Carbidopa, a drug in use for management of Parkinson disease inhibits T cell activation and autoimmunity

PLOS ONE, Nov 2019

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 (MOG-35-55) 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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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. - 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)


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Huabin Zhu, Henrique Lemos, Brinda Bhatt, Bianca N. Islam, Abhijit Singh, Ashish Gurav, Lei Huang, Darren D. Browning, Andrew Mellor, Sadanand Fulzele, Nagendra Singh. Carbidopa, a drug in use for management of Parkinson disease inhibits T cell activation and autoimmunity, PLOS ONE, 2017, Volume 12, Issue 9, DOI: 10.1371/journal.pone.0183484