Advertisement

The involvement of JAK/STAT signaling pathway in the treatment of Parkinson's disease

  • Naser-Aldin Lashgari
    Affiliations
    Faculty of Pharmacy, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
    Search for articles by this author
  • Nazanin Momeni Roudsari
    Affiliations
    Faculty of Pharmacy, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
    Search for articles by this author
  • Saeideh Momtaz
    Affiliations
    Medicinal Plants Research Center, Institute of Medicinal Plants, ACECR, Tehran, Iran

    Department of Toxicology and Pharmacology, School of Pharmacy, and Toxicology and Diseases Group, Pharmaceutical Sciences Research Center (PSRC), The Institute of Pharmaceutical Sciences (TIPS), Tehran University of Medical Sciences, Tehran, Iran

    Gastrointestinal Pharmacology Interest Group (GPIG), Universal Scientific Education and Research Network (USERN), Tehran, Iran
    Search for articles by this author
  • Thozhukat Sathyapalan
    Affiliations
    Academic Diabetes, Endocrinology and Metabolism, Hull York Medical School, University of Hull, Hull, United Kingdom
    Search for articles by this author
  • Amir Hossein Abdolghaffari
    Correspondence
    Correspondence to: A. H.Abdolghaffari, Faculty of Pharmacy, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
    Affiliations
    Faculty of Pharmacy, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran

    Medicinal Plants Research Center, Institute of Medicinal Plants, ACECR, Tehran, Iran

    Department of Toxicology and Pharmacology, School of Pharmacy, and Toxicology and Diseases Group, Pharmaceutical Sciences Research Center (PSRC), The Institute of Pharmaceutical Sciences (TIPS), Tehran University of Medical Sciences, Tehran, Iran

    Gastrointestinal Pharmacology Interest Group (GPIG), Universal Scientific Education and Research Network (USERN), Tehran, Iran
    Search for articles by this author
  • Amirhossein Sahebkar
    Correspondence
    Correspondence to: A. Sahebkar, Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran.
    Affiliations
    Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran

    Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran

    School of Medicine, The University of Western Australia, Perth, Australia

    School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
    Search for articles by this author

      Highlights

      • Parkinson's disease (PD) is a neurodegenerative disorder in which inflammation plays a key role.
      • Deregulation of the JAK/STAT signaling pathway is implicated in PD pathogenesis.
      • Several cytokines, chemokines, growth factors, and hormones stimulate the JAK/STAT pathway in PD.
      • JAK/STAT pathway represents a promising target for PD therapy.
      • A variety of synthetic or natural small-molecule JAK inhibitors with therapeutic effects have been identified.

      Abstract

      Parkinson's disease (PD) is a neurodegenerative disorder in which inflammation and oxidative stress play key etiopathological role. The pathology of PD brain is characterized by inclusions of aggregated α-synuclein (α-SYN) in the cytoplasmic region of neurons. Clinical evidence suggests that stimulation of pro-inflammatory cytokines leads to neuroinflammation in the affected brain regions. Upon neuroinflammation, the Janus Kinase/Signal Transducers and Activators of Transcription (JAK/STAT) signaling pathway, and other transcription factors such as nuclear factor κB (NF-κB), NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3), mammalian target of rapamycin (mTOR), and toll-like receptors (TLRs) are upregulated and induce the microglial activation, contributing to PD via dopaminergic neuron autophagy. Aberrant activation or phosphorylation of the components of JAK/STAT signaling pathway has been implicated in increased transcription of the inflammation-associated genes and many neurodegenerative disorders such as PD. Interferon gamma (IFN-γ), and interleukine (IL)-6 are two of the most potent activators of the JAK/STAT pathway, and it was shown to be elevated in PD. Stimulation of microglial cell with aggregated α-SYN results in production of nitric oxide (NO), tumor necrosis factor (TNF)-α, and IL-1β in PD. Dysregulation of the JAK/STAT in PD and its involvement in various inflammatory pathways make it a promising PD therapy approach. So far, a variety of synthetic or natural small-molecule JAK inhibitors (Jakinibs) have been found promising in managing a spectrum of ailments, many of which are in preclinical research or clinical trials. Herein, we provided a perspective on the function of the JAK/STAT signaling pathway in PD progression and gathered data that describe the rationale evidence on the potential application of Jakinibs to improve neuroinflammation in PD.

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Journal of Neuroimmunology
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Ai X.-Y.
        • Qin Y.
        • Liu H.-J.
        • Cui Z.-H.
        • Li M.
        • Yang J.-H.
        • et al.
        Apigenin inhibits colonic inflammation and tumorigenesis by suppressing STAT3-NF-κB signaling.
        Oncotarget. 2017; 8: 100216
        • Akita K.
        • Isoda K.
        • Okabayasi Y.
        • Shimada K.
        • Daida H.
        Lack of IκBNS accelerates atherosclerosis in LDL receptor-deficient mice via increased interleukin-6 production.
        Int. J. Cardiol. 2016; 211: 61-63
        • Alidadi M.
        • Jamialahmadi T.
        • Cicero A.F.G.
        • Bianconi V.
        • Pirro M.
        • Banach M.
        • et al.
        The potential role of plant-derived natural products in improving arterial stiffness: a review of dietary intervention studies.
        Trends Food Sci. Technol. 2020; 99: 426-440
        • Anup Kumar T.
        • Sunil Kumar K.
        • Piyush K.
        JAK-STAT pathway and JAK inhibitors: a primer for dermatologists.
        Iran. J. Dermatol. 2019; 22: 71-78
        • Armstrong M.J.
        • Okun M.S.
        Choosing a Parkinson disease treatment.
        Jama. 2020; 323 (1420-)
        • Balestrino R.
        • Schapira A.H.
        Parkinson disease.
        Eur. J. Neurol. 2020; 27: 27-42
        • Banerjee S.
        • Biehl A.
        • Gadina M.
        • Hasni S.
        • Schwartz D.M.
        JAK–STAT signaling as a target for inflammatory and autoimmune diseases: current and future prospects.
        Drugs. 2017; 77: 521-546
        • Boyle D.
        • Soma K.
        • Hodge J.
        • Kavanaugh A.
        • Mandel D.
        • Mease P.
        • et al.
        The JAK inhibitor tofacitinib suppresses synovial JAK1-STAT signalling in rheumatoid arthritis.
        Ann. Rheum. Dis. 2015; 74: 1311-1316
        • Brierley S.M.
        • Kelber O.
        Use of natural products in gastrointestinal therapies.
        Curr. Opin. Pharmacol. 2011; 11: 604-611
        • Caggiu E.
        • Arru G.
        • Hosseini S.
        • Niegowska M.
        • Sechi G.
        • Zarbo I.R.
        • et al.
        Inflammation, infectious triggers, and Parkinson’s disease.
        Front. Neurol. 2019; 10: 122
        • Chang C.
        • Zhao Y.
        • Song G.
        • She K.
        Resveratrol protects hippocampal neurons against cerebral ischemia-reperfusion injury via modulating JAK/ERK/STAT signaling pathway in rats.
        J. Neuroimmunol. 2018; 315: 9-14
        • Clarysse K.
        • Pfaff C.
        • Marquardt Y.
        • Huth L.
        • Kortekaas Krohn I.
        • Kluwig D.
        • et al.
        JAK1/3 inhibition preserves epidermal morphology in full-thickness 3D skin models of atopic dermatitis and psoriasis.
        J. Eur. Acad. Dermatol. Venereol. 2019; 33: 367-375
        • Cosgrove S.B.
        • Wren J.A.
        • Cleaver D.M.
        • Walsh K.F.
        • Follis S.I.
        • King V.I.
        • et al.
        A blinded, randomized, placebo-controlled trial of the efficacy and safety of the J anus kinase inhibitor oclacitinib (A poquel®) in client-owned dogs with atopic dermatitis.
        Vet. Dermatol. 2013; 24: 587-e142
        • D’Amico F.
        • Parigi T.L.
        • Fiorino G.
        • Peyrin-Biroulet L.
        • Danese S.
        Tofacitinib in the treatment of ulcerative colitis: efficacy and safety from clinical trials to real-world experience.
        Ther. Adv. Gastroenterol. 2019; 12 (1756284819848631)
        • de Souza A.L.J.
        • Pereira A.B.M.
        • de Oliveira J.R.
        • Ramalho L.S.
        • de Souza H.I.
        • Nascimento A.L.
        • et al.
        Dermatophagoides pteronyssinus-induced pro-inflammatory responses mediated via STAT3 and NF-kappaB signaling pathways in human bronchial epithelial cells–inhibitory effects of Lafoensia pacari and ellagic acid.
        J. Pharmacol. Sci. 2020; 142: 157-164
        • Fahn S.
        • Sulzer D.
        Neurodegeneration and neuroprotection in Parkinson disease.
        NeuroRx. 2004; 1: 139-154
        • Faour S.
        • Ashok A.
        An overview of stem cell therapies for Parkinson’s disease.
        UTSC’s J. Natural Sci. 2021; 2: 143-158
        • Foffani G.
        • Trigo-Damas I.
        • Pineda-Pardo J.A.
        • Blesa J.
        • Rodríguez-Rojas R.
        • Martínez-Fernández R.
        • et al.
        Focused ultrasound in Parkinson’s disease: a twofold path toward disease modification.
        Mov. Disord. 2019; 34: 1262-1273
        • Fukuyama T.
        • Ehling S.
        • Cook E.
        • Bäumer W.
        Topically administered Janus-kinase inhibitors tofacitinib and oclacitinib display impressive antipruritic and anti-inflammatory responses in a model of allergic dermatitis.
        J. Pharmacol. Exp. Ther. 2015; 354: 394-405
        • Fuxe K.G.
        • Tarakanov A.O.
        • Goncharova L.B.
        • Agnati L.F.
        A new road to neuroinflammation in Parkinson’s disease?.
        Brain Res. Rev. 2008; 58: 453-458
        • Gao W.
        • McGarry T.
        • Orr C.
        • McCormick J.
        • Veale D.
        • Fearon U.
        Tofacitinib regulates synovial inflammation in psoriatic arthritis, inhibiting STAT activation and induction of negative feedback inhibitors.
        Ann. Rheum. Dis. 2016; 75: 311-315
        • Garretti F.
        • Agalliu D.
        • Lindestam Arlehamn C.S.
        • Sette A.
        • Sulzer D.
        Autoimmunity in Parkinson’s disease: the role of α-synuclein-specific T cells.
        Front. Immunol. 2019; 10
        • Genovese M.C.
        • Smolen J.S.
        • Weinblatt M.E.
        • Burmester G.R.
        • Meerwein S.
        • Camp H.S.
        • et al.
        Efficacy and safety of ABT-494, a selective JAK-1 inhibitor, in a phase IIb study in patients with rheumatoid arthritis and an inadequate response to methotrexate.
        Arthritis Rheum. 2016; 68: 2857-2866
        • Genovese M.C.
        • Van Vollenhoven R.F.
        • Pacheco-Tena C.
        • Zhang Y.
        • Kinnman N.
        VX-509 (Decernotinib), an oral selective JAK-3 inhibitor, in combination with methotrexate in patients with rheumatoid arthritis.
        Arthritis Rheum. 2016; 68: 46-55
        • Genovese M.C.
        • Greenwald M.
        • Codding C.
        • Zubrzycka-Sienkiewicz A.
        • Kivitz A.J.
        • Wang A.
        • et al.
        Peficitinib, a JAK inhibitor, in combination with limited conventional synthetic disease-modifying antirheumatic drugs in the treatment of moderate-to-severe rheumatoid arthritis.
        Arthritis Rheum. 2017; 69: 932-942
        • George P.
        Concerns regarding the safety and toxicity of medicinal plants-an overview.
        J. Appl. Pharmaceut. Sci. 2011; 1: 40-44
        • Ghandadi M.
        • Sahebkar A.
        Curcumin: an effective inhibitor of interleukin-6.
        Curr. Pharm. Des. 2017; 23: 921-931
        • Ghasemi F.
        • Shafiee M.
        • Banikazemi Z.
        • Pourhanifeh M.H.
        • Khanbabaei H.
        • Shamshirian A.
        • et al.
        Curcumin inhibits NF-kB and Wnt/β-catenin pathways in cervical cancer cells.
        Pathol. Res. Pract. 2019; 215
        • Gonzales A.
        • Bowman J.
        • Fici G.
        • Zhang M.
        • Mann D.
        • Mitton-Fry M.
        Oclacitinib (APOQUEL®) is a novel Janus kinase inhibitor with activity against cytokines involved in allergy.
        J. Vet. Pharmacol. Ther. 2014; 37: 317-324
        • Groner B.
        • von Manstein V.
        Jak Stat Signaling and cancer: Opportunities, Benefits and Side Effects of Targeted Inhibition.
        Elsevier, 2017
        • Guttman-Yassky E.
        • Silverberg J.I.
        • Nemoto O.
        • Forman S.B.
        • Wilke A.
        • Prescilla R.
        • et al.
        Baricitinib in adult patients with moderate-to-severe atopic dermatitis: a phase 2 parallel, double-blinded, randomized placebo-controlled multiple-dose study.
        J. Am. Acad. Dermatol. 2019; 80 (913–21. e9)
        • Hedvat M.
        • Huszar D.
        • Herrmann A.
        • Gozgit J.M.
        • Schroeder A.
        • Sheehy A.
        • et al.
        The JAK2 inhibitor AZD1480 potently blocks Stat3 signaling and oncogenesis in solid tumors.
        Cancer Cell. 2009; 16: 487-497
        • Hermanowicz N.
        Parkinson Disease Psychosis: Evaluation and Treatment.
        2018
        • Ho M.S.
        Microglia in Parkinson’s disease.
        Neuroglia Neurodegenerat. Dis. 2019; : 335-353
        • Homayoun H.
        Parkinson disease.
        Ann. Intern. Med. 2018; 169: ITC33-ITC48
        • Hosseini A.
        • Gharibi T.
        • Marofi F.
        • Javadian M.
        • Babaloo Z.
        • Baradaran B.
        Janus kinase inhibitors: a therapeutic strategy for cancer and autoimmune diseases.
        J. Cell. Physiol. 2020; 235: 5903-5924
        • Hurwitz H.I.
        • Uppal N.
        • Wagner S.A.
        • Bendell J.C.
        • Beck J.T.
        • Wade III, S.M.
        • et al.
        Randomized, double-blind, phase II study of ruxolitinib or placebo in combination with capecitabine in patients with metastatic pancreatic cancer for whom therapy with gemcitabine has failed.
        J. Clin. Oncol. 2015; 33: 4039
        • Hutcheon D.A.
        The efficacy and safety of 4 natural products for the management of IBS.
        Top. Clin. Nutr. 2014; 29: 113-122
        • Jabbari A.
        • Sansaricq F.
        • Cerise J.
        • Chen J.
        • Bitterman A.
        • Ulerio G.
        • et al.
        An open-label pilot study to evaluate the efficacy of tofacitinib in moderate to severe patch-type alopecia areata, totalis, and universalis.
        J. Investig. Dermatol. 2018; 138: 1539-1545
        • Joshi N.
        • Singh S.
        Updates on immunity and inflammation in Parkinson disease pathology.
        J. Neurosci. Res. 2018; 96: 379-390
        • Kahl L.
        • Patel J.
        • Layton M.
        • Binks M.
        • Hicks K.
        • Leon G.
        • et al.
        Safety, tolerability, efficacy and pharmacodynamics of the selective JAK1 inhibitor GSK2586184 in patients with systemic lupus erythematosus.
        Lupus. 2016; 25: 1420-1430
        • Kalantari H.
        • Foruozandeh H.
        • Khodayar M.J.
        • Siahpoosh A.
        • Saki N.
        • Kheradmand P.
        Antioxidant and hepatoprotective effects of Capparis spinosa L. fractions and Quercetin on tert-butyl hydroperoxide-induced acute liver damage in mice.
        J. Tradit. Complement. Med. 2018; 8: 120-127
        • Kavanaugh A.
        • Kremer J.
        • Ponce L.
        • Cseuz R.
        • Reshetko O.
        • Stanislavchuk M.
        • et al.
        Filgotinib (GLPG0634/GS-6034), an oral selective JAK1 inhibitor, is effective as monotherapy in patients with active rheumatoid arthritis: results from a randomised, dose-finding study (DARWIN 2).
        Ann. Rheum. Dis. 2017; 76: 1009-1019
        • Kim Y.J.
        • Park W.
        Anti-inflammatory effect of quercetin on RAW 264.7 mouse macrophages induced with polyinosinic-polycytidylic acid.
        Molecules. 2016; 21: 450
        • Kim A.
        • Strober B.
        Janus Kinase Inhibitors. Biologic and Systemic Agents in Dermatology.
        Springer, 2018: 187-198
        • Kishore Kumar S.N.
        • Deepthy J.
        • Saraswathi U.
        • Thangarajeswari M.
        • Yogesh Kanna S.
        • Ezhil P.
        • et al.
        Morinda citrifolia mitigates rotenone-induced striatal neuronal loss in male Sprague-Dawley rats by preventing mitochondrial pathway of intrinsic apoptosis.
        Redox Rep. 2017; 22: 418-429
        • Kivitz A.
        • Gutierrez-Ureña S.
        • Poiley J.
        • Genovese M.
        • Kristy R.
        • Shay K.
        • et al.
        Peficitinib, a JAK inhibitor, in the treatment of moderate-to-severe rheumatoid arthritis in patients with an inadequate response to methotrexate.
        Arthritis Rheum. 2017; 69: 709-719
        • Kremer J.M.
        • Emery P.
        • Camp H.S.
        • Friedman A.
        • Wang L.
        • Othman A.A.
        • et al.
        A phase IIb study of ABT-494, a selective JAK-1 inhibitor, in patients with rheumatoid arthritis and an inadequate response to anti–tumor necrosis factor therapy.
        Arthritis Rheum. 2016; 68: 2867-2877
        • Lashgari N.
        • Roudsari N.
        • Momtaz S.
        • Ghanaatian N.
        • Kohansal P.
        • Farzaei M.
        • et al.
        Targeting mammalian target of rapamycin: prospects for the treatment of inflammatory bowel diseases.
        Curr. Med. Chem. 2021; 28: 1605-1624
        • Lee J.-H.
        • Park K.-S.
        • Alberobello A.T.
        • Kallakury B.
        • Weng M.-T.
        • Wang Y.
        • et al.
        The Janus kinases inhibitor AZD1480 attenuates growth of small cell lung cancers in vitro and in vivo.
        Clin. Cancer Res. 2013; 19: 6777-6786
        • Li L.
        • Li H.
        • Li M.
        Curcumin protects against cerebral ischemia-reperfusion injury by activating JAK2/STAT3 signaling pathway in rats.
        Int. J. Clin. Exp. Med. 2015; 8: 14985
        • Li Q.
        • Tian Z.
        • Wang M.
        • Kou J.
        • Wang C.
        • Rong X.
        • et al.
        Luteoloside attenuates neuroinflammation in focal cerebral ischemia in rats via regulation of the PPARγ/Nrf2/NF-κB signaling pathway.
        Int. Immunopharmacol. 2019; 66: 309-316
        • Liau N.P.
        • Laktyushin A.
        • Lucet I.S.
        • Murphy J.M.
        • Yao S.
        • Whitlock E.
        • et al.
        The molecular basis of JAK/STAT inhibition by SOCS1.
        Nat. Commun. 2018; 9: 1-14
        • Liu C.-W.
        • Lin H.-W.
        • Yang D.-J.
        • Chen S.-Y.
        • Tseng J.-K.
        • Chang T.-J.
        • et al.
        Luteolin inhibits viral-induced inflammatory response in RAW264. 7 cells via suppression of STAT1/3 dependent NF-κB and activation of HO-1.
        Free Radic. Biol. Med. 2016; 95: 180-189
        • Liu Y.
        • Wang L.
        • Du Y.
        • Chen Z.
        • Guo J.
        • Weng X.
        • et al.
        Effects of apigenin pretreatment against renal ischemia/reperfusion injury via activation of the JAK2/STAT3 pathway.
        Biomed. Pharmacother. 2017; 95: 1799-1808
        • López-Matencio J.M.S.
        • Baladrón A.M.
        • Castañeda S.
        JAK-STAT inhibitors for the treatment of immunomediated diseases.
        Medicina Clínica (English Edition). 2019; 152: 353-360
        • Machova Urdzikova L.
        • Karova K.
        • Ruzicka J.
        • Kloudova A.
        • Shannon C.
        • Dubisova J.
        • et al.
        The anti-inflammatory compound curcumin enhances locomotor and sensory recovery after spinal cord injury in rats by immunomodulation.
        Int. J. Mol. Sci. 2016; 17: 49
        • Malemud C.J.
        • Pearlman E.
        Targeting JAK/STAT signaling pathway in inflammatory diseases.
        Curr. Signal Transduct. Therapy. 2009; 4: 201-221
        • Mohajeri M.
        • Bianconi V.
        • Ávila-Rodriguez M.F.
        • Barreto G.E.
        • Jamialahmadi T.
        • Pirro M.
        • et al.
        Curcumin: a phytochemical modulator of estrogens and androgens in tumors of the reproductive system.
        Pharmacol. Res. 2020; 156
        • Mohamed M.-E.F.
        • Camp H.S.
        • Jiang P.
        • Padley R.J.
        • Asatryan A.
        • Othman A.A.
        Pharmacokinetics, safety and tolerability of ABT-494, a novel selective JAK 1 inhibitor, in healthy volunteers and subjects with rheumatoid arthritis.
        Clin. Pharmacokinet. 2016; 55: 1547-1558
        • Mohd Sairazi N.S.
        • Sirajudeen K.
        Natural products and their bioactive compounds: neuroprotective potentials against neurodegenerative diseases.
        Evid. Based Complement. Alternat. Med. 2020; 2020
        • Mortezaee K.
        • Salehi E.
        • Mirtavoos-mahyari H.
        • Motevaseli E.
        • Najafi M.
        • Farhood B.
        • et al.
        Mechanisms of apoptosis modulation by curcumin: implications for cancer therapy.
        J. Cell. Physiol. 2019; 234: 12537-12550
        • Mosley R.L.
        • Gendelman H.E.
        T cells and Parkinson’s disease.
        Lancet Neurol. 2017; 16: 769-771
        • Nabavi S.M.
        • Ahmed T.
        • Nawaz M.
        • Devi K.P.
        • Balan D.J.
        • Pittalà V.
        • et al.
        Targeting STATs in neuroinflammation: the road less traveled!.
        Pharmacol. Res. 2019; 141: 73-84
        • Naeimi R.
        • Safarpour F.
        • Hashemian M.
        • Tashakorian H.
        • Ahmadian S.R.
        • Ashrafpour M.
        • et al.
        Curcumin-loaded nanoparticles ameliorate glial activation and improve myelin repair in lyolecithin-induced focal demyelination model of rat corpus callosum.
        Neurosci. Lett. 2018; 674: 1-10
        • O’Shaughnessy J.
        • DeMichele A.
        • Ma C.X.
        • Richards P.
        • Yardley D.A.
        • Wright G.S.
        • et al.
        A randomized, double-blind, phase 2 study of ruxolitinib or placebo in combination with capecitabine in patients with advanced HER2-negative breast cancer and elevated C-reactive protein, a marker of systemic inflammation.
        Breast Cancer Res. Treat. 2018; 170: 547-557
        • Pagonabarraga J.
        • Kulisevsky J.
        • Strafella A.P.
        • Krack P.
        Apathy in Parkinson’s disease: clinical features, neural substrates, diagnosis, and treatment.
        Lancet Neurol. 2015; 14: 518-531
        • Pain S.
        • Vergote J.
        • Gulhan Z.
        • Bodard S.
        • Chalon S.
        • Gaillard A.
        Inflammatory process in Parkinson disease: neuroprotection by neuropeptide Y.
        Fundam. Clin. Pharmacol. 2019; 33: 544-548
        • Pal R.
        • Tiwari P.C.
        • Nath R.
        • Pant K.K.
        Role of neuroinflammation and latent transcription factors in pathogenesis of Parkinson’s disease.
        Neurol. Res. 2016; 38: 1111-1122
        • Panahi Y.
        • Ahmadi Y.
        • Teymouri M.
        • Johnston T.P.
        • Sahebkar A.
        Curcumin as a potential candidate for treating hyperlipidemia: a review of cellular and metabolic mechanisms.
        J. Cell. Physiol. 2018; 233: 141-152
        • Panahi Y.
        • Khalili N.
        • Sahebi E.
        • Namazi S.
        • Simental-Mendía L.E.
        • Majeed M.
        • et al.
        Effects of curcuminoids plus piperine on glycemic, hepatic and inflammatory biomarkers in patients with type 2 diabetes mellitus: a randomized double-blind placebo-controlled trial.
        Drug Res. 2018; 68: 403-409
        • Pezeshki-Nia S.
        • Asle-Rousta M.
        • Mahmazi S.
        Spinacia oleracea L. extract attenuates hippocampal expression of TNF-α and IL-1β in rats exposed to chronic restraint stress.
        Med. J. Islam Repub. Iran. 2020; 34: 10
        • Poewe W.
        • Mahlknecht P.
        Pharmacologic treatment of motor symptoms associated with Parkinson disease.
        Neurol. Clin. 2020; 38: 255-267
        • Punwani N.
        • Burn T.
        • Scherle P.
        • Flores R.
        • Shi J.
        • Collier P.
        • et al.
        Downmodulation of key inflammatory cell markers with a topical Janus kinase 1/2 inhibitor.
        Br. J. Dermatol. 2015; 173: 989-997
        • Qin H.
        • Buckley J.A.
        • Li X.
        • Liu Y.
        • Fox T.H.
        • Meares G.P.
        • et al.
        Inhibition of the JAK/STAT pathway protects against α-synuclein-induced neuroinflammation and dopaminergic neurodegeneration.
        J. Neurosci. 2016; 36: 5144-5159
        • Ramesh G.
        • MacLean A.G.
        • Philipp M.T.
        Cytokines and chemokines at the crossroads of neuroinflammation, neurodegeneration, and neuropathic pain.
        Mediat. Inflamm. 2013; 2013
        • Ransohoff R.M.
        How neuroinflammation contributes to neurodegeneration.
        Science. 2016; 353: 777-783
        • Roudsari N.M.
        • Lashgari N.-A.
        • Momtaz S.
        • Farzaei M.H.
        • Marques A.M.
        • Abdolghaffari A.H.
        Natural polyphenols for the prevention of irritable bowel syndrome: molecular mechanisms and targets; a comprehensive review.
        DARU J. Pharmaceut. Sci. 2019; : 1-26
        • Sadeghian M.
        • Rahmani S.
        • Jamialahmadi T.
        • Johnston T.P.
        • Sahebkar A.
        The effect of oral curcumin supplementation on health-related quality of life: a systematic review and meta-analysis of randomized controlled trials.
        J. Affect. Disord. 2021; 278: 627-636
        • Sahebkar A.
        Molecular mechanisms for curcumin benefits against ischemic injury.
        Fertil. Steril. 2010; 94 (e75-e6)
        • Sahebkar A.
        Effects of resveratrol supplementation on plasma lipids: a systematic review and meta-analysis of randomized controlled trials.
        Nutr. Rev. 2013; 71: 822-835
        • Sahebkar A.
        • Serban C.
        • Ursoniu S.
        • Wong N.D.
        • Muntner P.
        • Graham I.M.
        • et al.
        Lack of efficacy of resveratrol on C-reactive protein and selected cardiovascular risk factors - results from a systematic review and meta-analysis of randomized controlled trials.
        Int. J. Cardiol. 2015; 189: 47-55
        • Sands B.E.
        • Sandborn W.J.
        • Feagan B.G.
        • Lichtenstein G.R.
        • Zhang H.
        • Strauss R.
        • et al.
        Peficitinib, an oral janus kinase inhibitor, in moderate-to-severe ulcerative colitis: results from a randomised, phase 2 study.
        J. Crohn’s Colitis. 2018; 12: 1158-1169
        • Santangelo C.
        • Vari R.
        • Scazzocchio B.
        • De Sanctis P.
        • Giovannini C.
        • D’Archivio M.
        • et al.
        Anti-inflammatory activity of extra virgin olive oil polyphenols: which role in the prevention and treatment of immune-mediated inflammatory diseases? Endocrine.
        Metabolic & Immune Disorders-Drug Targets (Formerly Current Drug Targets-Immune, Endocrine & Metabolic Disorders). 2018; 18: 36-50
        • Scott L.M.
        Inhibitors of the JAK/STAT pathway, with a focus on ruxolitinib and similar agents.
        in: Resistance of Targeted Therapies Excluding Antibodies for Lymphomas. Springer, 2018: 107-134
        • Stern M.B.
        Parkinson’s disease: early diagnosis and management.
        J. Fam. Pract. 1993; 36 (439-)
        • Stover D.G.
        • Del Alcazar C.R.G.
        • Brock J.
        • Guo H.
        • Overmoyer B.
        • Balko J.
        • et al.
        Phase II study of ruxolitinib, a selective JAK1/2 inhibitor, in patients with metastatic triple-negative breast cancer.
        NPJ Breast Cancer. 2018; 4: 1-9
        • Subramaniam S.R.
        • Federoff H.J.
        Targeting microglial activation states as a therapeutic avenue in Parkinson’s disease.
        Front. Aging Neurosci. 2017; 9: 176
        • Teymouri M.
        • Pirro M.
        • Johnston T.P.
        • Sahebkar A.
        Curcumin as a multifaceted compound against human papilloma virus infection and cervical cancers: a review of chemistry, cellular, molecular, and preclinical features.
        BioFactors. 2017; 43: 331-346
        • Thomas J.
        • Garg M.L.
        • Smith D.W.
        Dietary supplementation with resveratrol and/or docosahexaenoic acid alters hippocampal gene expression in adult C57Bl/6 mice.
        J. Nutr. Biochem. 2013; 24: 1735-1740
        • Thomas J.
        • Garg M.L.
        • Smith D.W.
        Dietary resveratrol supplementation normalizes gene expression in the hippocampus of streptozotocin-induced diabetic C57Bl/6 mice.
        J. Nutr. Biochem. 2014; 25: 313-318
        • Tiwari P.C.
        • Pal R.
        The potential role of neuroinflammation and transcription factors in Parkinson disease.
        Dialogues Clin. Neurosci. 2017; 19: 71
        • van der Heijde D.
        • Baraliakos X.
        • Gensler L.S.
        • Maksymowych W.P.
        • Tseluyko V.
        • Nadashkevich O.
        • et al.
        Efficacy and safety of filgotinib, a selective Janus kinase 1 inhibitor, in patients with active ankylosing spondylitis (TORTUGA): results from a randomised, placebo-controlled, phase 2 trial.
        Lancet. 2018; 392: 2378-2387
        • Vanhoutte F.
        • Mazur M.
        • Voloshyn O.
        • Stanislavchuk M.
        • Van der Aa A.
        • Namour F.
        • et al.
        Efficacy, safety, pharmacokinetics, and pharmacodynamics of filgotinib, a selective JAK-1 inhibitor, after short-term treatment of rheumatoid arthritis: results of two randomized phase IIa trials.
        Arthritis Rheum. 2017; 69: 1949-1959
        • Vermeire S.
        • Schreiber S.
        • Petryka R.
        • Kuehbacher T.
        • Hebuterne X.
        • Roblin X.
        • et al.
        Clinical remission in patients with moderate-to-severe Crohn’s disease treated with filgotinib (the FITZROY study): results from a phase 2, double-blind, randomised, placebo-controlled trial.
        Lancet. 2017; 389: 266-275
        • Wagle Shukla A.
        • Zeilman P.
        • Fernandez H.
        • Bajwa J.A.
        • Mehanna R.
        DBS programming: an evolving approach for patients with Parkinson’s disease.
        Parkinson’s Dis. 2017; 2017
        • Wallace D.J.
        • Furie R.A.
        • Tanaka Y.
        • Kalunian K.C.
        • Mosca M.
        • Petri M.A.
        • et al.
        Baricitinib for systemic lupus erythematosus: a double-blind, randomised, placebo-controlled, phase 2 trial.
        Lancet. 2018; 392: 222-231
        • Wang S.
        • Cao M.
        • Xu S.
        • Zhang J.
        • Wang Z.
        • Mao X.
        • et al.
        Effect of luteolin on inflammatory responses in RAW264. 7 macrophages activated with LPS and IFN-γ.
        J. Funct. Foods. 2017; 32: 123-130
        • Wang P.
        • Sun J.
        • Lv S.
        • Xie T.
        • Wang X.
        Apigenin alleviates myocardial reperfusion injury in rats by downregulating miR-15b.
        Med. Sci. Monit: Int. Med. J.Experiment. Clin. Res. 2019; 25: 2764
        • Westhovens R.
        • Taylor P.C.
        • Alten R.
        • Pavlova D.
        • Enriquez-Sosa F.
        • Mazur M.
        • et al.
        Filgotinib (GLPG0634/GS-6034), an oral JAK1 selective inhibitor, is effective in combination with methotrexate (MTX) in patients with active rheumatoid arthritis and insufficient response to MTX: results from a randomised, dose-finding study (DARWIN 1).
        Ann. Rheum. Dis. 2017; 76: 998-1008
        • Xin P.
        • Xu X.
        • Deng C.
        • Liu S.
        • Wang Y.
        • Zhou X.
        • et al.
        The role of JAK/STAT signaling pathway and its inhibitors in diseases.
        Int. Immunopharmacol. 2020; 80: 106210
        • Yang L.
        • Mao K.
        • Yu H.
        • Chen J.
        Neuroinflammatory responses and Parkinson’ disease: pathogenic mechanisms and therapeutic targets.
        J. NeuroImmune Pharmacol. 2020; : 1-8
        • Zheng K.
        • Dai X.
        • Wu X.
        • Wei Z.
        • Fang W.
        • Zhu Y.
        • et al.
        Curcumin ameliorates memory decline via inhibiting BACE1 expression and β-amyloid pathology in 5× FAD transgenic mice.
        Mol. Neurobiol. 2017; 54: 1967-1977