Carbidopa, a drug in use for management of Parkinson disease inhibits T cell activation and autoimmunity
September
Carbidopa, a drug in use for management of Parkinson disease inhibits T cell activation and autoimmunity
Huabin Zhu 0 1
Henrique Lemos 1
Brinda Bhatt 0 1
Bianca N. Islam 0 1
Abhijit Singh 1
Ashish Gurav 1
Lei Huang 1
Darren D. Browning 0 1
Andrew Mellor 1
Sadanand Fulzele 1
Nagendra Singh 0 1
0 Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University , Augusta , Georgia , United States of America, 2 Institute of Cellular Medicine, Newcastle University , Newcastle-upon-Tyne , United Kingdom , 3 Department of Emergency Medicine, Medical College of Georgia, Augusta University , Augusta , Georgia , United States of America, 4 University of Pennsylvania School of Dental Medicine , Philadelphia, PA , United States of America, 5 Department of Orthopedics Surgery, Medical College of Georgia, Augusta University , Augusta, Georgia , United States of America
1 Editor: Hossam M. Ashour, Wayne State University , UNITED STATES
Carbidopa is a drug that blocks conversion of levodopa to dopamine outside of central nervous system (CNS) and thus inhibits unwanted side effects of levodopa on organs located outside of CNS during management of Parkinson's Disease (PD). PD is associated with increased expression of inflammatory genes in peripheral and central nervous system (CNS), infiltration of immune cells into brain, and increased numbers of activated/memory T cells. Animal models of PD have shown a critical role of T cells in inducing pathology in CNS. However, the effect of carbidopa on T cell responses in vivo is unknown. In this report, we show that carbidopa strongly inhibited T cell activation in vitro and in vivo. Accordingly, carbidopa mitigated myelin oligodendrocyte glycoprotein peptide fragment 35±55 (MOG35-55) induced experimental autoimmune encephalitis (EAE) and collagen induced arthritis in animal models. The data presented here suggest that in addition to blocking peripheral conversion of levodopa, carbidopa may inhibit T cell responses in PD individuals and implicate a potential therapeutic use of carbidopa in suppression of T cell mediated pathologies.
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Data Availability Statement: All relevant data are
within the paper and its Supporting Information
files.
Funding: This research was supported by National
Institutes of Health grant R01DK103576 to NS.
Competing interests: The authors have declared
that no competing interests exist.
Introduction
Parkinson's disease (PD) is characterized by a loss of dopaminergic neurons in substantia
nigra in the brain, resulting in decreased production of the neurotransmitter and messenger
dopamine. Loss of dopamine is the central to the development of PD [1±4]. Levodopa, the
dopamine precursor, is converted into dopamine by L-dopa decarboxylase (DDC). This leads
to increased production of dopamine. Therefore, levodopa is very effective in the management
of Parkinson's disease [3±6]. DDC is expressed by neurons in the central nervous system, liver,
kidney, pancreas, and T lymphocytes [7±9]. Consumption of levodopa results in systemic
production of dopamine, which limits production of dopamine in the central nervous system.
In addition, activation of peripheral dopamine receptors results in nausea and vomiting. Car
bidopa is an inhibitor of DDC and does not cross the blood-brain barrier, thus preferentially
inhibiting the conversion of levodopa to dopamine outside of the brain. However, the effects
of carbidopa on peripheral cells, specifically T lymphocytes, have not been studied in detail.
Under steady state conditions DDC catalyzes two reactions: 1) metabolism of tyrosine by
DDC is a key step in production of catecholamines; dopamine, epinephrine and
norepinephrine, and 2) DDC also catalyzes conversion of 5-hydroxytryptophan to serotonin. T
lymphocytes express DDC mRNA and functional enzyme and produce both dopamine and serotonin
[10±13]. Naïve T cells express type 7 5-hydroxytryptamine receptor (5-HT7R), whereas
activated T cells express 5-HT7R, 5-HT1BR and 5-HT2AR, which upon activation by serotonin
transduces signal to T cells [
11
]. Serotonin enhances the activation of T cells [
11
]. T cell express
both D1 and D2 class of dopamine receptors [
14
]. Acting through D1 receptors, dopamine
inhibits production of IL-10 and TGF-û1 by T regulatory cells (Treg cells) leading to enhanced
proliferation of conventional T cells [
15
]. It also induces differentiation of naïve T cells into
Th2 lineage [16]. Treatment of naïve T cells with dopamine results in increased adhesion to
fibronectin, production of TNF-α, and IL-10 [
17
]. On the other hand both dopamine and
L-dihydroxyphenylalanine (L-dopa), a precursor for dopamine, block mitogen driven prolifer
ation of T cells in vitro in a dose dependent manner [
10
]. High concentration of dopamine
inhibits anti-CD3 and IL-3 induced proliferation of human T cells in vitro [
18, 19
]. These
in vitro studies demonstrate that DDC activation may either promot (...truncated)