ABSTRACT NUMBER: ESOC2026YS125 DIMETHYLTRYPTAMINE INHIBITS SPREADING DEPOLARISATION IN BRAIN SLICES OF SIGMA-1 RECEPTORKNOCKOUT MICE

In acute ischemic stroke, spreading depolarizations worsen neuronal injury. The sigma-1 receptor agonist dimethyltryptamine (DMT) reduced the cortical area affected by spreading depolarizations in both wild-type and sigma-1 receptor knockout mice (53.3% vs. 65.7% in wild-type, 42.1% vs. 61.0% in knockout). In knockout animals only, DMT also reduced the area under the curve of depolarizations (299.9 vs. 543.3 mV·s) and their propagation velocity (2.6 vs. 3.8 mm/min). NeuN-positive cell numbers tended to increase with DMT. Surprisingly, DMT was more effective in knockout mice, indicating its neuroprotective effects involve aminergic receptors alongside sigma-1 receptor activation, supporting potential adjuvant use in stroke treatment.

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Abstract

Abstract Background and aims Spreading depolarizations (SDs) exacerbate neuronal injury during acute ischemic stroke (AIS). The sigma-1 receptor (S1R) agonist dimethyltryptamine (DMT) reduces cellular damage, inhibits SDs, and enhances neuronal survival in rodent models of AIS. Although DMT primarily acts on S1R, it also binds to aminergic receptors. Therefore, we aimed to determine the S1R-mediated neuroprotective effects of DMT. Methods 350-μm-thick brain slices were prepared from wild-type C57BL/6 (WT) and S1R receptor knockout (S1R-KO) mice (n=12). To model acute ischemic stroke (AIS), a medium of reduced glucose content was applied, and SDs were induced by hypoxia. SDs were recorded using intrinsic optical signal (white-light reflectance) imaging and local field potential recordings. Brain slices were incubated in solutions containing DMT (20 μM) or its vehicle. Neuronal viability was assessed using NeuN immunohistochemistry. Results DMT reduced the cortical area affected by SDs in both WT and S1R-KO animals (53.3±21.6% vs. 65.7±13.8% and 42.1±11.2% vs. 61.0±12.7%; WT+DMT vs. WT and S1R-KO+DMT vs. S1R-KO). Furthermore, DMT reduced the area under the curve of SDs (299.9±148.0 vs. 543.3±270.5 mV·s, S1R-KO+DMT vs. S1R-KO) and their propagation velocity (2.6±1.0 vs. 3.8±1.8 mm/min) in S1R KO animals only. NeuN-positive cell number tended to increase following DMT treatment. Contrary to our expectations, these results demonstrate that DMT is more effective in S1R-KO than in WT animals, suggesting that its neuroprotective effects are mediated by aminergic receptors in addition to S1R activation. These findings support the potential adjuvant use of DMT in the treatment of AIS. Conflict of interest Funding: EU H2020-HCEMM (No. 739593), NKFIH (No. K146725), The Hungarian Brain Research Program 3.0. to E.F. and Á.M., National Research, Development and Innovation Office of Hungary (PD137565) to N.S.