PARKINSON’S IMMUNITY AND INFLAMMATION: NEW ASPECTS

Letter to the Editor

G. Neri *

Department of Neuroscience, Imaging and Clinical Sciences, University G. d’Annunzio Chieti-Pescara, Chieti, Italy.

*Correspondence to:
Giampiero Neri, MD,
Department of Neuroscience, Imaging and Clinical Sciences,
University G. d’Annunzio Chieti-Pescara,
Chieti, Italy.
e-mail: giampiero.neri@unich.it

Received: 22 April, 2019 Accepted: 19 May, 2019

2279-5855 (2019) Copyright © by BIOLIFE This publication and/or article is for individual use only and may not be further reproduced without written permission from the copyright holder. Unauthorized reproduction may result in financial and other penalties Disclosure: all authors report no conflicts of interest relevant to this article.

KEYWORDS: Parkinson disease, immunity, inflammation

INTRODUCTION

Parkinson disease (PD) is a multisystem disorder which affects dopaminergic neurotransmission that is characterized by movement disorder with motor impairment, tremors, stiffness of the neck, trunk, and limbs, bradykinesia, postural instability, depression, anxiety, apathy, and soft voice. In PD, which typically develops around the age of 60 with an incidence of approximately 1.5% (1), there is neuroinflammation and a malfunction of the immune system that can lead to gastrointestinal dysfunction and sleep alterations (2,3). Individuals with PD present with a neurodegenerative syndrome involving both thalamocortical and non-motor motor circuits.

DISCUSSION

PD is one of the most frequent neurodegenerative diseases (4) and presents a degeneration of neurons in the substantia nigra causing motor dysfunction (5). The disease presents neuronal loss with the presence of proteins such as Lewy bodies (absent in mouse), but this mechanism still needs to be elucidated. The cause of these phenomena has often been attributed to oxidative stress, cytotoxicity, mitochondrial dysfunction, apoptosis, and low-grade inflammation (6-9). Inflammation is due to microglial activation, astrogliosis, and lymphocyte infiltration, contributing to neurodegeneration. Neurodegeneration could stimulate inflammatory proteins, causing brain dysfunction (10). Laboratory blood tests show that some cytokines such as IL-2, tumor necrosis factor (TNF), and IL-6 (11), as well as the chemokine RANTES (12), are increased in the serum of patients with PD. These highly inflammatory immune molecules could contribute to neurodegeneration. Autoantibodies against dopaminergic neurons may also be responsible or participate in this inflammatory process. Activated CD4+ and CD45RO+ T lymphocytes are involved in this immunopathological reaction, while naive CD45RA+ non-activated T lymphocytes are decreased. CD25 Treg lymphocytes are also increased in PD patients, demonstrating an immune reaction of the organism against the pathological phenomena. However, these results are still unclear and need to be confirmed.

The brain is an organ that has its own immune system in which cytokines can mediate both physiological and pathological phenomena. Pro-inflammatory cytokines such as IL-1, TNF, and IL-6, which can be generated by microglia and are important inflammatory markers, are also found in the cerebrospinal fluid of these patients (13). Microglia, which are sentinels of the central nervous system (CNS), exert a protective effect on the brain by maintaining homeostasis. These blood monocyte-like cells generate neurotrophic factors such as nerve growth factor (NGF) and fibroblast growth factor (FGF) (14). The activation of microglia by external insults leads to the production of pro-inflammatory cytokines, an effect that has also been confirmed in rodents (15). Inflammatory cytokines play a key role in the pathogenesis of neurodegenerative diseases (16,17). The cerebrospinal fluid of PD patients shows high levels of cytokines IL-1, IL-6, TNF, TGF-β1, VEGF, and the inflammatory chemokines MCP-1 and MIP-1α, highlighting that this disease also has inflammatory origins and that these cytokines/chemokines could be used as a target of this neurodegenerative pathology (18,11) (Table I).

Table I. Some factors that mediate neuroinflammation.

CONCLUSIONS

PD can be relieved by treating the affected patient with the dopamine precursor levodopa or with dopaminergic inhibitors (19). Therapeutic treatment with levodopa proves to be effective in the long term with neurological improvement and quality of life. Patients with PD can also be treated with the surgical technique of brain stimulation which consists of a pulse generator that sends electrical stimuli to the brain.

However, studies underway in our laboratory as well as others aim to clarify the etiological and pathogenetic mechanisms, and the specific action of cytokines in PD, allowing for better therapeutic treatment for this neurodegenerative disease which ranks, by incidence, in second place in the world after Alzheimer’s among brain disorders.

Conflict of interest

The author declares that they have no conflict of interest.

REFERENCES

1. Rizek P, Kumar N, Jog MS. An update on the diagnosis and treatment of Parkinson disease. Canadian Medical Association Journal. 2016;188(16):1157-1165. doi:https://doi.org/10.1503/cmaj.151179
2. Lindqvist D, Kaufman E, Brundin L, Hall S, Surova Y, Hansson O. Non-Motor Symptoms in Patients with Parkinson’s Disease – Correlations with Inflammatory Cytokines in Serum. Duda J, ed. PLoS ONE. 2012;7(10):e47387. doi:https://doi.org/10.1371/journal.pone.0047387
3. Savica R, Carlin JM, Grossardt BR, et al. Medical records documentation of constipation preceding Parkinson disease: A case-control study. Neurology. 2009;73(21):1752-1758. doi:https://doi.org/10.1212/wnl.0b013e3181c34af5
4. Kalia LV, Lang AE. Parkinson’s disease. The Lancet. 2015;386(9996):896-912. doi:https://doi.org/10.1016/s0140-6736(14)61393-3
5. Surmeier DJ. Determinants of dopaminergic neuron loss in Parkinson’s disease. The FEBS Journal. 2018;285(19):3657-3668. doi:https://doi.org/10.1111/febs.14607
6. Olanow CW. The pathogenesis of cell death in Parkinson’s disease – 2007. Movement Disorders. 2007;22(S17):S335-S342. doi:https://doi.org/10.1002/mds.21675
7. Mattson MP. Apoptosis in neurodegenerative disorders. Nature Reviews Molecular Cell Biology. 2000;1(2):120-130. doi:https://doi.org/10.1038/35040009
8. Abou-Sleiman PM, Muqit MMK, Wood NW. Expanding insights of mitochondrial dysfunction in Parkinson’s disease. Nature Reviews Neuroscience. 2006;7(3):207-219. doi:https://doi.org/10.1038/nrn1868
9. Tansey MG, McCoy MK, Frank-Cannon TC. Neuroinflammatory mechanisms in Parkinson’s disease: Potential environmental triggers, pathways, and targets for early therapeutic intervention. Experimental Neurology. 2007;208(1):1-25. doi:https://doi.org/10.1016/j.expneurol.2007.07.004
10. Phani S, Loike JD, Przedborski S. Neurodegeneration and Inflammation in Parkinson’s disease. Parkinsonism & Related Disorders. 2012;18:S207-S209. doi:https://doi.org/10.1016/s1353-8020(11)70064-5
11. Reale M, Greig NH, Kamal MA. Peripheral chemo-cytokine profiles in Alzheimer’s and Parkinson’s diseases. Mini reviews in medicinal chemistry. 2009;9(10):1229-1241. doi:https://doi.org/10.2174/138955709789055199
12. Rentzos M, Nikolaou C, Andreadou E, et al. Circulating interleukin-15 and RANTES chemokine in Parkinson’s disease. Acta Neurologica Scandinavica. 2007;116(6):374-379. doi:https://doi.org/10.1111/j.1600-0404.2007.00894.x
13. Starhof C, Winge K, Heegaard NHH, Skogstrand K, Friis S, Hejl A. Cerebrospinal fluid pro-inflammatory cytokines differentiate parkinsonian syndromes. Journal of Neuroinflammation. 2018;15(1). doi:https://doi.org/10.1186/s12974-018-1339-6
14. Elkabes S, DiCicco-Bloom E, Black I. Brain microglia/macrophages express neurotrophins that selectively regulate microglial proliferation and function. The Journal of Neuroscience. 1996;16(8):2508-2521. doi:https://doi.org/10.1523/jneurosci.16-08-02508.1996
15. Lam D, Lively S, Schlichter LC. Responses of rat and mouse primary microglia to pro- and anti-inflammatory stimuli: molecular profiles, K+ channels and migration. Journal of Neuroinflammation. 2017;14(1). doi:https://doi.org/10.1186/s12974-017-0941-3
16. Azizi G, Navabi SS, Al-Shukaili A, Seyedzadeh MH, Yazdani R, Mirshafiey A. The Role of Inflammatory Mediators in the Pathogenesis of Alzheimer’s Disease. Sultan Qaboos University Medical Journal. 2015;15(3):e305-316. doi:https://doi.org/10.18295/squmj.2015.15.03.002
17. Chen WW, Zhang X, Huang WJ. Role of neuroinflammation in neurodegenerative diseases (Review). Molecular Medicine Reports. 2016;13(4):3391-3396. doi:https://doi.org/10.3892/mmr.2016.4948
18. Chen X, Hu Y, Cao Z, Liu Q, Cheng Y. Cerebrospinal Fluid Inflammatory Cytokine Aberrations in Alzheimer’s Disease, Parkinson’s Disease and Amyotrophic Lateral Sclerosis: A Systematic Review and Meta-Analysis. Frontiers in Immunology. 2018;9. doi:https://doi.org/10.3389/fimmu.2018.02122
19. Salat D, Tolosa E. Levodopa in the Treatment of Parkinson’s Disease: Current Status and New Developments. Journal of Parkinson’s Disease. 2013;3(3):255-269. doi:https://doi.org/10.3233/jpd-130186