The connexin hemichannel inhibitor D4 produces rapid antidepressant-like effects in mice
Abstract Depression is a common mood disorder characterized by a range of clinical symptoms, including prolonged low mood and diminished interest. Although many clinical and animal studies have provided significant insights into the pathophysiology of depression, current treatment strategies are not...
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| Format: | Article |
| Language: | English |
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BMC
2023-08-01
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| Series: | Journal of Neuroinflammation |
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| Online Access: | https://doi.org/10.1186/s12974-023-02873-z |
| _version_ | 1797557658761297920 |
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| author | Huanhuan Li Anni Guo Magdiel Salgado Juan C. Sáez Chunyue Geoffrey Lau |
| author_facet | Huanhuan Li Anni Guo Magdiel Salgado Juan C. Sáez Chunyue Geoffrey Lau |
| author_sort | Huanhuan Li |
| collection | DOAJ |
| description | Abstract Depression is a common mood disorder characterized by a range of clinical symptoms, including prolonged low mood and diminished interest. Although many clinical and animal studies have provided significant insights into the pathophysiology of depression, current treatment strategies are not sufficient to manage this disorder. It has been suggested that connexin (Cx)-based hemichannels are candidates for depression intervention by modifying the state of neuroinflammation. In this study, we investigated the antidepressant-like effect of a recently discovered selective Cx hemichannel inhibitor, a small organic molecule called D4. We first showed that D4 reduced hemichannel activity following systemic inflammation after LPS injections. Next, we found that D4 treatment prevented LPS-induced inflammatory response and depressive-like behaviors. These behavioral effects were accompanied by reduced astrocytic activation and hemichannel activity in depressive-like mice induced by repeated low-dose LPS challenges. D4 treatment also reverses depressive-like symptoms in mice subjected to chronic restraint stress (CRS). To test whether D4 broadly affected neural activity, we measured c-Fos expression in depression-related brain regions and found a reduction in c-Fos+ cells in different brain regions. D4 significantly normalized CRS-induced hypoactivation in several brain regions, including the hippocampus, entorhinal cortex, and lateral septum. Together, these results indicate that blocking Cx hemichannels using D4 can normalize neuronal activity and reduce depressive-like symptoms in mice by reducing neuroinflammation. Our work provides evidence of the antidepressant-like effect of D4 and supports glial Cx hemichannels as potential therapeutic targets for depression. |
| first_indexed | 2024-03-10T17:19:44Z |
| format | Article |
| id | doaj.art-e6eb136212214f18a5ace3b5fde05b95 |
| institution | Directory Open Access Journal |
| issn | 1742-2094 |
| language | English |
| last_indexed | 2024-03-10T17:19:44Z |
| publishDate | 2023-08-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Neuroinflammation |
| spelling | doaj.art-e6eb136212214f18a5ace3b5fde05b952023-11-20T10:23:54ZengBMCJournal of Neuroinflammation1742-20942023-08-0120111810.1186/s12974-023-02873-zThe connexin hemichannel inhibitor D4 produces rapid antidepressant-like effects in miceHuanhuan Li0Anni Guo1Magdiel Salgado2Juan C. Sáez3Chunyue Geoffrey Lau4Department of Neuroscience, City University of Hong KongDepartment of Neuroscience, City University of Hong KongInstituto de Neurociencias, Centro Interdisciplinario de Neurociencias de Valparaíso, Universidad de ValparaísoInstituto de Neurociencias, Centro Interdisciplinario de Neurociencias de Valparaíso, Universidad de ValparaísoDepartment of Neuroscience, City University of Hong KongAbstract Depression is a common mood disorder characterized by a range of clinical symptoms, including prolonged low mood and diminished interest. Although many clinical and animal studies have provided significant insights into the pathophysiology of depression, current treatment strategies are not sufficient to manage this disorder. It has been suggested that connexin (Cx)-based hemichannels are candidates for depression intervention by modifying the state of neuroinflammation. In this study, we investigated the antidepressant-like effect of a recently discovered selective Cx hemichannel inhibitor, a small organic molecule called D4. We first showed that D4 reduced hemichannel activity following systemic inflammation after LPS injections. Next, we found that D4 treatment prevented LPS-induced inflammatory response and depressive-like behaviors. These behavioral effects were accompanied by reduced astrocytic activation and hemichannel activity in depressive-like mice induced by repeated low-dose LPS challenges. D4 treatment also reverses depressive-like symptoms in mice subjected to chronic restraint stress (CRS). To test whether D4 broadly affected neural activity, we measured c-Fos expression in depression-related brain regions and found a reduction in c-Fos+ cells in different brain regions. D4 significantly normalized CRS-induced hypoactivation in several brain regions, including the hippocampus, entorhinal cortex, and lateral septum. Together, these results indicate that blocking Cx hemichannels using D4 can normalize neuronal activity and reduce depressive-like symptoms in mice by reducing neuroinflammation. Our work provides evidence of the antidepressant-like effect of D4 and supports glial Cx hemichannels as potential therapeutic targets for depression.https://doi.org/10.1186/s12974-023-02873-zDepressionConnexin hemichannelsGliaStressAntidepressant |
| spellingShingle | Huanhuan Li Anni Guo Magdiel Salgado Juan C. Sáez Chunyue Geoffrey Lau The connexin hemichannel inhibitor D4 produces rapid antidepressant-like effects in mice Journal of Neuroinflammation Depression Connexin hemichannels Glia Stress Antidepressant |
| title | The connexin hemichannel inhibitor D4 produces rapid antidepressant-like effects in mice |
| title_full | The connexin hemichannel inhibitor D4 produces rapid antidepressant-like effects in mice |
| title_fullStr | The connexin hemichannel inhibitor D4 produces rapid antidepressant-like effects in mice |
| title_full_unstemmed | The connexin hemichannel inhibitor D4 produces rapid antidepressant-like effects in mice |
| title_short | The connexin hemichannel inhibitor D4 produces rapid antidepressant-like effects in mice |
| title_sort | connexin hemichannel inhibitor d4 produces rapid antidepressant like effects in mice |
| topic | Depression Connexin hemichannels Glia Stress Antidepressant |
| url | https://doi.org/10.1186/s12974-023-02873-z |
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