Browsing by Subject "fluoxetine"

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  • Fred, Senem Merve; Kuivanen, Suvi; Ugurlu, Hasan; Casarotto, Plinio Cabrera; Levanov, Lev; Saksela, Kalle; Vapalahti, Olli; Castren, Eero (2022)
    Repurposing of currently available drugs is a valuable strategy to tackle the consequences of COVID-19. Recently, several studies have investigated the effect of psychoactive drugs on SARS-CoV-2 in cell culture models as well as in clinical practice. Our aim was to expand these studies and test some of these compounds against newly emerged variants. Several antidepressants and antipsychotic drugs with different primary mechanisms of action were tested in ACE2/TMPRSS2-expressing human embryonic kidney cells against the infection by SARS-CoV-2 spike protein-dependent pseudoviruses. Some of these compounds were also tested in human lung epithelial cell line, Calu-1, against the first wave (B.1) lineage of SARS-CoV-2 and the variants of concern, B.1.1.7, B.1.351, and B.1.617.2. Several clinically used antidepressants, including fluoxetine, citalopram, reboxetine, imipramine, as well as antipsychotic compounds chlorpromazine, flupenthixol, and pimozide inhibited the infection by pseudotyped viruses with minimal effects on cell viability. The antiviral action of several of these drugs was verified in Calu-1 cells against the B.1 lineage of SARS-CoV-2. By contrast, the anticonvulsant carbamazepine, and novel antidepressants ketamine, known as anesthetic at high doses, and its derivatives as well as MAO and phosphodiesterase inhibitors phenelzine and rolipram, respectively, showed no activity in the pseudovirus model. Furthermore, fluoxetine remained effective against pseudoviruses with common receptor binding domain mutations, N501Y, K417N, and E484K, as well as B.1.1.7 (alpha), B.1.351 (beta), and B.1.617.2 (delta) variants of SARS-CoV-2. Our study confirms previous data and extends information on the repurposing of these drugs to counteract SARS-CoV-2 infection including different variants of concern, however, extensive clinical studies must be performed to confirm our in vitro findings.
  • Guirado, Ramon; Perez-Rando, Marta; Sanchez-Matarredona, David; Castren, Eero; Nacher, Juan (2014)
  • Moliner, Rafael (Helsingin yliopisto, 2019)
    Classical and rapid-acting antidepressant drugs have been shown to reinstate juvenile-like plasticity in the adult brain, allowing mature neuronal networks to rewire in an environmentally-driven/activity-dependent process. Indeed, antidepressant drugs gradually increase expression of brain-derived neurotrophic factor (BDNF) and can rapidly activate signaling of its high-affinity receptor TRKB. However, the exact mechanism of action underlying drug-induced restoration of juvenile-like plasticity remains poorly understood. In this study we first characterized acute effects of classical and rapid-acting antidepressant drugs on the interaction between TRKB and postsynaptic density (PSD) proteins PSD-93 and PSD-95 in vitro. PSD proteins constitute the core of synaptic complexes by anchoring receptors, ion channels, adhesion proteins and various signaling molecules, and are also involved in protein transport and cell surface localization. PSD proteins have in common their role as key regulators of synaptic structure and function, although PSD-93 and PSD-95 are associated with different functions during development and have opposing effects on the state of plasticity in individual synapses and neurons. Secondly, we investigated changes in mobility of TRKB in dendritic structures in response to treatment with antidepressant drugs in vitro. We found that antidepressant drugs decrease anchoring of TRKB with PSD-93 and PSD-95, and can rapidly increase TRKB turnover in dendritic spines. Our results contribute to the mechanistic model explaining drug-induced restoration of juvenile-like neuronal plasticity, and may provide a common basis for the effects of antidepressant drugs.
  • Brunotte, Linda; Zheng, Shuyu; Mecate-Zambrano, Angeles; Tang, Jing; Ludwig, Stephan; Rescher, Ursula; Schloer, Sebastian (2021)
    The ongoing SARS-CoV-2 pandemic requires efficient and safe antiviral treatment strategies. Drug repurposing represents a fast and low-cost approach to the development of new medical treatment options. The direct antiviral agent remdesivir has been reported to exert antiviral activity against SARS-CoV-2. Whereas remdesivir only has a very short half-life time and a bioactivation, which relies on pro-drug activating enzymes, its plasma metabolite GS-441524 can be activated through various kinases including the adenosine kinase (ADK) that is moderately expressed in all tissues. The pharmacokinetics of GS-441524 argue for a suitable antiviral drug that can be given to patients with COVID-19. Here, we analyzed the antiviral property of a combined treatment with the remdesivir metabolite GS-441524 and the antidepressant fluoxetine in a polarized Calu-3 cell culture model against SARS-CoV-2. The combined treatment with GS-441524 and fluoxetine were well-tolerated and displayed synergistic antiviral effects against three circulating SARS-CoV-2 variants in vitro in the commonly used reference models for drug interaction. Thus, combinatory treatment with the virus-targeting GS-441524 and the host-directed drug fluoxetine might offer a suitable therapeutic treatment option for SARS-CoV-2 infections.
  • Schloer, Sebastian; Brunotte, Linda; Mecate-Zambrano, Angeles; Zheng, Shuyu; Tang, Jing; Ludwig, Stephan; Rescher, Ursula (2021)
    Background and Purpose The SARS-COV-2 pandemic and the global spread of coronavirus disease 2019 (COVID-19) urgently call for efficient and safe antiviral treatment strategies. A straightforward approach to speed up drug development at lower costs is drug repurposing. Here, we investigated the therapeutic potential of targeting the interface of SARS CoV-2 with the host via repurposing of clinically licensed drugs and evaluated their use in combinatory treatments with virus- and host-directed drugs in vitro. Experimental Approach We tested the antiviral potential of the antifungal itraconazole and the antidepressant fluoxetine on the production of infectious SARS-CoV-2 particles in the polarized Calu-3 cell culture model and evaluated the added benefit of a combinatory use of these host-directed drugs with the direct acting antiviral remdesivir, an inhibitor of viral RNA polymerase. Key Results Drug treatments were well-tolerated and potently impaired viral replication. Importantly, both itraconazole?remdesivir and fluoxetine?remdesivir combinations inhibited the production of infectious SARS-CoV-2 particles?>?90% and displayed synergistic effects, as determined in commonly used reference models for drug interaction. Conclusion and Implications Itraconazole?remdesivir and fluoxetine?remdesivir combinations are promising starting points for therapeutic options to control SARS-CoV-2 infection and severe progression of COVID-19.
  • Guirado, Ramon; La Terra, Danilo; Bourguignon, Mathieu; Carceller, Hector; Umemori, Juzoh; Sipilä, Pia; Nacher, Juan; Castren, Eero (2016)
    Neuronal plasticity peaks during critical periods of postnatal development and is reduced towards adulthood. Recent data suggests that windows of juvenile-like plasticity can be triggered in the adult brain by antidepressant drugs such as Fluoxetine. Although the exact mechanisms of how Fluoxetine promotes such plasticity remains unknown, several studies indicate that inhibitory circuits play an important role. The polysialylated form of the neural cell adhesion molecules (PSA-NCAM) has been suggested to mediate the effects of Fluoxetine and it is expressed in the adult brain by mature interneurons. Moreover, the enzymatic removal of PSA by neuroaminidase-N not only affects the structure of interneurons but also has been shown to play a role in the onset of critical periods during development. We have here used ocular dominance plasticity in the mouse visual cortex as a model to investigate whether removal of PSA might influence the Fluoxetine-induced plasticity. We demonstrate that PSA removal in the adult visual cortex alters neither the baseline ocular dominance, nor the fluoxetine-induced shift in the ocular dominance. We also show that both chronic Fluoxetine treatment and PSA removal independently increase the basal FosB expression in parvalbumin (PV) interneurons in the primary visual cortex. Therefore, our data suggest that although PSA-NCAM regulates inhibitory circuitry, it is not required for the reactivation of juvenile like plasticity triggered by Fluoxetine.
  • Heine, Sari (Helsingfors universitet, 2014)
    Obesity is a significant problem for public health. Obesity develops when systems controlling food intake and consumption are imbalanced. Many different brain areas and transmitters contribute to maintain energy balance. Signals that are secreted proportional to body's fat storage (leptin and insulin) regulate energy balance in a long run. Hormones that are secreted from gastrointestinal tract control food intake in a short run. These hormones are for example cholecystokinin, peptide YY and ghrelin. Drug treatment for obesity is limited because effective drugs are lacking. The only drug to treat obesity in Europe is orlistat but it's effectiveness is modest. The development for new antiobesity drugs has been busy. Problems in drug development have however delayed drugs in the market. The aim of this study was to develop a method with which we could measure how much food zebrafish (Danio rerio) has been eaten and to study how different drugs affect feeding behavior of the zebrafish. The purpose was also to do high throughput screening of antiobesity drug with this method and to study how genes affect feeding. The amount of food that zebrafish ate was able to be measured by utilizing fluorescent rotifers as fish's food. Drugs that are known to affect feeding (fluoxetine and rimonabant) reduced the amount of food zebrafish ate when measurement was done in 6-well plate and with two hours feeding. Sibutramine did not affect food intake, although it has been shown to reduce food intake in zebrafish in another study. The effect of gene knock down was also studied with morpholino oligonucleotides. MANF, th2 or galanin gene knock down did not affect food intake in zebrafish. The conclusion is that the new method is well suited for food intake measurements and drug effectiveness studies. The method can not be used in high throughput screening because results can not be analyzed by a plate reader and the feeding can not be done in 96-well plate.