GAT inhibition preserves cerebral blood flow and reduces oxidant damage to mitochondria in rodents exposed to extreme hyperbaric oxygen
Oxygen breathing at elevated partial pressures (PO2’s) at or more than 3 atmospheres absolute (ATA) causes a reduction in brain γ-aminobutyric acid (GABA) levels that impacts the development of central nervous system oxygen toxicity (CNS-OT). Drugs that increase brain GABA content delay the onset of...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2023-01-01
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| Series: | Frontiers in Molecular Neuroscience |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fnmol.2022.1062410/full |
| _version_ | 1797956464840540160 |
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| author | Ivan T. Demchenko Ivan T. Demchenko Hagir B. Suliman Sergey Y. Zhilyaey Olga S. Alekseeva Tatyana F. Platonova Matthew S. Makowski Claude A. Piantadosi Heath G. Gasier |
| author_facet | Ivan T. Demchenko Ivan T. Demchenko Hagir B. Suliman Sergey Y. Zhilyaey Olga S. Alekseeva Tatyana F. Platonova Matthew S. Makowski Claude A. Piantadosi Heath G. Gasier |
| author_sort | Ivan T. Demchenko |
| collection | DOAJ |
| description | Oxygen breathing at elevated partial pressures (PO2’s) at or more than 3 atmospheres absolute (ATA) causes a reduction in brain γ-aminobutyric acid (GABA) levels that impacts the development of central nervous system oxygen toxicity (CNS-OT). Drugs that increase brain GABA content delay the onset of CNS-OT, but it is unknown if oxidant damage is lessened because brain tissue PO2 remains elevated during hyperbaric oxygen (HBO2) exposures. Experiments were performed in rats and mice to measure brain GABA levels with or without GABA transporter inhibitors (GATs) and its influence on cerebral blood flow, oxidant damage, and aspects of mitochondrial quality control signaling (mitophagy and biogenesis). In rats pretreated with tiagabine (GAT1 inhibitor), the tachycardia, secondary rise in mean arterial blood pressure, and cerebral hyperemia were prevented during HBO2 at 5 and 6 ATA. Tiagabine and the nonselective GAT inhibitor nipecotic acid similarly extended HBO2 seizure latencies. In mice pretreated with tiagabine and exposed to HBO2 at 5 ATA, nuclear and mitochondrial DNA oxidation and astrocytosis was attenuated in the cerebellum and hippocampus. Less oxidant injury in these regions was accompanied by reduced conjugated microtubule-associated protein 1A/1B-light chain 3 (LC3-II), an index of mitophagy, and phosphorylated cAMP response element binding protein (pCREB), an initiator of mitochondrial biogenesis. We conclude that GABA prevents cerebral hyperemia and delays neuroexcitation under extreme HBO2, limiting oxidant damage in the cerebellum and hippocampus, and likely lowering mitophagy flux and initiation of pCREB-initiated mitochondrial biogenesis. |
| first_indexed | 2024-04-10T23:50:47Z |
| format | Article |
| id | doaj.art-eef69bbadec3422d86f5bb6d59657ba8 |
| institution | Directory Open Access Journal |
| issn | 1662-5099 |
| language | English |
| last_indexed | 2024-04-10T23:50:47Z |
| publishDate | 2023-01-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Molecular Neuroscience |
| spelling | doaj.art-eef69bbadec3422d86f5bb6d59657ba82023-01-10T20:10:15ZengFrontiers Media S.A.Frontiers in Molecular Neuroscience1662-50992023-01-011510.3389/fnmol.2022.10624101062410GAT inhibition preserves cerebral blood flow and reduces oxidant damage to mitochondria in rodents exposed to extreme hyperbaric oxygenIvan T. Demchenko0Ivan T. Demchenko1Hagir B. Suliman2Sergey Y. Zhilyaey3Olga S. Alekseeva4Tatyana F. Platonova5Matthew S. Makowski6Claude A. Piantadosi7Heath G. Gasier8The Duke Center for Hyperbaric Medicine and Environmental Physiology, Duke University Medical Center, Durham, NC, United StatesSechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences, St. Petersburg, RussiaSechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences, St. Petersburg, RussiaSechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences, St. Petersburg, RussiaSechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences, St. Petersburg, RussiaSechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences, St. Petersburg, RussiaThe Duke Center for Hyperbaric Medicine and Environmental Physiology, Duke University Medical Center, Durham, NC, United StatesThe Duke Center for Hyperbaric Medicine and Environmental Physiology, Duke University Medical Center, Durham, NC, United StatesThe Duke Center for Hyperbaric Medicine and Environmental Physiology, Duke University Medical Center, Durham, NC, United StatesOxygen breathing at elevated partial pressures (PO2’s) at or more than 3 atmospheres absolute (ATA) causes a reduction in brain γ-aminobutyric acid (GABA) levels that impacts the development of central nervous system oxygen toxicity (CNS-OT). Drugs that increase brain GABA content delay the onset of CNS-OT, but it is unknown if oxidant damage is lessened because brain tissue PO2 remains elevated during hyperbaric oxygen (HBO2) exposures. Experiments were performed in rats and mice to measure brain GABA levels with or without GABA transporter inhibitors (GATs) and its influence on cerebral blood flow, oxidant damage, and aspects of mitochondrial quality control signaling (mitophagy and biogenesis). In rats pretreated with tiagabine (GAT1 inhibitor), the tachycardia, secondary rise in mean arterial blood pressure, and cerebral hyperemia were prevented during HBO2 at 5 and 6 ATA. Tiagabine and the nonselective GAT inhibitor nipecotic acid similarly extended HBO2 seizure latencies. In mice pretreated with tiagabine and exposed to HBO2 at 5 ATA, nuclear and mitochondrial DNA oxidation and astrocytosis was attenuated in the cerebellum and hippocampus. Less oxidant injury in these regions was accompanied by reduced conjugated microtubule-associated protein 1A/1B-light chain 3 (LC3-II), an index of mitophagy, and phosphorylated cAMP response element binding protein (pCREB), an initiator of mitochondrial biogenesis. We conclude that GABA prevents cerebral hyperemia and delays neuroexcitation under extreme HBO2, limiting oxidant damage in the cerebellum and hippocampus, and likely lowering mitophagy flux and initiation of pCREB-initiated mitochondrial biogenesis.https://www.frontiersin.org/articles/10.3389/fnmol.2022.1062410/fullanti-inflammationcerebellumGABAhippocampusmitophagymitochondrial biogenesis |
| spellingShingle | Ivan T. Demchenko Ivan T. Demchenko Hagir B. Suliman Sergey Y. Zhilyaey Olga S. Alekseeva Tatyana F. Platonova Matthew S. Makowski Claude A. Piantadosi Heath G. Gasier GAT inhibition preserves cerebral blood flow and reduces oxidant damage to mitochondria in rodents exposed to extreme hyperbaric oxygen Frontiers in Molecular Neuroscience anti-inflammation cerebellum GABA hippocampus mitophagy mitochondrial biogenesis |
| title | GAT inhibition preserves cerebral blood flow and reduces oxidant damage to mitochondria in rodents exposed to extreme hyperbaric oxygen |
| title_full | GAT inhibition preserves cerebral blood flow and reduces oxidant damage to mitochondria in rodents exposed to extreme hyperbaric oxygen |
| title_fullStr | GAT inhibition preserves cerebral blood flow and reduces oxidant damage to mitochondria in rodents exposed to extreme hyperbaric oxygen |
| title_full_unstemmed | GAT inhibition preserves cerebral blood flow and reduces oxidant damage to mitochondria in rodents exposed to extreme hyperbaric oxygen |
| title_short | GAT inhibition preserves cerebral blood flow and reduces oxidant damage to mitochondria in rodents exposed to extreme hyperbaric oxygen |
| title_sort | gat inhibition preserves cerebral blood flow and reduces oxidant damage to mitochondria in rodents exposed to extreme hyperbaric oxygen |
| topic | anti-inflammation cerebellum GABA hippocampus mitophagy mitochondrial biogenesis |
| url | https://www.frontiersin.org/articles/10.3389/fnmol.2022.1062410/full |
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