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CNS & Neurological Disorders - Drug Targets, 2014, 13, 137-149 137

TRYCAT Pathways Link Peripheral Inflammation, Nicotine, Somatization

and Depression in the Etiology and Course of Parkinson’s Disease
George Anderson*,1 and Michael Maes2

1
CRC, Rm: 30, 57 Laurel Street, Glasgow, Scotland
2
Department of Psychiatry Faculty of Medicine, Pathumwan, Bangkok 10330, Thailand

Abstract: Increased depression, somatization, gut inflammation and wider peripheral inflammation are all associated with the
early stages of Parkinson’s disease (PD). Classically such concurrent conditions have been viewed as “comorbidities”, driven
by high levels of stress in a still poorly understood and treated disorder. Here we review the data on how oxidative and
nitrosative stress in association with immuno-inflammatory responses, drives alteration in tryptophan catabolites, including
kynurenine, kynurenic acid and quinolinic acid that drive not only the ‘comorbidities” of PD but also important processes in
the etiology and course of PD per se. The induction of indoleamine 2,3-dioxygenase, leading to the driving of tryptophan into
neuroregulatory tryptophan catabolite products and away from serotonin and melatonin production, has significant
implications for understanding the role of nicotine, melatonin, and caffeine in regulating PD susceptibility. Tryptophan
catabolite pathway activation will also regulate blood-brain barrier permeability, glia and mast cell reactivity as well as wider
innate and adaptive immune cell responses, all relevant to the course of PD. As such, the “comorbidities” of PD such as
depression, somatization and peripheral inflammatory disorders can all be conceptualized as being an intricate part of the
biological underpinnings of both the etiology and course of PD. As a consequence, the data reviewed here has treatment
implications; relevant to both the course of PD and in the management of L-DOPA induced dyskinesias.
Keywords: Parkinson’s, depression, somatization, tryptophan, indoleamine 2,3-dioxygenase, nicotinic, melatonin, inflammation,
cytokines.

INTRODUCTION Here we look at the role of the tryptophan catabolite

With no current approved drugs capable of reducing
disease progression, but only inhibiting the expression of
motor symptoms, the development of treatment that tackles
the underlying neurodegenerative process in Parkinson’s
disease (PD) is a matter of extensive investigation. The delay
in effective treatment challenges researchers to better clarify
the etiology and course of PD.
Many susceptibility factors have been proposed,
including environmental toxin exposure e.g. fungicides,
herbicides, pesticides, and metals [1, 2]. Mutations in a
number of genes are associated with both familial and
sporadic forms of PD, including alpha-synuclein, Parkin and
many others [3-6]. How such environmental and genetic risk
factors drive the etiological and biological underpinnings of
PD, such as oxidative and nitrosative stress (O&NS),
mitochondrial dysfunction, peripheral and central
inflammation, as well as immune driven changes awaits
clarification. The primary conceptualization of the disorder
has linked such risk factors and biological changes directly
to atrophy of dopamine neurons in the substantia nigra (SN).
However, an early biomarker has remained elusive, meaning
that people only present when considerable damage has
already occurred, with symptoms predominantly involving
SN atrophy. A wider perspective on the processes involved
in PD may help to not only improve treatment, but to provide
an early biomarker allowing preventative intervention.
*Address correspondence to this author at the George Anderson, CRC, Rm 30,
57 Laurel St. Glasgow G11 7QT, Scotland; Tel: +447 505 623 759;
E-mail: anderson.george@rocketmail.com
(TRYCAT) pathways in linking the wider aspects of PD,
including somatization, depression and peripheral
inflammation, with the induction and course of PD, as well
as in the protection afforded by nicotine and caffeine. This
gives a wider systemic perspective on PD; emphasizing the
role of the immune system in driving alterations centrally,
especially via neuronal regulation by immune and glia cell
derived TRYCATs. First we review the data on the wider
aspects of PD presentations and the indicants that these give
to the underlying biological processes that drive this still
poorly understood and managed disorder.
PARKINSON’S: SOMATIZATION AND MDD
Comorbid psychiatric conditions are common in PD [7],
having a significant impact not only on quality of life and
resilience [8], but also disease outcome. Much of the focus
of psychiatric comorbidity has been on later stages of PD.
However, high levels of comorbid somatization (67%),
depression (36%), anxiety (27%) and obsessive-compulsive
symptoms ((53%) have also been found in the early motor
stages of PD, in non-demented patients [9]. These symptoms
are highly intercorrelated and thought driven by adrenergic
and serotonergic dysfunction, mediated by early
degeneration in brain stem nuclei, as shown by Braak [10].
Level of depression correlates with global cognitive
function, suggesting depression as an early marker of wider
brain dysfunction in PD 10]. The overlap of depression and
neurodegenerative processes is highlighted by the 2%
decrease in some cognitive measures occurring with every
depressive episode, linking to recent conceptualizations of

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138 CNS & Neurological Disorders - Drug Targets, 2014, Vol. 13, No. 1
psychiatric conditions as neuroprogressive disorders [11].
Other studies report similar rates of psychopathology in PD
[12], with striatal dopamine transporter levels and
dopaminergic tone correlating with depressive and anxiety
symptoms [13]. Single nucleotide polymorpisms (SNPs) in
the circadian clock controlled gene thyrotroph embryonic
factor (Tef) associate with depression in PD, suggesting
overlaps with the circadian dysregulation evident in PD [14].
Overall psychiatric comorbidities may predate motor
symptoms, correlate positively with motor symptoms,
negatively with cognition and are linked to changes in
circadian regulation.
PARKINSON’S: AUTONOMIC AND BP
A high prevalence of nocturnal nondipping blood
pressure (BP), defined as less than a 10% decrease at night
versus day BP, is evident in PD [15]. Nondipping in this
study occurred irrespective of orthostatic hypotension,
coexisting arterial hypertension or antihypertensive
treatment. Lewy bodies are evident in peripheral and central
structures involved in autonomic regulation [16], and
alterations in the autonomic nervous system, in association
with circadian dysregulation, occur in the early stages of PD
[10, 17]. Increased TRYCAT pathway activation decreases
melatonin, often evident in PD [18], contributing to
nondipping nocturnal BP.
PARKINSON’S: INFLAMMATION
Serum and CSF levels of proinflammatory cytokines and
CD4+ and CD8+ Tcells are increased in PD [19-23]. Genetic
variations in these cytokine and immune factors associate
with PD risk [24, 25]. Chronic users of some nonsterioidal
anti-inflammatory drugs (NSAIDs) show diminished PD
incidence [26], suggesting a significant role for inflammation
in the etiology of PD. Loss of function mutations in Parkin
are associated with PD, with inflammation decreasing Parkin
levels not only in neurons but also microglia and
macrophages [27]. Decreased Parkin enhances levels of
tumor necrosis factor-alpha (TNF-α), interleukin (IL)-1b and
inducible nitric oxide synthase (iNOS) mRNA in activated
macrophages, suggesting that inflammation mimicks Parkin
mutations, and likely interacts with Parkin mutations to
regulate levels of inflammatory response. Combinations of
proinflammatory cytokines, TNF-α, IL-1beta (IL-1β) and
interferon-gamma (IFN-γ) also impact on levels and
localization of glia α-synuclein and tau, suggesting wider
interactions of inflammation with other PD associated
proteins [28].
Inflammasome activation leads to IL-1β and IL-18
production and release. Remarkably little data is available on
the role of the inflammasome in PD, despite the well proven
role of IL-1β in peripheral and central inflammation, as well
as the genetic link of IL-18 SNPs to sporadic late onset PD
[29]. PINK1, a susceptibility gene for autosomal recessive
familial PD, regulates IL-1β activation [30], whilst α-
synuclein enhances IL-1β induced interferon-γ inducible
protein-10 (CXCL10), a proinflammatory and neurotoxic
chemokine in astrocytes [31]. Combined SNPs in TNF-α and
IL-1β modulate the susceptibility to PD [32], although not
all studies show IL-1β SNP links to PD [33]. IL-18 SNPs are
Anderson and Maes
associated with an increased risk for other conditions,
including Alzheimer’s, whilst the IL-18 induction of IFN-γ,
is the main driver of wider immuno-inflammation. Increased
O&NS, evident in PD, contributes to Nod-like receptor
family containing pyrin domain (Nlrp)3 inflammasome
activation [34]. As such inflammasome activation is likely to
interact with PD susceptibility genes in driving immuno-
inflammation both centrally and periphery, in co-ordination
with alterations in oxidant status and wider immuno-
inflammation.
CNS Inflammation
Increased cyclooxygenase-2 (COX2), IFN-γ, TNF-α and
IL-1β are found in postmortem PD brains [35]. Increased
vascular endothelial growth factor (VEGF) is evident in PD
and PD models [36]. VEGF increases blood-brain barrier
permeability (BBBp) [37], as found in PD [38] and PD
models [39], including the 1-methyl-4-phenyl-1,2,3,6-
tetrahydropyridine (MPTP) model, where the increased
BBBp is attenuated by caffeine [40]. Increased BBBp allows
the extravasation of monocytes/macrophages, neutrophils
and T-cells into the CNS. Increased CD4+ and CD8+ T-cells
are found in the SN in PD models, with CD4+ T-cells driving
dopaminergic toxicity [41]. Along with resident glia,
infiltrating leukocytes are a significant source of pro-
inflammatory cytokines, including TNF-α and IL-1β, which
have synergistic effects in the apoptosis of dopamine
neurons [42]. The over-expression of α-synuclein in the
CNS increases microglia activation, priming pro-
inflammatory responses, but only in the SN, suggesting
region specific α-synuclein effects [43]. Peripheral
inflammation enhances such α-synuclein priming of
microglia [44]. Also the loss of dopamine and
norepinephrine (NE) in PD will impact in the CNS more
widely [45], altering patterned CNS interactions.
Peripheral Inflammation
The first observable manifestations of PD may occur
peripherally, with increased levels of α-synuclein being
present in the intestine [46], leading to the suggestion that
colonic mucosal biopsy may provide a biomarker of
premotor PD. Likewise alterations in the intestine occur
prior to dopamine neuron loss, in α-synuclein over-
expressing mice [47]. Infection with helicobacter pylori (Hp)
is associated with the course of idiopathic PD [48, 49] and
not necessarily confined to those with current infection [50].
The eradication of Hp improves brady/hypokinesia but
worsens rigidity [51]. Antimicrobial resistance can
complicate Hp symptoms and treatment [52], with failure to
eradicate aggravating the effects of infection in PD [53].
Bladder dysregulation similarly predates motor dysfunction
in PD models [54]. Both bladder and bowel dysregulation
are associated with wider autonomic alterations. Peripheral
inflammation potentiates nigrostriatal dopamine neuron loss
in PD models [55-57]. As such peripheral inflammation is an
integral part of PD presentations, relevant to both etiology
and course, as well as the quest for an early premotor
biomarker.
Gastro-intestinal dysregulation commonly occurs early in
PD, with a history of constipation being a significant PD risk
TRYCAT Pathways Link Peripheral Inflammation
factor [58]. Animal models of gastro-intestinal disorders,
including ulcerative colitis, potentiate central atrophy in PD
models [59]. Such work has led to the suggestion of a
particular role for gastro-intestinal inflammation in the
etiology of idiopathic PD [60]. Other gastro-intestinal
changes occur in PD, including increased Lewy body
pathology [61], serum lipopolysaccharide (LPS) binding
protein [62], small intestinal bacterial overgrowth [63] and
gut permeability. The latter correlating with enhanced E. coli
intestinal mucosa staining, α-synuclein and oxidative stress.
Increased gut permeability also allows gram-negative
bacteria to translocate into the blood, leading to a IgM-
mediated immune response [64].
As to how these changes drive central alterations awaits
clarification. LPS leads to the atrophy of SN dopaminergic
neurons [65], partly via microglia activation, which is also
evident in depression [66]. Ulcerative colitis increases C-
reactive protein (CRP) [67], which increases BBBp [68],
contributing to central changes. Melatonin is protective in
ulcerative colitis, preventing the CRP increase [67],
suggesting a role for melatonin regulation of peripheral
influences on central PD processes. As well as peripherally
derived cytokines and decreased microglia reactivity
threshold [66, 69, 70], peripherally derived kynurenine (kyn)
has central consequences in PD, as detailed below.
Inflammation and Early Development
Given the role of central and peripheral inflammation in
PD, early developmental factors regulating immuno-
inflammatory responses will modulate the susceptibility to,
and course of, PD. Prenatal maternal infection increases the
toxicity to 6-hydroxydopamine (6-OHDA) in adulthood [71].
Decreased dopamine neurons levels or activity possibly
mediate this [42], given dopaminergic hypoacitivity
increases adult LPS inflammation [72]. Such an early
developmental influence on subsequent immuno-
inflammation overlaps to the early developmental priming
for comorbid depression and somatization in the etiology of
schizophrenia [11]. As well as priming for schizophrenia and
its comorbidities, prenatal viral infection increases the adult
levels of the Alzheimer’s associated peptide amyloid B [73].
This highlights the relevance of early immune responses to
adult neurodegenerative processes. Immunolocalization of
the influenza virus is evident in SN neurons and
macrophages of PD patients [74], suggesting a direct impact
of infection in SN dopamine neurons in PD, including
possibly within an early developmental context.
PARKINSON’S: PROTECTIVE FACTORS
A lack of history of cigarette smoking, having a family
member with PD and a history of constipation are the three
major risk factors for PD, each more than doubling the risk
[58]. A number of protective factors are evident in PD,
including nicotine and caffeine [75, 76], giving important
clues as to the relevant processes driving PD.
Nicotine
Smoking decreases the incidence of PD, and SNPs in
nicotinic cholinergic receptor gene cluster, CHRNA5-
CHRNA3-CHRNB4 modulate the age of development of PD
CNS & Neurological Disorders - Drug Targets, 2014, Vol. 13, No. 1 139
in current or previous smokers [75]. Of the thousands of
chemical products in cigarette smoke, nicotine affords the
predominant protection in PD. Other cigarette smoke factors
also provide protection, including 2,3,6-trimethyl-1,4-
naphthoquinone (TMN), a monoamine oxidase (MAO) A
and B inhibitor, which decreases dopamine metabolism and
MAO activation of endogenous neurotoxins [77]. Rasagiline,
an MAO B inhibitor and PD treatment, similarly prolongs
the action of dopamine [78].
Cigarette smoking also produces 2,3,7,8-tetrachloro-
dibenzo-p-dioxin (TCDD), which activates the aryl
hydrocarbon receptor (AHr). Interestingly the AHr, via AHr
response element III (AHRE-III) directly activates the
tyrosine hydroxylase (TH) gene, increasing TH mRNA and
protein [79], suggesting that activation of the AHr, and its
modulation by cyclic adenosine monophosphate (cAMP),
phosphodiesterases (PDE) and circadian genes, will directly
modulate levels of dopamine and NE produced [80]. The
role of the AHr in PD, especially in TH derived dopamine
and NE, will be important to determine. Two TRYCAT
products, kyn and kynurenic acid (KYNA) are known to
regulate the AHr. However, different AHr ligands can have
differential effects on AHr driven gene induction. As such
TCDD may have differential effects from kyn or KYNA.
Also cAMP, known to induce KYNA in astrocytes [81], is
an important activator of the AHr, with the transactivation of
the B2-adrenoceptor induction of cAMP being necessary for
some other ligands to activate the AHr [82]. The cAMP
regulation of the AHr is co-ordinated with circadian gene
(Period 1 and 2) induction, suggesting interactions of TCDD,
kyn and KYNA with cAMP/AHr/circadian genes, including
in the regulation of dopamine and NE. That said, smokeless
tobacco also affords protection against PD [83].
Nicotine is protective of dopamine neurons to different
ongoing toxicities, including MPTP, 6-OHDA and
aminochrome [84], but not after damage has already
occurred [85]. Short term administration of a low dose of
nicotine improves cognition and anti-oxidant status after 6-
OHDA lesions, with cognitive improvements positively
correlating with increased anti-oxidant status [86]. Multiple
subtypes of nicotinic acetylcholine receptors (nAChr) are
evident in the nigrostriatal pathway, including the α4β2,
α4α5β2, α6α4β2β3, and α6β2 β3 subunits, as well as
homomeric α7 [87]. All may be involved in the protective
effects of nicotine in PD [88], although the α7nAChr is less
densely expressed in SN dopamine neurons, being more
evident in SN astrocytes and GABAergic interneurons [89].
Nicotine also has wider cognitive benefits relevant to PD
[90], including increasing long-term potentiation (LTP). Of
the two phases of hippocampal LTP, early and late, the
α7nAChr increases both, whilst α4β2 agonism increases the
early phase [91]. This is suggestive of wider cognitive
protection by nicotine in PD.
The SN receives ACh inputs from the pedunculopontine
nucleus, an area subject to atrophy in PD. Nigrostriatal
damage by MPTP decreases nAChr levels generally, except
the α7nAChr [92], with non-α7nAChr mediating direct
protection in D neurons and PD models [93]. The α4β2 also
has anti-inflammatory effects [94]. Nicotine via the
α7nAChr activates a number of pathways, including the
cAMP, extracellular kinase (ERK)1/2 and
140 CNS & Neurological Disorders - Drug Targets, 2014, Vol. 13, No. 1
phosphatidylinositol 3-kinase (PI3K)/Akt paths [95]. These
diverse pathway activations decrease apoptosis and increase
trophic factor production [96]. Overall this suggests a direct
protective effect of nicotine via non-α7nAChr on D neurons,
with non-dopamine neuron protection by the α7nAChr.
Nicotine decreases L-DOPA induced dyskinesias in the
6-OHDA model by 50% [97], involving the β2 nAChr [98]
and partly dependent on dopamine terminal function [99]. In
about 50% of trials nicotine has direct motor symptom
benefits, possibly reflecting PD heterogeneity [100].
Non-Neuronal Impacts of Nicotine
Glia and Mast Cells
As well as direct nicotinic effects on dopamine neurons,
nicotine effects in other cell types are also thought protective
in PD, including immune cells, microglia and astrocytes
[101]. In the MPTP model α7nAChr protection is via the
inhibition of astrocyte activation [101], decreasing MPP+ or
LPS induced p38, ERK1/2 and TNF-α. ERK1/2 and p38 are
involved in the activation of astrocytes, increasing iNOS,
COX2 and cytokine production [102]. An increase in striatal
and SN glial fibrillary acidic protein (GFAP) is evident in
PD and astrocyte activation is concurrent to neuronal death
in the MPTP model [103]. α7nAChr activation also
decreases MPTP induced microglia activation [101].
Increased levels of activated microglia are found in the SN in
PD post-mortems [104].
Cigarette smokers are also less likely to develop some
inflammatory and allergic disorders [105], partly via nicotine
effects at the α7, α9, and α10 nAChRs on mast cells [106].
Nanomolar nicotine concentrations inhibit inflammatory
effluxes from rat mast cells, including TNF-α and IL-1β,
driven by decreased nuclear factor kappaBeta (NF-κB)
[106]. Nanomolar effects of nicotine in mast cells are far
lower than that required to produce action potentials,
suggesting that the combination of subunits is important in
modulating nicotine sensitivity.
Mast cells and especially astrocytes are crucial regulators
of BBBp, including via TNF-α and IL-1β efflux, which
nicotine inhibits. This suggests that nicotine will
significantly impact on BBBp and associated leukocyte
extravasation, important to the CNS degeneration occurring
in PD.
Adaptive and Innate Immunity
As well as modulating immune cells access to the CNS,
nicotine directly regulates immune responses. Adaptive and
innate immunity activation is evident in PD, with immuno-
suppression by regulatory T cells (RegT) affording
protection to MPTP [107], including via the inhibition of T-
helper (Th)17 induced damage [108]. α7nAChr stimulation
in murine RegT cells potentiates their immuno-suppressive
capacity [109], highlighting nicotine protection via immune
regulation [88]. Potentiating RegT cell immuno-suppression
decreases the damage arising from elevated CD4+ and CD8+
T cells in PD. The α7nAChr also directly dampens
proinflammatory production [110], including in T-cells [111]
and macrophages [112].
Anderson and Maes
The α7nAChr stimulation of RegTcells immuno-
suppression also has consequences for how peripheral
inflammation modulates PD. In the colon, cytokine induced
alterations in the α7nAChr in CD4+ Tcells mediate the
dichotomous response to nicotine in Th1/Th17 versus Th2
driven colitis [113]. IL-4 increases, whereas IL-12 decreases,
α7nAChr levels. As a consequence, in inflammatory bowel
disorders, nicotine ameliorates ulcerative colitis, increasing
RegTcells, but worsens Chrohn’s disease, increasing Th17
cells. As to whether these cytokines have opposing effects on
the α7nAChr in other cells relevant to PD, including
astrocytes and mast cells requires investigation. Overall, as
well as regulating leukocyte extravasation, nicotine will
modulate the peripheral driven immuno-inflammatory
responses that interact with the course of PD.
Autoimmunity
Recent conceptualizations of many disorders, including
depression have emphasized a role for O&NS induced
damage in the induction of autoimmune responses, including
to serotonin [114]. Autoimmunity is relevant in PD [115].
Increased autoantibodies are evident in PD, being
particularly associated with dyskinesia and depression [116].
Neuromelanin is highly expressed in dopamine neurons,
contributing to α-synuclein induced neurotoxicity [117].
High levels of anti-melanin antibodies are evident in PD,
being recognised by dendritic cells [118] and contributing to
autoimmunity [115]. Increased O&NS contributes to the L-
DOPA induction of neuromelanin [119], suggesting a role
for O&NS in interaction with L-DOPA in the induction of
autoimmunity. Both neuromelanin and α-synuclein are
increased in SN dopamine neurons over normal ageing
[120], highlighting how ageing associates with PD
autoimmune responses. α-synuclein increases neuromelanin
[121], increasing microglia activation by neuromelanin
[122]. Loss of olfaction occurs early in PD, driven by
autoimmunity [123].
In attenuating central inflammation, nicotine decreases
autoimmunity [124]. Melatonin decreases α-synuclein and
oxidants, suggesting protection against autoimmunity in PD.
Autoimmunity may also have protective effects, as
evidenced by increased IgG against α-synuclein [125].
CAFFEINE/ADENOSINE
Caffeine consumption decreases PD risk [76], and is
protective against MPTP, where, like nicotine it decreasing
BBBp [40, 126]. Caffeine decreases melatonin metabolism
by cytochrome P450 (CYP)1A2 [127]. As such, caffeine
efficacy in PD [128] may be partly mediated by melatonin,
in turn increasing the α7nAChr [129], potentiating nicotine
effects. Nicotine and caffeine protection in carriers of PD
SNP gene susceptibilities [130] may therefore be partly
regulated by melatonin.
However, caffeine efficacy is also via adenosine A1r and
A2Ar inhibition, supported by the protection afforded by
istradefylline, an A2Ar antagonist, when used as an
adjunctive to L-DOPA [131]. As well as the role of
adenosine in the striatum in the course of PD, cortex ecto-5-
nucleotidase (Ecto-5N) increases over ageing, elevating
adenosine, which normally contribute to night-time
TRYCAT Pathways Link Peripheral Inflammation
tiredness. cAMP increases astrocyte Ecto-5N and adenosine
[132]. As indicated above, the cAMP pathway also regulates
the AHr, circadian genes and TH, as well as tryptophan
catabolism. As such cAMP may have a role in co-ordinating
PD processes.
PARKINSON’S AND TRYCATs
TRYCATs
Tryptophan is the precursor necessary for serotonin and
melatonin synthesis. Over 95% of tryptophan is taken down
the kynurenine pathway, leading to various neuromodulatory
TRYCATs, including kyn, KYNA and quinolinic acid
(QUIN). TRYCAT production is driven by indoleamine 2,3-
dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO).
IDO is predominantly induced by IFN-γ, although other
proinflammatory cytokines, including IL-1β, TNF-α and IL-
18 also contribute [133]. TDO is increased by cortisol [134]
and perhaps cAMP, as indicated by cAMP induction of
astrocyte KYNA [81]. IDO activation produces all
TRYCATs, whereas astrocyte TDO is limited to kyn and
KYNA production. Kynurenine aminotransferase (KAT)
catalyzes KYNA from kyn. In the CNS, TDO is
predominantly expressed in astrocytes and some neurons,
whereas IDO is expressed in microglia and infiltrating
leukocytes.
TRYCATs and Parkinson’s
Elevated peripheral and central inflammation in PD
increases IDO, driving down serotonin and melatonin and
contributing to depression and circadian dysregulation. We
recently showed that increased peripheral kyn/KYNA ratio is
specifically associated with somatization, across a number of
disorders, including depression and myalgic
encephalomyelitis [135, 136]. Somatization and depression
levels are high in PD, including in the earliest stages [9], and
can predate PD motor symptoms, sometimes by decades.
This indicates altered TRYCAT levels and patterning. Over
60% of CNS kyn is peripherally derived, being readily
transported over the BBB. In the CNS, kyn is catalyzed by
astrocyte and neuronal TDO and KAT into KYNA. KYNA,
at physiological levels, is an antagonist of the α7nAChr and
will therefore inhibit the protection afforded by nicotine at
the α7nAChr, including in: immuno-inflammatory responses
by astrocytes and mast cells, cytokine induced BBBp [137]
and leukocyte extravasation and activation, as well as direct
immune cell regulation. Increased KYNA will inhibit these
manifold nicotine protections in PD, contributing to wider
presentations. As such peripheral inflammation, and
associated somatization and depression may not simply be
incidental comorbidities of PD, but may be intimately
involved in its etiology and course.
Following 6-OHDA there is a relative loss of KAT-I in
surviving dopamine neurons, although increased KAT-I in
astrocytes and microglia [138]. However, the resultant
increase in glia KYNA is insufficient to inhibit the N-methyl
d-aspartate receptor (NMDAr), but rather will inhibit the
α7nAChr, potentially increasing BBBp and neuronal
toxicity. Pre-treatment with high dose L-kynurenine
attenuates 6-OHDA and MPTP induced toxicity [139,140],
being mediated by conversion to KYNA, with resultant
CNS & Neurological Disorders - Drug Targets, 2014, Vol. 13, No. 1 141
NMDAr inhibition. These effects highlight the role of the
NMDAr in driving toxicity in these models. However,
KYNA inhibition of the NMDAr is unlikely to be achieved
by physiological variations in kyn. Given elevated peripheral
inflammation and somatization in PD, it is of note that KAT-
1 is decreased in PD red blood cells, coupled to decreased
plasma KYNA [141]. Peripheral KYNA is antinociceptive
via G-protein coupled receptor (GPR)-35 activation [142].
As to whether decreased peripheral KYNA reflects an
increase in the kyn/KYNA ratio, with links to peripheral
inflammation and somatization, as suggested by increased
neopterin and kyn/tryptophan ratio in PD [143], requires
investigation. Pharmacologically increasing KYNA lessens
L-DOPA induced dyskinesias in monkeys [144], suggesting
central benefits from KYNA analogs that cross the BBB,
unlike peripheral KYNA. However, such benefits are via
NMDAr inhibition, and may require adjunctive,
compensatory nicotine or an α7nAChr agonist.
Peripheral kyn can also be converted to other TRYCATs,
including QUIN, 3-hydroxykyurenine (3-HK), 3-
hydroxyanthranillic acid (3-HA) and picolinic acid (PA). At
the NMDAr, QUIN is excitotoxic and PA excitatory. Both 3-
HK and 3-HA decrease mitochondrial complexes I and II,
with 3-HK additionally inhibiting complex IV [145]. This
suggests that peripheral inflammation and somatization
induced kyn contributes to wider neuronal susceptibility in
PD, via mitochondrial inhibition by 3-HA and 3-HK.
Melatonin increases mitochondrial complexes I, II and IV,
and would be expected to inhibit such 3-HK and 3-HA
mitochondrial toxicity [146].
TRYCATs: Neurogenesis and LTP
Astrocyte and mast cell IL-1β induction modulates
BBBp, as well as inhibiting neurogenesis. IL-1β effects are
via IDO and downstream TRYCAT products, including kyn
and kynurenine 3-monooxygenase (KMO) [147]. KMO
inactivation prevents IL-1β inhibition of neurogenesis,
suggesting a powerful role for IDO and the TRYCAT
pathway in driving inflammation induced decreased
neurogenesis. TDO and IDO activation decreases mast cell
serotonin production, also important to dentate gyrus
neurogenesis, as well as learning and mood [148]. Such data
emphasizes the importance of the TRYCATs in mediating
depression/somatization associations with degenerative and
regenerative processes in PD. TDO activation decreases
neurogenesis, whilst increasing anxiety [149].
Nicotine, via the α7nAChr, increases early and late LTP
[91], suggesting that peripheral derived kyn and central
KYNA conversion contributes to PD cognitive deficits, as
evidenced in schizophrenia models [150]. As such nicotine’s
wider cognitive and neuroregenerative benefits [90] will be
inhibited by peripheral inflammation induced kyn.
Variability in nicotine benefit in PD studies may therefore be
a confound derived from somatization and peripheral
inflammation induced TRYCATs.
TRYCATs and Wider Immuno-Inflammation
Wider immune changes are evident in PD, linking to
increased inflammation. Increased natural killer (NK) cells
[151], IL-1β, and decreased IL-1RA occur in PD, correlating
142 CNS & Neurological Disorders - Drug Targets, 2014, Vol. 13, No. 1
with levels of fatigue and depression [152]. NK cells in PD
express decreased inhibitory NKG2A receptor levels,
indicative of priming for activation [153]. Regulated on
activation normal T-cell expressed and secreted (RANTES)
is also increased in the PD serum, suggesting increased
monocytes, macrophages and Tcells chemoattraction [154].
Increased gamma delta (γδ) Tcells occur in PD blood and
CSF [155]. In vitro, γδTcells and NK cells can be neurotoxic
via astrocytes [156]. Such inflammatory processes increase
cytokine production, in turn inducing IDO, kyn and KYNA,
with KYNA inhibiting the α7nAChr benefits in many cell
types and processes.
The α7nAChr is a treatment target for many
inflammatory conditions, including ulcerative colitis [157],
suggesting KYNA regulation of nicotine modulation of
peripheral inflammatory effects in PD. As such the absolute,
as well as local, levels of KYNA would be relevant. The
inability of peripheral inflammation to potentiate SN atrophy
in PD models, when monocytes are depleted [59], highlights
the importance of increased BBBp and infiltrating
leukocytes. An increase in infiltrating Tcells in the SN is
evident in PD patients [158].
TRYCATs and AHr
Given that different AHr ligands, including kyn, KYNA
and cAMP, can have differential effects on AHr induced
transcriptions, including reactive oxygen species (ROS) but
also NF-E2-related factor 2 (Nrf-2) induced endogenous
antioxidants, it will be important to determine how different
endogenous and exogenous ligands modulate TH levels, and
how cAMP and circadian genes interact with this. A role for
the AHr suggests that cigarette smoke, which contains high
levels of TCDD, may have impacts on PD processes, as well
as the known effects of nicotine. The interactions of the AHr,
cAMP and circadian genes can be relevant to the course of
peripheral inflammation, including in gastro-intestinal
disorders [80]. Given the role of such peripheral
inflammatory disorders in PD, and their possible etiological
importance, the regulation of the AHr, peripherally and
centrally, requires investigation. Developmental exposure to
AHr ligands can impact on TH levels and dopamine
production [159], and may mediate early
developmental/epigenetic driven changes relevant to PD
etiology. As such TRYCAT variations may interact with the
AHr, circadian genes and cAMP in the regulation of central
dopamine and NE, as well as in peripheral and early
developmental PD factors.
Interestingly the activation of the AHr can increase IDO,
leading to TRYCAT induction [160]. This suggests that kyn
[161] or KYNA activation of the AHr could induce a
positive feedback loop via the induction of IDO. Given the
important role of TRYCATs in PD, neuronal regulation,
excitotoxicity and BBBp, it will be important to determine if
this occurs and what are the feedback paths that inhibit this
kyn/KYNA-AHr loop. It may be that the prolonged
activation of cAMP paths leading to PDEs is relevant to the
inhibition of such a putative positive feedback loop. PDE2
can bind to one of the cytosolic factors that associate with
the AHr, the hepatitis B virus X-activating protein 2 (XAP2),
preventing AHr nuclear translocation and transcription
inductions. In modulating cAMP regulation of the AHr,
Anderson and Maes
PDE2 inhibitors may change the AHr activation and gene
inductions by other AHr ligands. Given the role of the AHr
in regulation of TH, dopamine and NE, this will be important
to clarify. PDE inhibitors are an area of active investigation
in the treatment of neurodegenerative disorders, including
PD [162].
TRYCATs and Stress
PD is a stressful condition, with unexpected symptoms
and comorbidities/wider presentations often emerging.
Within the animal literature chronic unpredictable mild
stress (CUMS) is known to increase depression, with effects
being mediated by increased peripheral kyn, driving raised
levels of excitotoxic QUIN in the amygdala and striatum
coupled to a trend increase in cortex KYNA [163,164].
Excitatory activity in the amygdala, coupled to KYNA
inhibition of cortex acetylcholine, dopamine and glutamate
suggests increased affective processing at the expense of
higher order cognition [165]. Stressful life events are major
susceptibility factors for the emergence of depression,
including in PD [166]. As such stress, as with peripheral
inflammation, mediates its effects in the CNS, at least in
part, via conversion by glia into neuronal regulating
TRYCATs.
Alexithymia
Other PD comorbidities may be similarly related. Up to
20% of people with PD show symptoms of alexithymia, with
altered emotional recognition and expression leading to
deficits in empathy and the emotional aspects of social
interactions [167]. In PD patients, alexithymia is associated
with cognitive deficits [168], linked to decreased cortex
α7nAChr level and activity [165]. Alexithymia also
associates with increased impulsivity [169], although not
correlating with measures of depression in PD [170].
However, alexithymia is classically associated with
somatization [171], and it requires investigation as to
whether alexithymia in PD associates with increased
peripheral kyn/KYNA ratio.
TRYCATs and Melatonin
Melatonin affords protection in the MPTP and 6-OHDA
models [172, 173]. The driving down of melatonin levels,
including pineal but also local glia/leukocyte melatonin in
the SN [18], by enhanced IDO and TDO activation in PD,
means not only the loss of melatonin’s potentiation of
α7nAChr levels and effects. Melatonin is an anti-oxidant,
anti-inflammatory, anti-nociceptive and increases
mitochondrial oxidative phosphorylation [146]. Melatonin
also increases activity induced dentate gyrus neurogenesis
and new cell survival [174]. Melatonin receptors are
decreased in the SN in PD, suggesting a loss of local
melatonin effects, given that melatonin increases its own
receptors. Decreased melatonin will contribute to the sleep
disturbance and circadian dysregulation common in PD [18].
Melatonin receptors are negatively coupled to adenylyl
cyclase, leading to cAMP inhibition. As such melatonin may
inhibit any cAMP induction of TDO/KYNA, as well as
regulating AHr activation and circadian gene inductions. As
such, variations in melatonin can be intimately associated
TRYCAT Pathways Link Peripheral Inflammation
with TRYCAT regulation and will impact on many aspects
of PD and its associated presentations.
The regulation of astrocyte melatonin production,
including by available serotonin and MAOA/B, will be
important to determine in PD.
TREATMENT IMPLICATIONS
Melatonin
Melatonin’s inhibition of oxidative stress, inflammation,
α-synuclein and nociception, coupled to its increase in
mitochondrial oxidative phosphorylation, neurogenesis and
new cell survival, as well as its induction of the α7nAChr
[129], all suggest benefits in PD. Melatonin would decrease
the high levels (88%) of nocturnal non-dipping hypertension
in PD [15]. Melatonin also decreases ageing associated
decrements in neurogenesis [175]. Melatonin decreases
nigrostriatal neurodegeneration, behavioural motor deficits
and mitochondrial dysfunction, as well as maintaining TH
and dopamine transporter levels [172]. In comparison to L-
DOPA, melatonin treatment can improve performance on
motor tasks, with no dyskinesias evident [176]. Importantly
melatonin decreases α-synuclein induced neurotoxicity,
whilst inhibiting α-synuclein protofibril formation,
oligomerization, and secondary structure transitions [177],
including SN α-synuclein induced by amphetamine [178].
Sleep dysregulation is common in PD and in animal
models contributes to the disease process [179]. Melatonin, a
key circadian entrainer, improves sleep regulation [18].
Melatonin has anti-depressant effects, including potentiation
buspirone efficacy [180]. N-acetylserotonin, the immediate
precursor of melatonin, has similar beneficial effects,
including via the activation of tyrosine kinase receptor-beta,
the brain-derived neurotrophic factor receptor [181].
Melatonin’s protection in ulcerative colitis, preventing the
CRP rise and subsequent BBBp [67], highlights how the
prevention of inflammatory processes in peripheral disorders
will modulate the etiology and course of PD.
Nicotine and Melatonin Combined
Nicotine affords some benefits in PD, including on motor
symptoms in some studies. The lack of clarity as to how it is
best administered (patches, gum, intermittent versus chronic
etc) seems somewhat amiss, and requires clarification. Also
it will be important to determine the most beneficial dose of
melatonin for the induction of the α7nAChr in PD [129],
especially in astrocytes and mast cells, and therefore on
BBBp. Melatonin modulates the LPS regulation of the
α7nAChr mRNA in astrocytes [182]. As to whether a
combination of melatonin and nicotine/α7nAChr agonist
would prevent or delay the development of PD, is hard to
test, given the lack of an early biomarker. However, it is
likely that such a combination would, at the very least, have
immediate benefit in offsetting L-DOPA induced dyskinesias
[183].
However, not all studies using PD models have found
benefits of melatonin [184,185], raising questions as to
whether variations in experimental protocol, including
detrimental effects of very high levels of melatonin, mediate
such lack of protection. Intermittent nicotinic receptor
CNS & Neurological Disorders - Drug Targets, 2014, Vol. 13, No. 1 143
activation increases subventricular zone neurogenesis via the
induction of fibroblast growth factor-2 [186], whereas
chronic nicotine decreases new neuron survival in the
dentate gyrus [187]. As to whether differential regulation of
neurogenesis or the lack of optimized temporal activation of
the α7nAChr is relevant to some of the mixed results
regarding melatonin efficacy in PD models requires
investigation.
Caffeine
Caffeine decreases the risk of PD [76] and also decreases
melatonin metabolism by CYP1A2 [127]. As such, some of
the efficacy of caffeine in the treatment of PD [128] may be
mediated by its influence on melatonin and nictotine at the
α7nAChr [129]. Caffeine, like nicotine at the α7nAChr,
decreases BBBp [126]. The effects of caffeine in PD may
then be linked to alterations in the TRYCATs, as well as via
adenosine receptors.
Vitamin D
Hypovitaminosis D associates with neurodegeneration,
including PD [188], leading to vitamin D being proposed as
an adjunctive treatment for PD [189]. Vitamin D is also a
significant regulator of neurogenesis, both in the dentate
gyrus and subventricular zone, generally decreasing
proliferation but increasing the neuron/astrocyte ratio [190,
191]. Vitamin D is also a significant immune regulator, and
therefore a decrease in vitamin D is likely to contribute to
the role of peripheral and central immuno-inflammation in
PD. As to how vitamin D interacts with TRYCATs requires
investigation.
Anti-Inflammatories
Chronic use of NSAIDs associates with decreased PD
incidence [26], suggesting a significant role for inflammation
in the etiology of PD. However, later data shows that the
protection afforded by NSAIDs is mediated primarily by
ibuprofen [192], supported by a meta-analysis of all NSAID
studies [193]. Meloxicam, an oxicam NSAID, affords
protection in the MPTP model, increasing TH levels and
prosurvival pathway activation, independent of COX
inhibition [194]. The NSAIDs, tolmetin and sulindac,
decrease levels of hepatic TDO, suggesting an impact on
peripheral TRYCATs [195]. Although increasing
hippocampal serotonin, these NSAIDs also decrease striatal
dopamine levels; with potential adverse effects in PD.
NSAID use may also inhibit antidepressant response [196].
No evidence suggests a benefit from aspirin.
Some of these studies are confounded by increased
NSAID use in the years immediate to a PD diagnosis [197],
where increased peripheral inflammation may be intimately
associated with PD. Such data therefore confounds
preventative effects with impacts on the early course of
degenerative processes, and possibly with indirect, non-
identifiable early course PD symptoms. As a consequence an
increase in PD incidence has been associated with NSAID
use in some studies [197]. Gastric dysregulation is
heightened in depression, with NSAIDs exacerbating gastric
disorders, including acid secretion and ulcer formation [198].
Given the putative role of gastro-intestinal disorders in PD,
144 CNS & Neurological Disorders - Drug Targets, 2014, Vol. 13, No. 1 Anderson and Maes

this could be another route for NSAID interactions with PD IFN-γ = Interferon-gamma
etiology and course.
IL = Interleukin
COX-2 inhibitors may also increase neuroinflammation,
KAT = Kynurenine aminotransferase
Th1 responses and lipid peroxidation, as well as decreasing
antioxidants and damaging mitochondria [199]. COX-2 Kyn = Kynurenine
inhibitors may therefore negatively modulate the course of KYNA = Kynurenic acid
PD and depression. Importantly for PD, COX-2 inhibitors
may potentiate bacterial translocation via enhanced Th1 LPS = Lipopolysaccharide
effects. Overall, the conceptualization of PD in the context LTP = Long term potentiation
of wider immuno-inflammatory processes, does not lead
simply to treatment with classical anti-inflammatories. MAO = Monoamine oxidase
MPTP = 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
PDE Inhibitors NE = Norepinephrine
PDE inhibitors are being extensively investigated for NK = Natural killer cells
their efficacy in the treatment of a range of
neurodegenerative disorders, including PD [162], affording NMDAr = N-methyl d-aspartate receptor
protection in the MPTP model [200] and on BBBp [201]. NSAID = Non-steroidal anti-inflammatory drug
PDE4 inhibitors will also increase night-time melatonin
levels [202]. PDE2A inhibitors are under extensive research O&NS = Oxidative and nitrosative stress
in the treatment of inflammatory processes [203], which as PD = Parkinson’s disease
indicated above would have significance in PD and therefore
PDE = Phosphodiesterase inhibitor
in peripherally derived TRYCATs, as well as on AHr
regulation. QUIN = Quinolinic acid
How the various treatments highlighted would interact RegT = Regulatory T cells
with TRYCATs and biological processes in PD will be
SN = Substantia nigra
important to determine. A number of future research
directions are suggested by including TRYCATs in the SNP = Single nucleotide polymorphism
etiology and course of PD. Perhaps the most fruitful to TCDD = 2,3,7,8-tetrachlorodibenzo-p-dioxin
clarify will be the role of local melatonin production by SN
glia. TDO = Tryptophan 2,3-dioxygenase
Th = T-helper
CONCLUSIONS
TH = Tyrosine hydroxylase
The role of altered TRYCATs in PD in driving the TNF-α = Tumor necrosis factor-alpha
effects of inflammation, stress/CUMS and somatization has
implications for the conceptualization and treatment of PD. TRYCAT = Tryptophan catabolites
Peripheral inflammation and somatization may not be simple
comorbidities, but rather an intimate part of the processes CONFLICT OF INTEREST
driving the etiology and course of PD. A combination of
melatonin, nicotine/α7nAChr agonist, vitamin D and Neither author has any conflicts of interest to declare.
caffeine are likely to have interactive benefits at different
sites and cells, both peripherally and centrally. ACKNOWLEDGEMENTS
Declared none.
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