Sigma-1 receptor and seizures

Vāvers, Edijs; Zvejniece, Liga; Dambrova, Maija

doi:10.1016/j.phrs.2023.106771

Cited by 9 publications

(6 citation statements)

References 315 publications

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“…Since no 5-HTR antagonist challenged DPT’s antiepileptic efficacy in the AGS assay, we tested whether a nonserotonergic receptor could mediate DPT’s antiepileptic effects. DPT and other tryptamines bind sigma1Rs, which studies have shown modulate epileptic activity. ,,,, NE-100, a selective sigma1R antagonist, is structurally similar to DPT, sharing an N,N -dipropyl moiety (see Figures and ). NE-100 potentiates seizures at a 25 mg/kg dose and induces seizures at 50 mg/kg and above .…”

Section: Resultsmentioning

confidence: 99%

“…DPT and other tryptamines bind sigma1Rs, which studies have shown modulate epileptic activity. 14,59,61,62,73 NE-100, a selective sigma1R antagonist, is structurally similar to DPT, sharing an N,N-dipropyl moiety 74 (see Figures 1 and 6). NE-100 potentiates seizures at a 25 mg/ kg dose and induces seizures at 50 mg/kg and above.…”

Section: ■ Resultsmentioning

confidence: 99%

“…Sigma1Rs are targets of several tryptamines 11 and modulate epileptiform activity, 59 which provided us the rationale to investigate them as antiepileptic targets of DPT. We used the sigma1R antagonist, NE-100, based on its structural similarity to DPT.…”

Section: ■ Discussionmentioning

confidence: 99%

“…Sigma1Rs are another target of tryptamines that can modulate epileptiform activity. ,− Also, fenfluramine was shown to act as a positive allosteric modulator at sigma1Rs in mice and zebrafish models, and sigma1R modulation prevents seizures in models of Dravet syndrome, amphetamine-induced seizures, and epileptic encephalopathies. ,, We tested the hypothesis that the serotonergic psychedelic N,N -dipropyltryptamine (DPT) would prevent AGS in juvenile Fmr1 KO mice and that it would be effective via a serotonergic or sigma1R mechanism. DPT is a short-acting psychedelic tryptamine, but there is limited knowledge about its pharmacology and behavioral effects; in vivo, it possesses agonist activity at 5-HT 1A and 5-HT 2A Rs, − and in vitro it has been shown to be a substrate of the 5-HT transporter .…”

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confidence: 99%

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The Psychedelic N,N-Dipropyltryptamine Prevents Seizures in a Mouse Model of Fragile X Syndrome via a Mechanism that Appears Independent of Serotonin and Sigma1 Receptors

Tyagi,

Saraf,

Canal

2023

ACS Pharmacol. Transl. Sci.

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The serotonergic psychedelic psilocybin shows efficacy in treating neuropsychiatric disorders, though the mechanism(s) underlying its therapeutic effects remain unclear. We show that a similar psychedelic tryptamine, N,N-dipropyltryptamine (DPT), completely prevents audiogenic seizures (AGS) in an Fmr1 knockout mouse model of fragile X syndrome at a 10 mg/kg dose but not at lower doses (3 or 5.6 mg/kg). Despite showing in vitro that DPT is a serotonin 5-HT 2A , 5-HT 1B , and 5-HT 1A receptor agonist (with that rank order of functional potency, determined with TRUPATH Gα/βγ biosensors), pretreatment with selective inhibitors of 5-HT 2A/2C , 5-HT 1B , or 5-HT 1A receptors did not block DPT's antiepileptic effects; a pan-serotonin receptor antagonist was also ineffective. Because 5-HT 1A receptor activation blocks AGS in Fmr1 knockout mice, we performed a dose−response experiment to evaluate DPT's engagement of 5-HT 1A receptors in vivo. DPT elicited 5-HT 1A -dependent effects only at doses greater than 10 mg/kg, further supporting that DPT's antiepileptic effects were not 5-HT 1A -mediated. We also observed that the selective sigma1 receptor antagonist, NE-100, did not impact DPT's antiepileptic effects, suggesting DPT engagement of sigma1 receptors was not a crucial mechanism. Separately, we observed that DPT and NE-100 at high doses caused convulsions on their own that were qualitatively distinct from AGS. In conclusion, DPT dose-dependently blocked AGS in Fmr1 knockout mice, but neither serotonin nor sigma1 receptor antagonists prevented this action. Thus, DPT might have neurotherapeutic effects independent of its serotonergic psychedelic properties. However, DPT also caused seizures at high doses, showing that DPT has complex dosedependent in vivo polypharmacology.

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Section: Resultsmentioning

confidence: 99%

Section: ■ Resultsmentioning

confidence: 99%

Section: ■ Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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The Psychedelic N,N-Dipropyltryptamine Prevents Seizures in a Mouse Model of Fragile X Syndrome via a Mechanism that Appears Independent of Serotonin and Sigma1 Receptors

Tyagi,

Saraf,

Canal

2023

ACS Pharmacol. Transl. Sci.

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“…The targeting of Sig1R has been shown to impact cytokine production when using immune cells in vitro. Sig1R ligands include psychotropic and neuroprotective agents, and many of them are currently in clinical use, placing Sig1R as an attractive therapeutic target [ 29 , 30 , 31 , 32 , 33 ].…”

Section: Introductionmentioning

confidence: 99%

The Protective Role of Mitochondria-Associated Endoplasmic Reticulum Membrane (MAM) Protein Sigma-1 Receptor in Regulating Endothelial Inflammation and Permeability Associated with Acute Lung Injury

Mahamed,

Shadab,

Najar

et al. 2023

Cells

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Earlier studies from our lab identified endoplasmic reticulum (ER) chaperone BiP/GRP78, an important component of MAM, to be a novel determinant of endothelial cell (EC) dysfunction associated with acute lung injury (ALI). Sigma1R (Sig1R) is another unique ER receptor chaperone that has been identified to associate with BiP/GRP78 at the MAM and is known to be a pluripotent modulator of cellular homeostasis. However, it is unclear if Sig1R also plays a role in regulating the EC inflammation and permeability associated with ALI. Our data using human pulmonary artery endothelial cells (HPAECs) showed that siRNA-mediated knockdown of Sig1R potentiated LPS-induced the expression of proinflammatory molecules ICAM-1, VCAM-1 and IL-8. Consistent with this, Sig1R agonist, PRE-084, known to activate Sig1R by inducing its dissociation from BiP/GRP78, blunted the above response. Notably, PRE-084 failed to blunt LPS-induced inflammatory responses in Sig1R-depleted cells, confirming that the effect of PRE-084 is driven by Sig1R. Furthermore, Sig1R antagonist, NE-100, known to inactivate Sig1R by blocking its dissociation from BiP/GRP78, failed to block LPS-induced inflammatory responses, establishing that dissociation from BiP/GRP78 is required for Sig1R to exert its anti-inflammatory action. Unlike Sig1R, the siRNA-mediated knockdown or Subtilase AB-mediated inactivation of BiP/GRP78 protected against LPS-induced EC inflammation. Interestingly, the protective effect of BiP/GRP78 knockdown or inactivation was abolished in cells that were depleted of Sig1R, confirming that BiP/GRP78 knockdown/inactivation-mediated suppression of EC inflammation is mediated via Sig1R. In view of these findings, we determined the in vivo relevance of Sig1R in a mouse model of sepsis-induced ALI. The intraperitoneal injection of PRE-084 mitigated sepsis-induced ALI, as evidenced by a decrease in ICAM-1, IL-6 levels, lung PMN infiltration, and lung vascular leakage. Together, these data evidence a protective role of Sig1R against endothelial dysfunction associated with ALI and identify it as a viable target in terms of controlling ALI in sepsis.

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Astrocyte-specific activation of sigma-1 receptors in mPFC mediates the faster onset antidepressant effect by inhibiting NF-κB-induced neuroinflammation

Wang,

Ren,

Cui

et al. 2024

Brain, Behavior, and Immunity

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Sigma-1 receptor and seizures

Cited by 9 publications

References 315 publications

The Psychedelic N,N-Dipropyltryptamine Prevents Seizures in a Mouse Model of Fragile X Syndrome via a Mechanism that Appears Independent of Serotonin and Sigma1 Receptors

The Psychedelic N,N-Dipropyltryptamine Prevents Seizures in a Mouse Model of Fragile X Syndrome via a Mechanism that Appears Independent of Serotonin and Sigma1 Receptors

The Protective Role of Mitochondria-Associated Endoplasmic Reticulum Membrane (MAM) Protein Sigma-1 Receptor in Regulating Endothelial Inflammation and Permeability Associated with Acute Lung Injury

Astrocyte-specific activation of sigma-1 receptors in mPFC mediates the faster onset antidepressant effect by inhibiting NF-κB-induced neuroinflammation

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