Sprague-Dawley rats | 2018 | Experimental study |
Citations in the library
Cited by 20
- N, N-Dimethyltryptamine, a natural hallucinogen, ameliorates Alzheimer's disease by restoring neuronal Sigma-1 receptor-mediated endoplasmic reticulum-mitochondria crosstalk. Alzheimer's Research & Therapy May 1, 2024
- The evolution of N, N-Dimethyltryptamine: from metabolic pathways to brain connectivity. Psychopharmacology April 11, 2025
- The Missing Piece? A Case for Microglia's Prominent Role in the Therapeutic Action of Anesthetics, Ketamine, and Psychedelics. Neurochemical Research April 1, 2023
- Bedside to bench: the outlook for psychedelic research Frontiers in Pharmacology October 2, 2023
- The immunomodulatory effects of classical psychedelics: A systematic review of preclinical studies Progress in Neuro-Psychopharmacology and Biological Psychiatry September 7, 2024
and 15 more in the library
Cites 22
- Psychedelics Promote Structural and Functional Neural Plasticity Cell Reports June 1, 2018
- The Hallucinogen N,N -Dimethyltryptamine (DMT) Is an Endogenous Sigma-1 Receptor Regulator Science February 13, 2009
- Receptor interaction profiles of novel psychoactive tryptamines compared with classic hallucinogens. European Neuropsychopharmacology May 20, 2016
- Effects of psilocybin on hippocampal neurogenesis and extinction of trace fear conditioning Experimental Brain Research June 1, 2013
- Neuropharmacology of N,N-dimethyltryptamine Brain Research Bulletin April 30, 2016
and 17 more in the library