{"id":600,"date":"2011-06-04T10:10:33","date_gmt":"2011-06-04T09:10:33","guid":{"rendered":"https:\/\/touchneurology.com\/2011\/06\/04\/tryptophan-metabolism-as-a-new-target-for-the-treatment-of-schizophrenia-2\/"},"modified":"2020-08-20T21:53:08","modified_gmt":"2020-08-20T20:53:08","slug":"tryptophan-metabolism-as-a-new-target-for-the-treatment-of-schizophrenia-2","status":"publish","type":"post","link":"https:\/\/touchneurology.com\/psychiatric-disorders\/journal-articles\/tryptophan-metabolism-as-a-new-target-for-the-treatment-of-schizophrenia-2\/","title":{"rendered":"Tryptophan Metabolism as a New Target for the Treatment of Schizophrenia"},"content":{"rendered":"<p>Kynurenine is further metabolized along two distinct routes:<\/p>\n<ul>\n<li>the kynurenine\u2013kynurenic acid (KYNA) pathway, regulated by kynurenine amino transferase (in both astrocytes and microglia) and resulting in production of KYNA, the only known endogenous N-methyl-D-aspartic acid (NMDA) antagonist; and<\/li>\n<li>the kynurenine\u2013(quinolinic acid)\u2013nicotinic acid pathway, which is initiated by kynurenine hydroxylase in microglia, but not in astrocytes, and results in the production of NMDA agonists and free radical generators (e.g. quinolinic and picolinic acids), the precursors of nicotinic acid.<\/li>\n<\/ul>\n<p>The crosstalk between the methoxyindole and kynurenine pathways is provided by NMDA-agonist-induced stimulation and NMDA-antagonistinduced inhibition of melatonin formation from serotonin, respectively. A type 1 immune response triggers microglial production of cytokines able to induce IDO. The most powerful inducer of IDO is interferon (IFN)-g. The other type-1 cytokine, tumor necrosis factor (TNF)-\u03b1, stimulates and\/or drastically potentiates IFN-\u03b3-induced IDO activity. Production of IFN-\u03b3 and TNF-\u03b1 is controlled by (IFN-\u03b3)+874 (T\/A) and (TNF-\u03b1)-308 (G\/A) genotypes, respectively. The high promoter T allele is associated with high IFN-\u03b3 production and increased IDO activity (i.e. elevated plasma kynurenine levels and kynurenine\/tryptophan ratios) in healthy individuals. The presence of (TNF-\u03b1)-308 high promoter (A) may, therefore, strengthen the association between (IFN-\u03b3)+874 high promoter (T) and IDO activity.<\/p>\n<p>There are no published studies of IFN-\u03b3 gene polymorphism in schizophrenia. The TNF-\u03b1 A allele is associated with high vulnerability to the late-onset paranoid-type schizophrenia in males. Genetic regulation of IDO may be affected by hormones; although IDO is not inducible by hormones, application of hydrocortisone, dexamethasone, and prolactin drastically potentiates IFN-\u03b3-induced IDO, while the expression of the IFN-\u03b3 gene may be subject to direct hormonal control by estradiol and prolactin.<\/p>\n<p>The type 2 immune response\u2014which is predominant in schizophrenia\u2014is characterized by inhibition of IDO in microglia and activation of TDO in astrocytes. Due to the the absence of kynurenine hydroxylase in astrocytes, activation of TDO results in a shift from the kynurenine\u2013(quinolinic acid)\u2013nicotinic acid to the kynurenine\u2013KYNA pathway. Increased levels of KYNA in the brain (particularly in the prefrontal cortex) and cerebrospinal fluid (CSF) in schizophrenia may be accounted for by dopaminergic hyperfunction\/glutaminergic hypofunction (and related clinical manifestations) in schizophrenia, as KYNA\u2014the only known endogenous NMDA antagonist\u2014activates mid-brain dopaminergic neurons similar to the effect of MK-801, an exogenous NMDA antagonist and psychotomimetic. Furthermore, the higher affinity of KYNA antagonism to a-7-nicotinic acetylcholine receptors than to NMDA receptors may explain the existence of cognitive impairment without psychotic symptoms, while psychotic symptoms are always associated with cognitive impairment.<\/p>\n","protected":false},"excerpt":{"rendered":"<p>Kynurenine is further metabolized along two distinct routes: the kynurenine\u2013kynurenic acid (KYNA) pathway, regulated by kynurenine amino transferase (in both astrocytes and microglia) and resulting in production of KYNA, the only known endogenous N-methyl-D-aspartic acid (NMDA) antagonist; and the kynurenine\u2013(quinolinic acid)\u2013nicotinic acid pathway, which is initiated by kynurenine hydroxylase in microglia, but not in astrocytes, [&hellip;]<\/p>\n","protected":false},"author":53489,"featured_media":0,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"_relevanssi_hide_post":"","_relevanssi_hide_content":"","_relevanssi_pin_for_all":"","_relevanssi_pin_keywords":"","_relevanssi_unpin_keywords":"","_relevanssi_related_keywords":"","_relevanssi_related_include_ids":"","_relevanssi_related_exclude_ids":"","_relevanssi_related_no_append":"","_relevanssi_related_not_related":"","_relevanssi_related_posts":"","_relevanssi_noindex_reason":"","rank_math_lock_modified_date":false,"footnotes":""},"categories":[1],"tags":[],"class_list":["post-600","post","type-post","status-publish","format-standard","hentry","category-uncategorized","vocabulary_1-psychiatric-disorders"],"acf":[],"_links":{"self":[{"href":"https:\/\/touchneurology.com\/wp-json\/wp\/v2\/posts\/600"}],"collection":[{"href":"https:\/\/touchneurology.com\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/touchneurology.com\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/touchneurology.com\/wp-json\/wp\/v2\/users\/53489"}],"replies":[{"embeddable":true,"href":"https:\/\/touchneurology.com\/wp-json\/wp\/v2\/comments?post=600"}],"version-history":[{"count":1,"href":"https:\/\/touchneurology.com\/wp-json\/wp\/v2\/posts\/600\/revisions"}],"predecessor-version":[{"id":16532,"href":"https:\/\/touchneurology.com\/wp-json\/wp\/v2\/posts\/600\/revisions\/16532"}],"wp:attachment":[{"href":"https:\/\/touchneurology.com\/wp-json\/wp\/v2\/media?parent=600"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/touchneurology.com\/wp-json\/wp\/v2\/categories?post=600"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/touchneurology.com\/wp-json\/wp\/v2\/tags?post=600"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}