1. 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

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

3. Absorbtion

4. Two Pathways: Melatonin and Niacin

5. Tryptophan Crosses the Blood
Brain Barrier via Active Transport

6. Deficiency of the Niacin Pathway Leads
to Pellagra

7. "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.

8. 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,

9. 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)

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

11. 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

12. Once Produced Kynurenine Crosses
the Blood Brain Barrier

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

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

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

16. Astrocytes and Microglia are Both
Sources and Targets of Cytokines

17. 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

18. 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]

19. 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

20. 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.

21. 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.

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

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

24. 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.
 Collectivelythese 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]

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

26. 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 .

27. 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”.

28. 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

29. 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

30. High IDO activity - persistent and
progressive granuloma
High IDO activity induces
apoptosis of immune and
inflammatory cells that
may prevent the
clearance of the micro-
organisms/antigen and
leading to persistent and
progressive granuloma.
Principal Investigator
René Lutter, PhD; http://www.amc.nl/web/Research/Departments/Overview/Experimental-Immunology-1/Experimental-
Immunology/Current-research/Lung-Immunology.htm