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Dual Modulator of ASIC Channels and GABA_A Receptors from Thyme Alters Fear-Related Hippocampal Activity.

ABSTRACT: Acid-sensing ion channels (ASICs) are proton-gated ion channels that mediate nociception in the peripheral nervous system and contribute to fear and learning in the central nervous system. Sevanol was reported previously as a naturally-occurring ASIC inhibitor from thyme with favorable analgesic and anti-inflammatory activity. Using electrophysiological methods, we found that in the high micromolar range, the compound effectively inhibited homomeric ASIC1a and, in sub- and low-micromolar ranges, positively modulated the currents of α1β2γ2 GABA_A receptors. Next, we tested the compound in anxiety-related behavior models using a targeted delivery into the hippocampus with parallel electroencephalographic measurements. In the open field, 6 µM sevanol reduced both locomotor and θ-rhythmic activity similar to GABA, suggesting a primary action on the GABAergic system. At 300 μM, sevanol markedly suppressed passive avoidance behavior, implying alterations in conditioned fear memory. The observed effects could be linked to distinct mechanisms involving GABA_AR and ASIC1a. These results elaborate the preclinical profile of sevanol as a candidate for drug development and support the role of ASIC channels in fear-related functions of the hippocampus.

SUBMITTER: Kalinovskii AP

PROVIDER: S-EPMC10487430 | biostudies-literature | 2023 Aug

REPOSITORIES: biostudies-literature

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Dual Modulator of ASIC Channels and GABA<sub>A</sub> Receptors from Thyme Alters Fear-Related Hippocampal Activity.

Kalinovskii Aleksandr P AP Pushkarev Anton P AP Mikhailenko Anastasia D AD Kudryavtsev Denis S DS Belozerova Olga A OA Shmygarev Vladimir I VI Yatskin Oleg N ON Korolkova Yuliya V YV Kozlov Sergey A SA Osmakov Dmitry I DI Popov Alexander A Andreev Yaroslav A YA

International journal of molecular sciences 20230824 17

Acid-sensing ion channels (ASICs) are proton-gated ion channels that mediate nociception in the peripheral nervous system and contribute to fear and learning in the central nervous system. Sevanol was reported previously as a naturally-occurring ASIC inhibitor from thyme with favorable analgesic and anti-inflammatory activity. Using electrophysiological methods, we found that in the high micromolar range, the compound effectively inhibited homomeric ASIC1a and, in sub- and low-micromolar ranges, ...[more]

PMID: 37685955

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Dual Modulator of ASIC Channels and GABA_A Receptors from Thyme Alters Fear-Related Hippocampal Activity.

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Dual Modulator of ASIC Channels and GABA<sub>A</sub> Receptors from Thyme Alters Fear-Related Hippocampal Activity.

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Dual Modulator of ASIC Channels and GABAA Receptors from Thyme Alters Fear-Related Hippocampal Activity.

Publications

Dual Modulator of ASIC Channels and GABA<sub>A</sub> Receptors from Thyme Alters Fear-Related Hippocampal Activity.

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OmicsDI is part of the ELIXIR infrastructure

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Dual Modulator of ASIC Channels and GABA_A Receptors from Thyme Alters Fear-Related Hippocampal Activity.