N,N-Dimethyltryptamine attenuates spreading depolarization and restrains neurodegeneration by sigma-1 receptor activation in the ischemic rat brain (original) (raw)
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Experimental Neurology, 2020
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 minutes 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 1mg/kg body weight (bw) DMT dissolved in 1ml 7% ethanol/saline vehicle, followed by a maintenance dose of 2mg/Kg-bw/hour delivered over 24 hours via osmotic minipumps. Controls (n=10) received a vehicle bolus only. A third group (n=10) received a Sig-1R antagonist (BD1063, 1mg/kg-bw bolus + 2mg/kg-bw/hour maintenance) in parallel with the DMT. Lesion volume was measured by MRI 24 hours 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=0.0373), and better functional recovery (p= 0.0084) 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 ichemic brain injury following exogenous DMT administration in rats, presumably through a combined antiapoptotic, pro-neurotrophic and anti-inflammatory treatment effect.
Neuroscience Chronicles, 2021
The article entitled “N,N-Dimethyltryptamine [DMT] attenuates spreading depolarization and restrains neurodegeneration by sigma-1 receptor activation in the ischemic rat brain” by Szabo et al. published recently in Neuropharmacology [192:108612] is the last one in the series of studies on the potential benefits of DMT administration in different clinical forms of ischemia-reperfusion injury (IRI). The larger scope of the project – initiated and organized by Ede Frecska – is to collect support for a hypothesized biological function of this and related endogenous hallucinogen compounds such as 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), 5-hydroxy-N,N-dimethyl-tryptamine (bufotenine). Establishing beneficial effects of these naturally occurring components of the mammalian body is a necessary but not satisfactory criterion for a physiological role. We wish to mention here early on, that regard-less of the fulfilment of this second bold aim, if accumulating evidence with independent replications support our findings on the tissue (especially neuro-) protective effects of DMT and its analogues, than ways may open for therapeutic applications and their current classification as Schedule I agents may change for better. The latter carries a stigma and impedes scientific research of these neurochemically very potent and enigmatic molecules.
N,N-dimethyltryptamine (DMT) is a potent endogenous hallucinogen present in the brain of humans and other mammals. Despite extensive research, its physiological role remains largely unknown. Recently, DMT has been found to activate the sigma-1 receptor (Sig-1R), an intracellular chaperone fulfilling an interface role between the endoplasmic reticulum (ER) and mitochondria. It ensures the correct transmission of ER stress into the nucleus resulting in the enhanced production of antistress and antioxidant proteins. Due to this function, the activation of Sig-1R can mitigate the outcome of hypoxia or oxidative stress. In this paper, we aimed to test the hypothesis that DMT plays a neuroprotective role in the brain by activating the Sig-1R. We tested whether DMT can mitigate hypoxic stress in in vitro cultured human cortical neurons (derived from induced pluripotent stem cells, iPSCs), monocyte-derived macrophages (moMACs), and dendritic cells (moDCs). Results showed that DMT robustly increases the survival of these cell types in severe hypoxia (0.5% O 2) through the Sig-1R. Furthermore, this phenomenon is associated with the decreased expression and function of the alpha subunit of the hypoxia-inducible factor 1 (HIF-1) suggesting that DMT-mediated Sig-1R activation may alleviate hypoxia-induced cellular stress and increase survival in a HIF-1-independent manner. Our results reveal a novel and important role of DMT in human cellular physiology. We postulate that this compound may be endogenously generated in situations of stress, ameliorating the adverse effects of hypoxic/ischemic insult to the brain.
A prototypical Sigma1 receptor antagonist protects against brain ischemia
Brain Research, 2007
Previous studies indicate that the Sigma-1 ligand 4-phenyl-1-(4-phenylbutyl) piperidine (PPBP) protects the brain from ischemia. Less clear is whether protection is mediated by agonism or antagonism of the Sigma-1 receptor, and whether drugs already in use for other indications and that interact with the Sigma-1 receptor might also prevent oxidative damage due to conditions such as cerebral ischemic stroke. The antipsychotic drug haloperidol is an antagonist of Sigma-1 receptors and in this study it potently protects against oxidative stress-related cell death in vitro at low concentrations. The protective potency of haloperidol and a number of other butyrophenone compounds positively correlate with their affinity for a cloned Sigma-1 receptor, and the protection is mimicked by a Sigma-1 receptor-selective antagonist (BD1063), but not an agonist (PRE-084). In vivo, an acute low dose (0.05 mg/kg s.c.) of haloperidol reduces by half the ischemic lesion volume induced by a transient middle cerebral artery occlusion. These in vitro and in vivo preclinical results suggest that a low dose of acutely administered haloperidol might have a novel application as a protective agent against ischemic cerebral stroke and other types of brain injury with an ischemic component.
Advances in Psychedelic Medicine: State-of-the-Art Therapeutic Applications, 2019
The vast majority of research on dimethyltryptamine (DMT) has targeted its psychotropic properties and serotonergic activity, with little focus on its effects beyond the nervous system and at other receptor molecules. The recent discovery that DMT is an endogenous agonist of the sigma-1 receptor (sigmaR-1) (Fontanilla et al., 2009) may shed light on yet undiscovered physiological and therapeutic mechanisms of DMT action and reveal some of its putative biological functions. Since the sigmaR-1 has an extensive role in mitigation of several forms of intracellular stress such as mitochondrion, endoplasmic reticulum, and oxidative stress, as well as protecting against apoptotic cell death and regulating immune processes, one may suppose similar effects from DMT administration. In this chapter, we present an overview of the literature on the effects of sigmaR-1 in cellular bioenergetics with a focus on the processes involved in ischemia-reperfusion injury. Ischemia-reperfusion injury is a complex phenomenon with mechanisms underlying organ transplantation, stroke, myocardial infarct, general brain hypoxia, cardiovascular surgery, neonatology, and cardiopulmonary resuscitation. We conclude that the function of DMT may extend beyond central nervous system activity and
Stroke, 2000
Background and Purpose-We previously showed that the intravenous administration of the potent 1-receptor ligand 4-phenyl-1-(4-phenylbutyl)-piperidine (PPBP) provides neuroprotection against transient focal cerebral ischemia and that the protection depends on treatment duration. We tested the hypothesis that PPBP would provide neuroprotection in a model of transient focal ischemia and 7 days of reperfusion in the rat as assessed with neurobehavioral outcome and infarction volume. Methods-Under the controlled conditions of normoxia, normocarbia, and normothermia, halothane-anesthetized male Wistar rats were subjected to 2 hours of middle cerebral artery occlusion (MCAO) with the intraluminal suture occlusion technique. We used laser Doppler flowmetry to assess MCAO. At 60 minutes after the onset of ischemia, rats were randomly assigned to 1 of 4 treatment groups in a blinded fashion and received a continuous intravenous infusion of control saline or 0.1, 1, or 10 mol ⅐ kg Ϫ1 ⅐ h Ϫ1 PPBP for 24 hours. Neurobehavioral evaluation was performed at baseline (3 to 4 days before MCAO) and at 3 and 7 days of reperfusion. Infarction volume was assessed with triphenyltetrazolium chloride staining on day 7 of reperfusion in all rats. Results-Triphenyltetrazolium chloride-determined infarction volume of ipsilateral cortex was smaller in rats treated with 10 mol ⅐ kg Ϫ1 ⅐ h Ϫ1 PPBP (nϭ15, 68Ϯ12 mm 3 , 18Ϯ3% of contralateral structure, PϽ0.05) (meanϮSEM) compared with corresponding rats treated with saline (nϭ15, 114Ϯ11 mm 3 , 31Ϯ3% of contralateral structure). PPBP did not provide significant neuroprotection in the caudoputamen complex. Although MCAO was associated with several alterations in behavior, the treatment with PPBP had no effect on behavioral outcomes. Conclusions-The data demonstrate that the potent 1-receptor ligand PPBP decreases cortical infarction volume without altering neurobehavior after transient focal ischemia and prolonged reperfusion in the rat. (Stroke. 2000;31:976-982.
Neurobiology of Disease, 2003
Although experimental studies have widely shown that the pharmacological blockade of ionotropic glutamate receptors reduces ischemic damage, clinical trials with classical AMPA and NMDA glutamate receptor antagonists have provided negative results. To address the involvement of ionotropic glutamate receptors in ischemic damage, corticostriatal brain slices were prepared from adult rats. Extracellular recordings were performed in the striatum after stimulation of the glutamatergic corticostriatal fibres. In vitro ischemia was induced for a 10-min period by omitting oxygen and glucose from the external medium. Under control conditions, ischemia produced an irreversible loss of the corticostriatal field potential amplitude, AP5, a competitive NMDA receptor antagonist, induced a slight rescue of the potential, while ifenprodil, a positive modulator of the proton sensor of the NMDA receptors, allowed a complete recovery from the ischemic insult. Similar neuroprotection was achieved by utilizing either CNQX, a broad spectrum AMPA receptors antagonist, or Joro spider toxin, a selective blocker of calcium permeable AMPA receptors. Interestingly, while CNZX also fully suppressed physiological excitatory transmission, Joro spider toxin was ineffective on this parameter. Finally, lamotrigine and remacemide, two antiepileptic drugs that differentially affect excitatory transmission, exerted neuroprotective effects against ischemia. Noticeably, a combination of low concentrations of these two drugs exerted a stronger neuroprotection than a single drug given in isolation. Thus, it might be possible to reach a neuroprotective action by utilizing doses of these compounds low enough to avoid side effects. Our experimental data still support the idea that a negative modulation of excitatory transmission can be neuroprotective against ischemia. In addition, our findings support the concept that it is possible to produce a significant neuroprotective action in the absence of a relevant interference with normal synaptic transmission.
Journal of Cerebral Blood Flow & Metabolism, 1993
We investigated the neuroprotective potential of MK-801 (dizocilpine), a noncompetitive N-methyl-D aspartate (NMDA) antagonist, in the setting of three 5-min periods of global cerebral ischemia separated by I-h intervals in halothane-anesthetized rats. Each isch emic insult was produced by bilateral carotid artery oc clusions plus hypotension (50 mm Hg). Brain temperature was maintained at normothermic levels (36.5-37.0°C) throughout the experiment. MK-801 (3 mg/kg) (n = 6) or saline (n = 6) was injected intraperitoneally 45 min fol lowing the end of the first ischemic insult. Following 7-day survival, quantitative neuronal counts of perfusion fixed brains revealed severe ischemic damage in hippo campal CAl area, neocortex, ventrolateral thalamus, and striatum of untreated rats. By contrast, significant pro tection was observed in MK-801-treated rats. In area CAl of the hippocampus, numbers of normal neurons were increased 11-to 14-fold by MK-801 treatment (p < 0.01). The ventrolateral thalamus of MK-801-treated rats It has been well established that repetitive epi sodes of global brain ischemia separated by inter vals of 1 h markedly enhance the extent and inten sity of neuronal injury when compared with equiv alent single periods of ischemia (Mrsulja et aI., 1977; Tomida et aI., 1987; Vass et aI., 1988; Ikeda et aI., 1989; Kato et aI., 1989; Nakano et aI., 1989; Araki et aI., 1990; Hossmann et aI., 1990; Nowak et aI., 1990; Lin et aI., 1992). Glutamate has been pos tulated to play a key role in the pathophysiology of ischemic injury Mel-
Stroke, 1992
Excitatory amino acids and their receptors are involved in mediating ischemic neuronal damage. The sigma-agonists are believed to interact with the N-methyl-D-aspartate receptor. Therefore, we studied the neuroprotective, hypothermic, and motor deficit effects of the sigma-agonist SKF 10,047 and the N-methyl-D-aspartate antagonist MK-801. Neuroprotective effects were compared using an in vitro ischemia model of cultured rat cerebellar granule cells and the gerbil model of global brain ischemia induced by 5 minutes of bilateral carotid artery occlusion followed by 7 days of reperfusion. In vitro, (+)MK-801 protected against 100 microM glutamate with a 50% protective concentration of 30 nM, followed by (-)MK-801 (150 nM), cyclazocine (0.5 microM), (+)SKF 10,047 (3.3 microM), pentazocine (5 microM), and (-)SKF 10,047 (10 microM). In vivo, (+)SKF 10,047 pretreatment (60 mg/kg) or multiple postischemic treatments provided neuroprotection comparable with MK-801 pretreatment (10 mg/kg). Wh...