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Browsing by Subject "rapid-acting antidepressants"

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  • Järvinen, Janina (2021)
    Current treatments for major depressive disorder have notable limitations including the delay achieving the therapeutic effect. Ketamine has been shown to alleviate the symptoms of depression rapidly and promising findings have also been found when using nitrous oxide. However, the mechanisms behind rapid antidepressant effect are not fully discovered. It seems that rapid-acting treatments alter brain energy metabolism, enhance synaptic plasticity, and repair neuronal dysfunction connected to depression. Particularly, the activation of brain derived neurotrophic factor (BDNF) mediated tropomyosin receptor kinase B (TrkB) signaling has been connected to rapid antidepressant effect. Fasting is also known to induce BDNF production and it is thought to activate BDNF-TrkB signaling. In addition, both of these treatments alter the brain energy metabolism. The objective of this study was to find out how fasting and nitrous oxide alone and in combination affect the rapid antidepressant effect and synaptic plasticity related BDNF-TrkB signaling in mice. Another aim of the research was to determine whether the body temperature changes after these treatments as a marker of metabolic rate. The analyzed brain samples of the mice were collected 15 minutes after cessation of nitrous oxide administration. As a result, it was found that the fasting protocol used in this study did not activate the studied BDNF-TrkB signaling. However, after nitrous oxide administration, the studied signaling and markers related to synaptic plasticity were partly activated. The results from the combination of nitrous oxide and fasting were similar compared to nitrous oxide administration only. It is therefore conceivable, that the effects were caused exclusively by nitrous oxide. Furthermore, a fascinating finding related to energy metabolism was that nitrous oxide reduced the body temperature of the mice significantly 15 minutes after cessation of the gas administration. Overall, these results are promising and consistent with previous research indicating that nitrous oxide administration could be related to induced synaptic plasticity and therefore have antidepressant associated effects. Nitrous oxide could be used to understand the mechanisms behind rapid antidepressant effect and it could be a potential option to treat depression in the future. Based on these results, it seems that energy metabolism could be related to rapid antidepressant effect. It also supports the observations that all different rapid-acting treatments alter the brain energy metabolism.
  • Annala, Iina (2021)
    Subanesthetic-dose ketamine, an N-methyl-D-aspartate receptor (NMDAR) blocker, exerts rapid antidepressant effects that sustain long after its elimination from the body. The precise mechanism remains unknown, but regulation of TrkB (tropomyosin receptor kinase B), ERK (extracellular-regulated kinase 1 and 2), GSK3β (glycogen synthase kinase 3β) and mTOR (mammalian target of rapamycin) signaling within the prefrontal cortex (PFC) have been deemed important for its antidepressant-like effects in rodents. In addition, activation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) is thought to be an important step in its mechanism. Nitrous oxide (N2O), another NMDAR antagonist and a putative rapid-acting antidepressant, regulates the same molecular pathways as ketamine in the rodent PFC. The fast pharmacokinetics of N2O have been exploited to show that markers of neuronal excitation, including phosphorylation of ERK, are upregulated in the PFC during its acute pharmacological effects (NMDAR blockade), while regulation of TrkB, GSK3β and P70S6K emerges only upon N2O withdrawal. In the first part of this study, we investigated the N2O-induced biochemical changes associated with neuronal excitation and BDNF-TrkB signaling in the PFC and further, the requirement for AMPAR activation in inducing them. We focused on the effects seen after the acute pharmacological effects of N2O. N2O (65% for 20 min) was administered to adult male C57BL/6 mice with or without pretreatment with AMPAR antagonist (NBQX, 10 mg/kg) and PFC samples were collected 15 minutes after stopping N2O delivery. Within this time N2O is expected to be completely eliminated. The brain samples were analyzed using western blot, enzyme-linked immunosorbent assay and quantitative reverse transcription PCR. We observed that N2O increased levels of phosphorylated TrkB, GSK3β and P70S6K, and these effects were not attenuated by NBQX pretreatment. At the same time, we observed a decrease in the levels of phosphorylated ERK, which was attenuated in mice that received NBQX prior to N2O. Tissue levels of BDNF protein or messenger RNA (exon IV) were not different between control and experimental groups. These results indicate that the mechanism of N2O is associated with TrkB and ERK signaling that are regulated independently of each other. It appears that AMPAR activation is not required for TrkB signaling, although it might play a role in ERK signaling. Further, N2O-induced TrkB phosphorylation in the PFC is not associated with changes in total levels of BDNF. In the second part of the study, we aimed to search for new ketamine-like NMDAR blockers with antidepressant potential. Ketamine was used as a query compound for in silico substructure search to find commercial ketamine analogs. The retrieved ketamine analogs were filtered by their computed ADMET properties and then further screened virtually by docking them to the pore region of NMDAR complex (protein data bank code: 4TLM), around the predicted binding site of ketamine. Finally, we sought to study if selected ketamine analogs could elicit ketamine-like effects on TrkB and ERK signaling in mouse primary cortical neurons. However, we did not proceed to test the analogs since ketamine (positive control) did not show any effects on TrkB or ERK phosphorylation in our culture. Overall, this study advances the understanding of the mechanism of N2O, possibly giving new insight of the antidepressant mechanisms of NMDAR-blocking agents more generally. Additionally, we found promising ketamine analogs that await experimental testing.
  • Halinen, Sara (2023)
    Current pharmacological treatments for major depressive disorder leave many patients unresponsive to treatment or treatment response is delayed by weeks. More effective treatments with quicker effect onset are therefore needed. Ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonists has demonstrated sustained rapid antidepressant activity after single dose. Precise mechanisms behind this effect are unknown, however some crucial contributors to ketamine-induced behavioural effects in rodents include phosphorylation of Tropomyosin receptor kinase B (TrkB), ribosomal protein s6 kinase (p70s6k), glycogen synthase kinase 3 (GSK3), mitogen activated protein kinases (MAPKs), and activation of α-amino-3-hydroxy-5- methyl-4- isoxazolepropionic acid receptors (AMPAR). Similar TrkB related signaling cascades are also activated with another NMDA receptor antagonist and a putative rapid-acting antidepressant, nitrous oxide (N2O). During acute effects of N2O, cortical excitation increases MAPK phosphorylation and upregulates expression of activity dependent immediate early genes (IEG; c-Fos and Bdnf IV). Phosphorylation of TrkB, GSK3 and p70s6k appearing only after N2O has been eliminated suggest that TrkB signaling is induced as an adaptive response to treatment. The first objective of this study was to corroborate previous results from our group to validate our gas administration set up and protein analysis protocol. To analyze N2O-induced phosphorylation of proteins implicated in ketamine’s behavioral effects in mice, we treated C57BL/6J male mice with either room air (control) or 65% nitrous oxide for 20 minutes. After gas exposure and 15-minute washout period, medial prefrontal cortex samples were dissected to be analyzed with western blotting. In this study nitrous oxide exposure did not induce increased TrkB signaling in nitrous oxide withdrawal. Another aim of this study was to investigate the involvement of AMPARs in inducing cortical excitation with N2O. Pretreatment of AMPAR antagonist (10 mg/kg, NBQX) or saline was given to C57BL/6J male mice 10 minutes prior to 1 hour exposure to 50 % O2 or 50 % N2O, a N2O dose previously shown to induce IEG expression. One hour after gas exposure mice were euthanized and mPFCs were dissected and analyzed with reverse transcriptase quantitative PCR (RT-qPCR). No regulation in IEG expression was induced with nitrous oxide, NBQX pretreatment or combination compared to control. Additional studies factoring in limitations of this study are needed to uncover the involvement of AMPAR in inducing cortical excitation and antidepressant-like behavioral effects of N2O in preclinical models of depression.