N,N-dimethyltryptamine reduces infarct size and improves functional recovery following transient focal brain ischemia in rats
Abstract
Background and purpose N,N-dimethyltryptamine (DMT) is an endogenous ligand of the Sigma 1 receptor (Sig-1R) with documented in vitro cytoprotective properties against hypoxia. Our aim was to demonstrate the in vivo neuroprotective effect of DMT following ischemia-reperfusion injury in the rat brain. Methods Transient middle cerebral occlusion (MCAO) was induced for 60 min in male Wistar rats using the filament occlusion model under general anaesthesia. Before the removal of the filament the treatment group (n = 10) received an intra-peritoneal (IP) bolus of 1 mg/kg-body weight (bw) DMT dissolved in 1 ml 7% ethanol/saline vehicle, followed by a maintenance dose of 2 mg/Kg-bw/h delivered over 24 h via osmotic minipumps. Controls (n = 10) received a vehicle bolus only. A third group (n = 10) received a Sig-1R antagonist (BD1063, 1 mg/kg-bw bolus +2 mg/kg-bw/h maintenance) in parallel with the DMT. Lesion volume was measured by MRI 24 h following the MCAO. Shortly after imaging the animals were terminated, and the native brains and sera were removed. Four rats were perfusion fixed. Functional recovery was studied in two separate group of pre-trained animals (n = 8-8) using the staircase method for 30 days. The expression levels of proteins involved in apoptosis, neuroplasticity and inflammatory regulation were assessed by real-time qPCR and ELISA. Results DMT treated rats were characterized by lower ischemic lesion volume (p = .0373), and better functional recovery (p = .0084) compared to the controls. Sig-1R was expressed both in neurons and in microglia in the peri-infarct cortex, and the DMT induced change in the lesion volume was hindered by BD1063. Lower APAF1 expression (mRNA and protein) and higher BNDF levels were documented on DTM, while decreased TNF-α, IL1-β, IL-6 and increased IL-10 expressions indicated the compound's anti-inflammatory potential. Conclusion Our results indicate a Sig-1R dependent reduction of the ischemic brain injury following exogenous DMT administration in rats, presumably through a combined anti-apoptotic, pro-neurotrophic and anti-inflammatory treatment effect.
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Animals treated with DMT combined with an S1R antagonist (BD-1,063) exhibited a higher lesion volume than DMT-treated animals 24 h after brain damage was inflicted.
“Moreover, animals (n = 10) treated with DMT combined with an S1R antagonist (BD-1,063) exhibited a higher lesion volume than DMT-treated animals 24 h after brain damage was inflicted, suggesting that the effects of DMT are S1R-mediated (46).”
From Psychedelics and Neuroplasticity: A Systematic Review Unraveling the Biological Underpinnings of Psychedelics. (2021) · cites this paper as [46]
In brain-damaged rats, DMT treatment increased motor function that lasted up to 30 days after treatment.
“On a behavioral level, rats (n = 8) showed an increased motor function that lasted up to 30 days after treatment (46).”
From Psychedelics and Neuroplasticity: A Systematic Review Unraveling the Biological Underpinnings of Psychedelics. (2021) · cites this paper as [46]
The effects of DMT are S1R-mediated.
“suggesting that the effects of DMT are S1R-mediated (46).”
From Psychedelics and Neuroplasticity: A Systematic Review Unraveling the Biological Underpinnings of Psychedelics. (2021) · cites this paper as [46]
In brain-damaged rats, DMT treatment (1 mg/kg, i.p., followed by 2 mg/kg/h for 24 h) led to stimulated cortical mRNA and plasma BDNF protein levels 1 h after DMT treatment cessation.
“DMT led to stimulated cortical (mRNA) and plasma BDNF (protein) levels 1 h after DMT treatment cessation (46).”
From Psychedelics and Neuroplasticity: A Systematic Review Unraveling the Biological Underpinnings of Psychedelics. (2021) · cites this paper as [46]
The activity of DMT at sigma-1 receptors mediates cytoprotective properties against hypoxic neuron injury in vitro, and in the reperfusion injury model in vivo.
“Indeed, the activity of DMT (9) at sigma-1 receptors mediates cytoprotective properties against hypoxic neuron injury in vitro, and in the reperfusion injury model in vivo [55].”
From Molecular and Functional Imaging Studies of Psychedelic Drug Action in Animals and Humans. (2021) · cites this paper as [55]
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A BDNF autocrine loop in adult sensory neurons prevents cell death
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The Hallucinogen <i>N,N</i> -Dimethyltryptamine (DMT) Is an Endogenous Sigma-1 Receptor Regulator
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de Vos, C. M. H., Mason, N. L., & Kuypers, K. P. C. (2021) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2021.724606 · Cited by 269 · see citing works
“These techniques can be used in healthy, intact animals or after surgical damage to the brain using suturing of an internal carotid artery to test neuroplasticity changes after drug administration and brain damage (46).”
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“Indeed, the activity of DMT (9) at sigma-1 receptors mediates cytoprotective properties against hypoxic neuron injury in vitro, and in the reperfusion injury model in vivo [55].”
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- Authors
- Nardai, S., László, M., Szabó, A., Alpár, A., Hanics, J., Zahola, P., Merkely, B., Frecska, E., & Nagy, Z.
- Affiliations
- Semmelweis University (HU)
- Oslo University Hospital (NO)
- University of Debrecen (HU)
- Venue
- Experimental Neurology
- Publisher
- Elsevier BV
- Published
- 2020-05
- Volume
- 327
- Pages
- 113245
- ISSN
- 0014-4886 (ISSN-L)
- OpenAlex
- W3006005031
- Cited by
- 94
- References
- 4
- Citations by year
- 2026: 17 · 2025: 22 · 2024: 16 · 2023: 8 · 2022: 15 · 2021: 12 · 2020: 3
- FWCI
- 3.09
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Experimental Neurology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Heart Program (NVKP_16-1-2016-0017)
- National Research, Development and Innovation Fund of Hungary (NVKP_16)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pharmacological Receptor Mechanisms and Effects
- Life Sciences › Neuroscience › Neurology › Neurological Disorders and Treatments
- Health Sciences › Medicine › Epidemiology › Acute Ischemic Stroke Management
- Keywords
- N,N-dimethyltryptamine, sigma-1 receptor, transient focal cerebral ischemia, ischemia-reperfusion injury, neuroprotection, infarct size, functional recovery, apoptosis, neurotrophic factors, brain-derived neurotrophic factor, anti-inflammatory activity, microglia, middle cerebral artery occlusion, neuroinflammation, hypoxia
- MeSH terms
- Animals, Brain, Brain Ischemia, N,N-Dimethyltryptamine, Disease Models, Animal, Male, Motor Activity, Piperazines, Treatment Outcome, Rats, Wistar, Neuroprotective Agents, Recovery of Function, Rats
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