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Other Drugs Used to Treat Seizures
Published in Stanley R. Resor, Henn Kutt, The Medical Treatment of Epilepsy, 2020
Allopurinol inhibits tryptophan-2,3-dioxygenase, the key enzyme in the oxidation of tryptophan, leading to a reduction in quinolinic acid. Quinolinic acid is a potent endogenous neuroexcitatory substance, which causes epileptic seizures when administered intracerebroventricularly (15). Allopurinol may also act as an inhibitor of tryptophan pyrrolase, which catalyzes the synthesis of kynurenine as well as quinolinic acid. Kynurenine is also an endogenous convulsant (16,17).
Addendum I: Transneuronal Retrograde Messengers in Chronic Fatigue Syndrome
Published in Jay A. Goldstein, Chronic Fatigue Syndromes, 2020
Low central levels of NO in CFS should reflect decreased concentrations of EAAs. CFS quinolinic acid and a related metabolite, kynurenic acid, were measured in a variety of neurologic disorders, including CFS.20 Quinolinic acid is an endogenous NMDA agonist synthesized from L-tryptophan, and kynurenic acid is an NMDA antagonist. Very small increases in quinolinic acid and neopterin were found in patients with CFS (n=18), suggesting immune activation. Glutamate was not measured. Patients with depression were normal in all measured variables. I am not sure yet how this finding relates to my postulated CFS glutamate deficiency. It is certainly possible that subgroups of CFS (especially those who feel worse after NTG) could have elevated concentrations of NO, glutamate, and possibly IL-1 beta and other cytokines. The quinolinic acid results in CFS should be confirmed by using larger samples and measuring more EAAs. Elevated quinolinic acid may be related to the tendency of central alpha interferon to shunt tryptophan into the kynurenine pathway.
Micronutrients for Improved Management of Huntington’s Disease
Published in Kedar N. Prasad, Micronutrients in Health and Disease, 2019
Using a transgenic HD mouse model, caspase-1 and caspase-3 were found to be transcriptionally upregulated and activated. The degree of activation of caspases correlated with the progression of this disease in HD mice.72 Similar observations were made in autopsied brain samples of HD patients. Activation of caspase-2 cleaves HD protein selectively at amino acid 552, and fragmented HD proteins become aggregated. The aggregated form of HD protein causes selective neuronal cell death in the striatum and cortex of autopsied brain samples of human HD as well as in HD mouse model expressing full length HD gene (YAC72 mice).73 Inhibitors of caspase delayed the onset of symptoms in the transgenic HD mouse model. Treatment of animals with quinolinic acid- and 3-NP increased oxidative stress and induced HD-like changes in the brain.74,75 HD protein also activates microglia causing the release of pro-inflammatory cytokines and reactive oxygen species (ROS).
Body image dissatisfaction in pregnant and non-pregnant females is strongly predicted by immune activation and mucosa-derived activation of the tryptophan catabolite (TRYCAT) pathway
Published in The World Journal of Biological Psychiatry, 2018
Chutima Roomruangwong, Buranee Kanchanatawan, André F. Carvalho, Sunee Sirivichayakul, Sebastien Duleu, Michel Geffard, Michael Maes
In the present study, we found that the best predictors of a lowered T1 BIS score were: (1) IgM responses directed against kynurenine; (2) IgA responses against the sum of quinolinic acid, kynurenine, 3-OH-kynurenine and 3-OH-anthranillic acid, which reflects brain quinolinic acid contents, and (3) IgA levels directed against 3-OH-kynurenine. Thus, a generalised increased production (as indicated by increased IgM values) of kynurenine and mucosa-derived (as indicated by increased IgA levels) quinolinic acid and 3-OH-kynurenine are strongly related to BIS scores. Quinolinic acid is one of the most neurotoxic metabolites produced by the TRYCAT pathway (Lovelace et al. 2016). It functions as a N-methyl-d-aspartate receptor agonist, and inhibits adenosine triphosphate production by mitochondria, leading to the activation of O&NS pathways, a disruption of neuron-glial interactions and blood–brain barrier integrity, which finally induces apoptosis of glial cells, and damage of neurons (Morris et al. 2016). 3-OH-kynurenine is a strong pro-oxidant (Majoie et al. 2011), which contributes to neuro-degeneration by inducing neuronal apoptosis (Okuda et al. 1998). Higher levels of 3-OH-kynurenine are observed in mood disorders and various neurological disorders, e.g., seizures, Huntington’s disease and Alzheimer’s dementia (Lapin 1981; Pearson and Reynolds 1992; Baran et al. 1999; Wichers and Maes 2004; Myint et al. 2007a,b; Yao et al. 2010). These neurotoxic metabolites may thus influence mood regulation and neurocognitive processes, thus eventually contributing to body image dissatisfaction.
Gut microbes and metabolites as modulators of blood-brain barrier integrity and brain health
Published in Gut Microbes, 2020
Aimée Parker, Sonia Fonseca, Simon R. Carding
Amino acid metabolites: the gut microbiota plays an essential role in amino acid catabolism the products of which can influence the balance between the production of excitatory and inhibitory neurotransmitters essential for correct brain functioning.67 Species of the genera Lactobacillus and Bifidobacterium metabolize glutamate, the most abundant free amino acid and excitatory neurotransmitter in the brain, to produce γ-aminobutyric acid (GABA), a major inhibitory neurotransmitter.68 Decarboxylases secreted by Clostridium sporogenes contribute to converting tryptophan, an essential amino acid found in a wide range of foods,69 to the neurotransmitter tryptamine, involved in the release of serotonin by cells of the enteroendocrine and enteric nervous systems.70,71 Germfree mice display increased plasma tryptophan levels, which are normalized after conventionalization.72Bifidobacterium infantis can increase plasma levels of tryptophan.73 Bacterial conversion of tryptophan to indoles, ligands for aryl hydrocarbon receptor (AHR), can decrease brain inflammation and limit disease severity in murine models of MS by activating astrocytes.74 Tryptophan is a precursor of many other diverse microbial and host metabolites75 including kynurenic acid, which has anti-inflammatory properties in the gastrointestinal tract76 and is considered to be neuroprotective,77 and quinolinic acid, which is a neurotoxin and a BBB modulator implicated in the etiology of psychiatric disorders and neurodegenerative diseases.78,79 Tryptophan and glutamate-metabolizing microbes may therefore perform important BBB and brain-protective functions, but greater understanding and care are needed to harness their therapeutic potential while avoiding the effects of potentially harmful derivatives.
Current state on tryptophan 2,3-dioxygenase inhibitors: a patent review
Published in Expert Opinion on Therapeutic Patents, 2019
Arina Kozlova, Raphaël Frédérick
Dysregulations in the KP were also linked to neuropsychiatric disorders such as schizophrenia, depression, Alzheimer’s, and Parkinson’s disease [7–11]. Alterations in kynurenic acid (KYNA) and quinolinic acid (QUIN) levels were characterized in several neuropathological states [7,12].