Exploring the Role of Drug Repurposing in Bridging the Hypoxia–Depression Connection
High levels of oxidative stress are implicated in hypoxia, a physiological response to low levels of oxygen. Evidence supports a connection between this response and depression. Previous studies indicate that tryptophan hydroxylase can be negatively affected in hypoxia, impairing serotonin synthesis...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-09-01
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| Series: | Membranes |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2077-0375/13/9/800 |
| _version_ | 1797578873029787648 |
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| author | Ana Salomé Correia Lara Marques Armando Cardoso Nuno Vale |
| author_facet | Ana Salomé Correia Lara Marques Armando Cardoso Nuno Vale |
| author_sort | Ana Salomé Correia |
| collection | DOAJ |
| description | High levels of oxidative stress are implicated in hypoxia, a physiological response to low levels of oxygen. Evidence supports a connection between this response and depression. Previous studies indicate that tryptophan hydroxylase can be negatively affected in hypoxia, impairing serotonin synthesis and downstream pathways. Some studies also hypothesize that increasing hypoxia-inducible factor-1 (HIF-1) levels may be a new therapeutic modality for depression. Hence, this study delved into the influence of hypoxia on the cellular response to drugs designed to act in depression. By the induction of hypoxia in SH-SY5Y cells through a hypoxia incubator chamber or Cobalt Chloride treatment, the effect of Mirtazapine, an antidepressant, and other drugs that interact with serotonin receptors (TCB-2, Dextromethorphan, Ketamine, Quetiapine, Scopolamine, Celecoxib, and Lamotrigine) on SH-SY5Y cellular viability and morphology was explored. The selection of drugs was initially conducted by literature search, focusing on compounds with established potential for employment in depression therapy. Subsequently, we employed in silico approaches to forecast their ability to traverse the blood–brain barrier (BBB). This step was particularly pertinent as we aimed to assess their viability for inducing potential antidepressant effects. The effect of these drugs in hypoxia under the inhibition of HIF-1 by Echinomycin was also tested. Our results revealed that all the potential repurposed drugs promoted cell viability, especially when hypoxia was chemically induced. When combined with Echinomycin, all drugs decreased cellular viability, possibly by the inability to interact with HIF-1. |
| first_indexed | 2024-03-10T22:27:52Z |
| format | Article |
| id | doaj.art-4fa4be9fae8242ac8edc787b473b7a62 |
| institution | Directory Open Access Journal |
| issn | 2077-0375 |
| language | English |
| last_indexed | 2024-03-10T22:27:52Z |
| publishDate | 2023-09-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Membranes |
| spelling | doaj.art-4fa4be9fae8242ac8edc787b473b7a622023-11-19T11:54:38ZengMDPI AGMembranes2077-03752023-09-0113980010.3390/membranes13090800Exploring the Role of Drug Repurposing in Bridging the Hypoxia–Depression ConnectionAna Salomé Correia0Lara Marques1Armando Cardoso2Nuno Vale3OncoPharma Research Group, Center for Health Technology and Services Research (CINTESIS), Rua Doutor Plácido da Costa, 4200-450 Porto, PortugalOncoPharma Research Group, Center for Health Technology and Services Research (CINTESIS), Rua Doutor Plácido da Costa, 4200-450 Porto, PortugalCINTESIS@RISE, Faculty of Medicine, University of Porto, Alameda Professor Hernâni Monteiro, 4200-319 Porto, PortugalOncoPharma Research Group, Center for Health Technology and Services Research (CINTESIS), Rua Doutor Plácido da Costa, 4200-450 Porto, PortugalHigh levels of oxidative stress are implicated in hypoxia, a physiological response to low levels of oxygen. Evidence supports a connection between this response and depression. Previous studies indicate that tryptophan hydroxylase can be negatively affected in hypoxia, impairing serotonin synthesis and downstream pathways. Some studies also hypothesize that increasing hypoxia-inducible factor-1 (HIF-1) levels may be a new therapeutic modality for depression. Hence, this study delved into the influence of hypoxia on the cellular response to drugs designed to act in depression. By the induction of hypoxia in SH-SY5Y cells through a hypoxia incubator chamber or Cobalt Chloride treatment, the effect of Mirtazapine, an antidepressant, and other drugs that interact with serotonin receptors (TCB-2, Dextromethorphan, Ketamine, Quetiapine, Scopolamine, Celecoxib, and Lamotrigine) on SH-SY5Y cellular viability and morphology was explored. The selection of drugs was initially conducted by literature search, focusing on compounds with established potential for employment in depression therapy. Subsequently, we employed in silico approaches to forecast their ability to traverse the blood–brain barrier (BBB). This step was particularly pertinent as we aimed to assess their viability for inducing potential antidepressant effects. The effect of these drugs in hypoxia under the inhibition of HIF-1 by Echinomycin was also tested. Our results revealed that all the potential repurposed drugs promoted cell viability, especially when hypoxia was chemically induced. When combined with Echinomycin, all drugs decreased cellular viability, possibly by the inability to interact with HIF-1.https://www.mdpi.com/2077-0375/13/9/800drug repurposinghypoxia-inducible factor-1serotonin receptorscobalt chlorideEchinomycin |
| spellingShingle | Ana Salomé Correia Lara Marques Armando Cardoso Nuno Vale Exploring the Role of Drug Repurposing in Bridging the Hypoxia–Depression Connection Membranes drug repurposing hypoxia-inducible factor-1 serotonin receptors cobalt chloride Echinomycin |
| title | Exploring the Role of Drug Repurposing in Bridging the Hypoxia–Depression Connection |
| title_full | Exploring the Role of Drug Repurposing in Bridging the Hypoxia–Depression Connection |
| title_fullStr | Exploring the Role of Drug Repurposing in Bridging the Hypoxia–Depression Connection |
| title_full_unstemmed | Exploring the Role of Drug Repurposing in Bridging the Hypoxia–Depression Connection |
| title_short | Exploring the Role of Drug Repurposing in Bridging the Hypoxia–Depression Connection |
| title_sort | exploring the role of drug repurposing in bridging the hypoxia depression connection |
| topic | drug repurposing hypoxia-inducible factor-1 serotonin receptors cobalt chloride Echinomycin |
| url | https://www.mdpi.com/2077-0375/13/9/800 |
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