Tryptophan and Madness ADONIS SFERA, MD Gaspar Casal: Historia Natural y Medicina del Principado de Asturias Natural and Medical History of the the Principality of Asturias 1762

Tryptophan Tryptophan is an essential amino acid, which means that we must obtain it from the diet.

Absorbtion

Two Pathways: Melatonin and Niacin

Tryptophan Crosses the Blood Brain Barrier via Active Transport

Deficiency of the Niacin Pathway Leads to Pellagra

"Asturian leprosy" Pellagra was first described in Spain in 1735 by Gaspar Casal in his Natural and Medical History of the Asturian Principality (1762). It came to be known as “Asturian leprosy”. It was later named pellagra by Francesco Frapoli of Milan.

Deficiency of the Serotonin/Melatonin Pathway Serotonin is synthetized by two distinct Tryptophan hydroxylase (TPH) enzymes in the brain (TPH2) and in the periphery (TPH1). Thus, the indicated peripheral and central functions of serotonin are differentially regulated and can be targeted independently. In the pathogenesis of migraine, serotonin from both sources may be involved. Diego J. Walther, Michael Bader; A unique central tryptophan hydroxylase isoform Max Delbrück Center for Molecular Medicine (MDC), Robert-Rossle-Strasse 10, D-13092 Berlin-Buch, Germany http://dx.doi.org/10.1016/S0006-2952(03)00556-2,

Let’s Focus on the Kynurenine Pathway (KP) Inflammatory cytokines or excess cortisol can force the tryptophan into kynurenine pathway (KP). This is accomplished by two enzymes: -indoleamine 2,3-dioxygenase (IDO) -tryptophan 2,3-dioxygenase (TDO)

Alteration of tryptophan metabolism by immune stimuli or cortisol In monocytes, macrophages and microglia IDO is activated by cytokines (immune stimuli). In the liver TDO is activated by cortisol.

KP and Depression KP depletes the body of serotonin and may precipitate depressive symptoms associated with interferon treatment for hepatitis C. Shift of tryptophan metabolism in depression (Lapin, Oxenkrug, 1969; Oxenkrug, 2010). IFNG – interferon-gamma; NAS – N-acetylserotonin, IDO-indoleamine 2,3-dioxygenase; TDO – tryptophan 2,3- dioxygenase

Once Produced Kynurenine Crosses the Blood Brain Barrier

Kinurenine Is Processed Differently by Astrocytes and Microglia Astrocytes process kynurenine to kynurenic acid (KYNA) Microglia process kynurenine to quinolonic acid (QUIN)

Kynurenic and Quinolonic Acids Bind to NMDA Receptors KYNA is NMDA receptor antagonist QUIN is NMDA receptor agonist

Kynurenine Pathway (KP) Is Controlled By the Immune System This is where Immunology meets Psychiatry

Astrocytes and Microglia are Both Sources and Targets of Cytokines

Cytokines Come in Two Flavors Pro-Inflammatory Cytokines: IL-1, IL-6, TNF, interferon-alpha - activate IDO and KMO Anti-Inflammatory Cytokines:IL-4, IL-5, IL-10 - inhibit IDO and KMO IDO = indoleamine 2,3-dioxygenase KMO = kynurenine 3-monoxygenase

KP and Psychosis Reduced KMO expression and increased CSF KYNA levels were found in schizophrenia and bipolar disorder type 1 with psychotic features. A genetic variant of KMO (Arg452 allele) was associated with psychotic features during manic episodes. KMO mRNA levels and activity in prefrontal cortex (PFC) are reduced in schizophrenia. Molecular Psychiatry advance online publication, 5 March 2013; doi:10.1038/mp.2013.11. PMID: 23459468 [PubMed - as supplied by publisher]

KP in Alzheimer’s Disease Kynurenine production is increased in Alzheimer's disease where its metabolites are associated with both cognitive deficits and depressive symptoms. IDO = indoleamine 2,3-dioxygenase KMO = kynurenine 3-monoxygenase

Autoimmune Pellagric Dementia (Nasu-Hakola Disease or PLOSL) IDO dysregulation (manifest as autoimmune pellagric dementia) is genetically illustrated by Nasu-Hakola Disease (or PLOSL). A mutation in the IDO antagonizing genes TYROBP/DAP12 or TREM2 leads to PLOSL. Increases in microglial IDO expression depletes neurons of tryptophan causing psychotic symptoms and neurodegeneration.

IDO - Immune Tolerance and Acceptance of the Fetus Cells at the maternal-fetal interface express IDO to consume all local tryptophan and prevent an immunologic attack by the T-cells against the fetus.

IDO creates a sort of “force field” around the fetus by tranquilizing all T-cells that come too close

Inhibition of IDO Inhibition of IDO using 1-methyl-tryptophan causes a sudden catastrophic rejection of the mammalian fetus.

Autoimmune Diseases- Localized Pellagra? Pharmacological doses of NAD precursors sometimes provide dramatic therapeutic benefit for rheumatoid arthritis, type 1 diabetes, multiple sclerosis, colitis, other autoimmune diseases, and schizophrenia in either the clinic or animal models. Collectively these observations support the idea that autoimmune disease may in part be considered as localized pellagra manifesting with symptoms particular to the inflamed target tissues. Penberthy WT.; Pharmacological targeting of IDO-mediated tolerance for treating autoimmune disease; Curr Drug Metab. 2007 Apr;8(3):245-66; PMID: 17430113 [PubMed - indexed for MEDLINE]

Immunologic Tolerance - Good News For the Baby, Bad News for Cancer

Visualizing IDO in Cancer (HRPimmunoperoxidase) Expression of the tryptophan-catabolizing enzyme IDO by endothelial cells of infantile hemangioma A. proliferative phase in proliferative phase B. involutive phase Sheila Fallon Friedlander, Matthew R. Ritter, and Martin Friedlander; Recent Progress in Our Understanding of the Pathogenesis of Infantile Hemangiomas ;Lymphatic Research and Biology. 2005, 3(4): 219-225. doi:10.1089/lrb.2005.3.219.

IDO and Autoimmunity - Loss of Tolerance to “self” In autoimmune diseases the individual loses normal tolerance to “self” proteins. A newly described role for IDO is in the regulation of tolerance towards own proteins and DNA. Increasing IDO production or its downstream effects might be a way to regain lost tolerance for “self”.

The Hope is to Create a Molecule with Maximum IDO Inhibiting Abilities and Minimum Side Effects Manipulations of the kynurenine pathway might help rectify neurodegenerative and psychiatric diseases alike. Inhibiting the enzyme kynurenine 3-monooxygenase (KMO) prevents synapse loss and ameliorates symptoms in models of Alzheimer's and Huntington's diseases. B.S. Rawdin, S.H. Mellon, F.S. Dhabhar E.S. Epel , E. Puterman et al; Dysregulated relationship of inflammation and oxidative stress in major depression; Brain, Behavior, and Immunity xxx (2012) xxx–xxx

M. tuberculosis infection increases IDO-1 expression in human and murine macrophages. M. tuberculosis Induces Potent Activation of IDO-1 Blumenthal A, Nagalingam G, Huch JH, Walker L, et al. (2012) M. tuberculosis Induces Potent Activation of IDO-1, but This Is Not Essential for the Immunological Control of Infection. PLoS ONE 7(5): e37314. doi:10.1371/journal.pone.0037314 http://www.plosone.org/article/info:doi/10.1371/journal.pone.0037314