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 via PubMed
Summary
AI-generated from the abstractDimethyltryptamine (DMT), a natural compound that activates sigma-1 receptors, reduced spreading depolarizations—waves of electrical disruption in the brain that worsen stroke injury—in rats subjected to global forebrain ischemia. DMT also decreased the number of dying cells and supported astrocyte survival. The protective effects were shared by a selective sigma-1 receptor agonist and were blocked by a sigma-1 receptor antagonist, indicating the receptor mediates the protection. DMT remained effective even when serotonin receptors were blocked. These results suggest DMT could be an additional treatment for acute stroke.
Study at a glance
| Characteristics | Controlled laboratory study Peer reviewed |
|---|---|
| Population | Anesthetized rats |
| Interventions | DMT PRE-084 NE-100 asenapine |
| Topics | 5-MeO-DMT |
| Keywords | Cerebral ischemia N,N-Dimethyltryptamine Sigma-1 receptor Spreading depolarization Stroke neuroprotection |
| Citations | 67 |
| Key finding | 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.