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Herbs with Antidepressant Effects
Published in Scott Mendelson, Herbal Treatment of Major Depression, 2019
Several studies have found antidepressant-like effects of Ginkgo biloba and obtained neurochemical data to help determine the mechanisms by which those effects occur. In one such study, mice were treated with EGb761 for 17 days. After these animals were found to exhibit the expected antidepressant effect of that treatment – i.e., reduced immobility in the forced swim test – they were sacrificed and their brains studied. The antidepressant effects of Ginkgo biloba were associated with reductions in lipid peroxidation and superoxide radical production in the midbrain, hippocampus, and prefrontal cortex. Treatment also increased dopaminergic and serotonergic neurotransmission in those areas.14 Daily treatment with diterpene ginkgolides purified from Ginkgo biloba also decreased immobility in the tail suspension test and increased sucrose consumption. Subsequent neurochemical analysis of hippocampal tissue showed enhanced neurotransmitter metabolism, reduction in oxidative stress, increased glutathione metabolism, improved lipid and glucose metabolism, and reductions in the neurotoxic metabolite kynurenic acid.15
Overview of Neurotransmission: Relationship to the Action of Antiepileptic Drugs
Published in Carl L. Faingold, Gerhard H. Fromm, Drugs for Control of Epilepsy:, 2019
Glycine also has an action at a strychnine-insensitive receptor that has been linked to the NMDA excitatory amino acid receptor.75 This is a high affinity site (Kd for 3H-glycine of 100 to 200 nM) that appears to increase the action of glutamate at its NMDA receptor.123 This strychnine-insensitive glycine binding site has a widespread distribution in brain and seems to be similar to that of the NMDA receptors. Thus, glycine in submicromolar concentrations appears to enhance the action of excitant amino acid neurotransmitters and may even be necessary.123 It appears to enhance excitant amino acid action by binding to a site within the channel and producing an allosteric modification. In this regard it appears to be analogous to the interaction between the GABA receptor and the benzodiazepine binding site. The strychnine-insensitive glycine binding site also appears to have an endogenous antagonist. The tryptophan metabolite, kynurenic acid is an antagonist of the glycine binding site on the NMDA receptor. However, 7-chlorokynurenic acid is a more selective and more potent antagonist and is now being widely used to study this glycine receptor.123
Emotional Health and Stress Management
Published in James M. Rippe, Lifestyle Medicine, 2019
Neil Nedly, Francisco E Ramirez
Exercise is an integral part of stress management as well. It is understood that general health is improved by a regular and sustainable exercise routine and that excessive exercise can lead to fatigue, injury, and decrease the ability to maintain the program in the long term. Exercise is also important for general brain health (stimulating Brain-derived Neurotrophic Factor, etc.) and it is protective against chronic stress effects. Exercise training induces changes at the level of the muscle gene expression that can increase kynurenine aminotransferases, enhancing the conversion of kynurenine into kynurenic acid, which protects the brain from stress-induced changes associated with depression.86 Moderate exercise not only decreases current stress but research shows that the effect lasts for extended periods post-workout.87
How could we forget immunometabolism in SARS-CoV2 infection or COVID-19?
Published in International Reviews of Immunology, 2021
The serum of severe COVID-19 patients shows a decrease in the apolipoprotein A1 (APOA1) and apolipoprotein M (APOM) [100]. Metabolites of kynurenate, kynurenine, and 8-methoxykynurenate are also high in circulation of severe COVID-19 patients. This indicates the depletion of tryptophan, which is one of the nine essential amino acids (AAs) through tryptophan 2,3-dioxygenase (TDO), indoleamine 2,3-dioxygenase 1 (IDO-1, predominant extra-hepatically, including macrophages, microglia, and T cells) or IDO-2 [101, 102]. The tryptophan catabolism suppresses T cell proliferation and induces their anergy due to the reduced supply of this essential AA that activates general control non-derepressible 2 (GCN2) or eukaryotic initiation factor 2α (eIF2α) stress kinase, which is indicated by the decrease in different circulating T cells in severe COVID-19 patients [103–105]. The increased kynurenic acid or kynurenate in the circulation inhibits the pro-inflammatory function of monocytes/macrophages [106, 107]. For example, in severe COVID-19 patients, circulating monocytes/macrophages do not take part in the cytokine storm generation. Also, the tryptophan depletion in the circulating DCs, monocytes/macrophages induces GCN2 activation that stimulates the anti-inflammatory cytokine production (IL-10 and TGF-β) via eIF2α phosphorylation at serine 51 and inactivating it [104, 108, 109]. Hence, circulating tryptophan metabolites suppress circulating monocytes/macrophages, DCs, and T cells in severe COVID-19 patients as a result of altered immunometabolism.
The contribution of gut bacterial metabolites in the human immune signaling pathway of non-communicable diseases
Published in Gut Microbes, 2021
F. Hosseinkhani, A. Heinken, I. Thiele, P. W. Lindenburg, A. C. Harms, T. Hankemeier
Tryptophan metabolism through the kynurenine pathway is mediated by either indoleamine 2,3-dioxygenase (IDO) or tryptophan 2,3-dioxygenase which leads to the production of kynurenine and downstream products, such as kynurenic acid and quinolinic acid (QUIN). The gut microbiota is known for its contribution to the kynurenine pathway by regulating IDO 1 expression.61,71 Although IDO-dependent tryptophan metabolism plays a minor role under normal conditions, it is strongly upregulated in response to inflammatory factors (e.g., interferon gamma, TNF-α and NF-κB).17,72 Overexpression of IDO 1 and increased QUIN levels have been reported in IBD patients and different neurological disorders such as Alzheimer’s disease, anxiety, depression, epilepsy and human immunodeficiency virus-associated neurocognitive disorders.73 Gut bacteria such as Lactobacillus spp., Pseudomonas aeruginosa, Pseudomonas fluorescens possess the enzyme aspartate aminotransferase, and produce kynurenic acid by transamination of kynurenine.72 Increased level of kynurenic acid has been reported in patients suffering from IBD, T2D, and multiple sclerosis.74 Kynurenic acid can modulate the intestinal inflammation and limit inflammation-induced cell damage in CNS through GPCR35 and AhR mediated signals. Moreover, kynurenic acid can increase energy expenditure by activating GPCR35, which stimulates lipid metabolism and anti-inflammatory phenotype in adipose tissue.75
Recent advances from metabolomics and lipidomics application in alzheimer’s disease inspiring drug discovery
Published in Expert Opinion on Drug Discovery, 2020
Miroslava Cuperlovic-Culf, Amanpreet Badhwar
A reduction in the concentration of tryptophan and its metabolic product, neurotransmitter serotonin, have been consistently associated with AD development with evidence for the degeneration of the serotonin system and disruption in function of serotonin transporter in MCI and AD dementia [32]. In addition to serotonin production, tryptophan can be used for the synthesis of proteins and melatonin production. However, over 90% of peripheral tryptophan is metabolized via the kynurenine pathway (KP) to kynurenic acid (KYNA), or anthranilic acid (AA) and 3-hydroxykynurenine (3-HK) [33]. KP has been shown to be dysregulated in neuroinflammatory diseases including AD, with a particularly significant increase in activation of KP in female patients with high β-amyloid load leading to an increased utilization of tryptophan for the KP pathway, likely resulting in the observed reduction in serotonin concentration in AD. Therefore, significant effort is currently underway in developing inhibitors for KP pathway enzymes [34]. Further reductions in the serotonin level can be linked to the observed serum BCAA concentration increase, possibly competitively reducing the transfer of tryptophan through the blood–brain barrier, thereby reducing possible serotonin synthesis [31]. Therefore, it is interesting to note that serotonin receptors function has been linked to both Aβ and tau [35]. Additionally, a limited number of reports have shown the possible role of serotonin in microglia activation through an independent serotonin receptor available on microglia [36].