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Browsing by Subject "mercaptoacetate"

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  • Niittymäki, Erika (2021)
    Since the discovery of ketamine’s antidepressant response, numerous of studies have been observed it to alleviate depressive symptoms rapidly and effectively within hours. This is a significant advantage compared to traditional antidepressants, which take weeks to show treatment efficacy. Ketamine is a N- methyl-D-aspartate receptor (NMDA) antagonist and its underlying mechanism of is proposed to be in its ability to increase synaptic plasticity and this is ultimately believed to improve mood. On a molecular level, the antidepressant effects have been observed to be dependent on the activation of tropomyosin receptor kinase B (TrkB) signalling pathway. However, the antidepressant mechanism of ketamine remains still poorly understood as no new NMDA-antagonist or other rapid-acting antidepressants have been successfully developed for clinical use despite many years of effort. Therefore, some have proposed that the missing pieces of understanding its antidepressant effects might be linked to ketamine’s ability to modify sleep patterns and circadian-related molecules. Ketamine has especially been demonstrated to increase slow-wave activity during the following night of treatment and these changes have been shown to predict the clinical outcome in patients with major depressive disorder (MDD). Slow-wave activity is a low-frequency and high-amplitude wave seen in electroencephalography, which is highly expressed during the deepest stage of sleep, and this has been prominently found to be reduced in MDD patients. Even more intriguing, there are indications that ketamine might increase slow-wave activity also immediately after its administration. During this time, TrkB signalling is observed to became active. Following these molecular findings, we sought to investigate the link between the TrkB signalling pathway and two prominent processes occurring during slow-wave sleep. During slow-wave sleep processes such as (1) reduction of brain’s energy expenditure and (2) the activation of glymphatic system is known to occur. The glymphatic system is as lymphatic-perivascular network, which is responsible for clearing the brain from the metabolic waste. Thus, in this study, our objective was to investigate whether by causing an acute decline in adenosine-triphosphate (ATP) production or by stimulating the glymphatic network, we could activate the same plasticity-related pathways as ketamine is capable of activating in mice prefrontal cortex. The results of this study suggest that acute metabolic reduction can trigger pathways regarding synaptic plasticity. The metabolic inhibitor, 2-deoxy-D-glucose and mercaptoacetate (2DG+MA), was found to phosphorylate the TrkB receptor and its downstream signalling molecules GSK3β and p70S6K, while MAPK was dephosphorylated. These results correlate with the previous findings of ketamine’s effect after its administration. We also found a plasticity-related marker, MAP2, to be heavily phosphorylated by 2DG+MA, indicating 2DG+MA having a surprising role on neuroplasticity. These results are promising indication of understanding the rapid effects of ketamine and might even give important insight to developing novel antidepressants. However, these findings are only preliminary, and more research is needed to directly link antidepressant effects and energy metabolic inhibition together, as our study did not directly investigate antidepressants and depression-like behaviour in mice.