Dual Modulator of ASIC Channels and GABA<sub>A</sub> Receptors from Thyme Alters Fear-Related Hippocampal Activity
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...
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MDPI AG
2023-08-01
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| author | Aleksandr P. Kalinovskii Anton P. Pushkarev Anastasia D. Mikhailenko Denis S. Kudryavtsev Olga A. Belozerova Vladimir I. Shmygarev Oleg N. Yatskin Yuliya V. Korolkova Sergey A. Kozlov Dmitry I. Osmakov Alexander Popov Yaroslav A. Andreev |
| author_facet | Aleksandr P. Kalinovskii Anton P. Pushkarev Anastasia D. Mikhailenko Denis S. Kudryavtsev Olga A. Belozerova Vladimir I. Shmygarev Oleg N. Yatskin Yuliya V. Korolkova Sergey A. Kozlov Dmitry I. Osmakov Alexander Popov Yaroslav A. Andreev |
| author_sort | Aleksandr P. Kalinovskii |
| collection | DOAJ |
| description | 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<sub>A</sub> 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<sub>A</sub>R 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. |
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| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T23:23:06Z |
| publishDate | 2023-08-01 |
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| series | International Journal of Molecular Sciences |
| spelling | doaj.art-f1f45347b7d24bdb9c1bc4fdbb292d542023-11-19T08:13:09ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-08-0124171314810.3390/ijms241713148Dual Modulator of ASIC Channels and GABA<sub>A</sub> Receptors from Thyme Alters Fear-Related Hippocampal ActivityAleksandr P. Kalinovskii0Anton P. Pushkarev1Anastasia D. Mikhailenko2Denis S. Kudryavtsev3Olga A. Belozerova4Vladimir I. Shmygarev5Oleg N. Yatskin6Yuliya V. Korolkova7Sergey A. Kozlov8Dmitry I. Osmakov9Alexander Popov10Yaroslav A. Andreev11Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, ul. Miklukho-Maklaya 16/10, 117997 Moscow, RussiaShemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, ul. Miklukho-Maklaya 16/10, 117997 Moscow, RussiaMoscow State Academy of Veterinary Medicine and Biotechnology—MVA named after K.I. Skryabin, ul. Akademika Skryabina, 23, 109472 Moscow, RussiaShemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, ul. Miklukho-Maklaya 16/10, 117997 Moscow, RussiaShemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, ul. Miklukho-Maklaya 16/10, 117997 Moscow, RussiaShemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, ul. Miklukho-Maklaya 16/10, 117997 Moscow, RussiaShemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, ul. Miklukho-Maklaya 16/10, 117997 Moscow, RussiaShemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, ul. Miklukho-Maklaya 16/10, 117997 Moscow, RussiaShemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, ul. Miklukho-Maklaya 16/10, 117997 Moscow, RussiaShemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, ul. Miklukho-Maklaya 16/10, 117997 Moscow, RussiaShemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, ul. Miklukho-Maklaya 16/10, 117997 Moscow, RussiaShemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, ul. Miklukho-Maklaya 16/10, 117997 Moscow, RussiaAcid-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<sub>A</sub> 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<sub>A</sub>R 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.https://www.mdpi.com/1422-0067/24/17/13148acid-sensing ion channelsγ-aminobutyric acid receptorsopen field testpassive avoidance testθ rhythmanxiety |
| spellingShingle | Aleksandr P. Kalinovskii Anton P. Pushkarev Anastasia D. Mikhailenko Denis S. Kudryavtsev Olga A. Belozerova Vladimir I. Shmygarev Oleg N. Yatskin Yuliya V. Korolkova Sergey A. Kozlov Dmitry I. Osmakov Alexander Popov Yaroslav A. Andreev Dual Modulator of ASIC Channels and GABA<sub>A</sub> Receptors from Thyme Alters Fear-Related Hippocampal Activity International Journal of Molecular Sciences acid-sensing ion channels γ-aminobutyric acid receptors open field test passive avoidance test θ rhythm anxiety |
| title | Dual Modulator of ASIC Channels and GABA<sub>A</sub> Receptors from Thyme Alters Fear-Related Hippocampal Activity |
| title_full | Dual Modulator of ASIC Channels and GABA<sub>A</sub> Receptors from Thyme Alters Fear-Related Hippocampal Activity |
| title_fullStr | Dual Modulator of ASIC Channels and GABA<sub>A</sub> Receptors from Thyme Alters Fear-Related Hippocampal Activity |
| title_full_unstemmed | Dual Modulator of ASIC Channels and GABA<sub>A</sub> Receptors from Thyme Alters Fear-Related Hippocampal Activity |
| title_short | Dual Modulator of ASIC Channels and GABA<sub>A</sub> Receptors from Thyme Alters Fear-Related Hippocampal Activity |
| title_sort | dual modulator of asic channels and gaba sub a sub receptors from thyme alters fear related hippocampal activity |
| topic | acid-sensing ion channels γ-aminobutyric acid receptors open field test passive avoidance test θ rhythm anxiety |
| url | https://www.mdpi.com/1422-0067/24/17/13148 |
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