Dorsey ER, Constantinescu R, Thompson JP, Biglan KM, Holloway RG, Kieburtz K, et al. Projected number of people with Parkinson disease in the most populous nations, 2005 through 2030. Neurology. 2007;68:384–6.
Kowal SL, Dall TM, Chakrabarti R, Storm MV, Jain A. The current and projected economic burden of Parkinson’s disease in the United States. Mov Disord. 2013;28:311–8.
Maiti P, Manna J, Dunbar GL. Current understanding of the molecular mechanisms in Parkinson’s disease: targets for potential treatments. Transl. Neurodegener. 2017;6:28.
Athauda D, Foltynie T. The ongoing pursuit of neuroprotective therapies in Parkinson disease. Nat. Rev. Neurol. 2014;11:25–40.
DiMasi JA, Grabowski HG, Hansen RW. Innovation in the pharmaceutical industry: new estimates of R&D costs. J Health Econ. 2016;47:20–33.
Strittmatter SM. Overcoming drug development bottlenecks with repurposing: old drugs learn new tricks. Nat Med. 2014;20:590–1.
Kola I, Landis J. Can the pharmaceutical industry reduce attrition rates? Nat Rev Drug Discov. 2004;3:711–5.
Reaume AG. Drug repurposing through nonhypothesis driven phenotypic screening. Drug Discov Today Ther Strateg. 2011;8:85–8.
Ashburn TT, Thor KB. Drug repositioning: identifying and developing new uses for existing drugs. Nat Rev Drug Discov. 2004;3:673–83.
Schwab RS, Poskanzer DC, England AC, Young RR. Amantadine in Parkinson’s disease. JAMA. 1972;222:792.
Corsello SM, Bittker JA, Liu Z, Gould J, McCarren P, Hirschman JE, et al. The drug repurposing hub: a next-generation drug library and information resource. Nat Med. 2017;23:405–8.
Hughes RE, Nikolic K, Ramsay RR. One for all? Hitting multiple Alzheimer’s Disease targets with one drug. Front Neurosci Front. 2016;10:177.
Rakshit H, Chatterjee P, Roy D. A bidirectional drug repositioning approach for Parkinson’s disease through network-based inference. Biochemistry. 2015;457:280–7.
Fukuoka Y, Takei D, Ogawa H. A two-step drug repositioning method based on a protein-protein interaction network of genes shared by two diseases and the similarity of drugs. Bioinformation. 2013;9:89–93.
Johnston TH, Lacoste AMB, Visanji NP, Lang AE, Fox SH, Brotchie JM. Repurposing drugs to treat l-DOPA-induced dyskinesia in Parkinson’s disease. Neuropharmacology. 2018. https://doi.org/10.1016/j.neuropharm.2018.05.035.
Meissner WG, Frasier M, Gasser T, Goetz CG, Lozano A, Piccini P, et al. Priorities in Parkinson’s disease research. Nat Rev Drug Discov. 2011;10:377–93.
Tilley BC, Galpern WR. Screening potential therapies: lessons learned from new paradigms used in Parkinson disease. Stroke. 2007;38:800–3.
Ravina BM, Fagan SC, Hart RG, Hovinga CA, Murphy DD, Dawson TM, et al. Neuroprotective agents for clinical trials in Parkinson’s disease: a systematic assessment. Neurology. 2003;60:1234–40.
Writing Group for the NINDS Exploratory Trials in Parkinson Disease (NET-PD) Investigators WG for the NET in PD (NET-P, Kieburtz K, Tilley BC, Elm JJ, Babcock D, Hauser R, et al. Effect of creatine monohydrate on clinical progression in patients with Parkinson disease: a randomized clinical trial. JAMA. 2015;313:584–93.
Brundin P, Barker RA, Conn PJ, Dawson TM, Kieburtz K, Lees AJ, et al. Linked clinical trials–the development of new clinical learning studies in Parkinson’s disease using screening of multiple prospective new treatments. J Parkinsons Dis. 2013;3:231–9.
Mortiboys H, Aasly J, Bandmann O. Ursocholanic acid rescues mitochondrial function in common forms of familial Parkinson’s disease. Brain. 2013;136:3038–50.
Sandor C, Robertson P, Lang C, Heger A, Booth H, Vowles J, et al. Transcriptomic profiling of purified patient-derived dopamine neurons identifies convergent perturbations and therapeutics for Parkinson’s disease. Hum Mol Genet 2017;26:ddw412.
O’Regan G, deSouza R-M, Balestrino R, Schapira AH. Glucocerebrosidase mutations in Parkinson disease. J Parkinsons Dis. 2017;7:411–22.
Gegg ME, Burke D, Heales SJR, Cooper JM, Hardy J, Wood NW, et al. Glucocerebrosidase deficiency in substantia nigra of parkinson disease brains. Ann Neurol. 2012;72:455–63.
Murphy KE, Halliday GM. Glucocerebrosidase deficits in sporadic Parkinson disease. Autophagy. 2014;10:1350–1.
Neumann J, Bras J, Deas E, O’Sullivan SS, Parkkinen L, Lachmann RH, et al. Glucocerebrosidase mutations in clinical and pathologically proven Parkinson’s disease. Brain. 2009;132:1783–94.
Sardi SP, Clarke J, Viel C, Chan M, Tamsett TJ, Treleaven CM, et al. Augmenting CNS glucocerebrosidase activity as a therapeutic strategy for parkinsonism and other Gaucher-related synucleinopathies. Proc Natl Acad Sci USA. 2013;110:3537–42.
Maegawa GHB, Tropak MB, Buttner JD, Rigat BA, Fuller M, Pandit D, et al. Identification and characterization of ambroxol as an enzyme enhancement agent for Gaucher disease. J Biol Chem. 2009;284:23502–16.
Ambrosi G, Ghezzi C, Zangaglia R, Levandis G, Pacchetti C, Blandini F. Ambroxol-induced rescue of defective glucocerebrosidase is associated with increased LIMP-2 and saposin C levels in GBA1 mutant Parkinson’s disease cells. Neurobiol Dis. 2015;82:235–42.
McNeill A, Magalhaes J, Shen C, Chau K-Y, Hughes D, Mehta A, et al. Ambroxol improves lysosomal biochemistry in glucocerebrosidase mutation-linked Parkinson disease cells. Brain. 2014;137:1481–95.
Yang S-Y, Beavan M, Chau K-Y, Taanman J-W, Schapira AHV. A human neural crest stem cell-derived dopaminergic neuronal model recapitulates biochemical abnormalities in GBA1 mutation carriers. Stem Cell Rep. 2017;8:728–42.
Sanchez-Martinez A, Beavan M, Gegg ME, Chau K-Y, Whitworth AJ, Schapira AHV. Parkinson disease-linked GBA mutation effects reversed by molecular chaperones in human cell and fly models. Sci Rep. 2016;6:31380.
Migdalska-Richards A, Daly L, Bezard E, Schapira AHV. Ambroxol effects in glucocerebrosidase and α-synuclein transgenic mice. Ann Neurol. 2016;80:766–75.
Migdalska-Richards A, Ko WKD, Li Q, Bezard E, Schapira AHV. Oral ambroxol increases brain glucocerebrosidase activity in a nonhuman primate. Synapse. 2017;71:e21967.
Zimran A, Altarescu G, Elstein D. Pilot study using ambroxol as a pharmacological chaperone in type 1 Gaucher disease. Blood Cells Mol Dis. 2013;50:134–7.
Narita A, Shirai K, Itamura S, Matsuda A, Ishihara A, Matsushita K, et al. Ambroxol chaperone therapy for neuronopathic Gaucher disease: a pilot study. Ann Clin Transl Neurol. 2016;3:200–15.
Aflaki E, Borger DK, Moaven N, Stubblefield BK, Rogers SA, Patnaik S, et al. A new glucocerebrosidase chaperone reduces-synuclein and glycolipid levels in iPSC-derived dopaminergic neurons from patients with gaucher disease and parkinsonism. J Neurosci. 2016;36:7441–52.
Chan CS, Guzman JN, Ilijic E, Mercer JN, Rick C, Tkatch T, et al. “Rejuvenation” protects neurons in mouse models of Parkinson’s disease. Nature. 2007;447:1081–6.
Marras C, Gruneir A, Rochon P, Wang X, Anderson G, Brotchie J, et al. Dihydropyridine calcium channel blockers and the progression of parkinsonism. Ann Neurol. 2012;71:362–9.
Becker C, Jick SS, Meier CR. Use of antihypertensives and the risk of Parkinson disease. Neurology. 2008;70:1438–44.
Ritz B, Rhodes SL, Qian L, Schernhammer E, Olsen JH, Friis S. L-type calcium channel blockers and Parkinson disease in Denmark. Ann Neurol. 2010;67:600–6.
Pasternak B, Svanström H, Nielsen NM, Fugger L, Melbye M, Hviid A. Use of calcium channel blockers and Parkinson’s disease. Am J Epidemiol. 2012;175:627–35.
Surmeier DJ, Halliday GM, Simuni T. Calcium, mitochondrial dysfunction and slowing the progression of Parkinson’s disease. Exp Neurol. 2017;298:202–9.
Sinnegger-Brauns MJ, Huber IG, Koschak A, Wild C, Obermair GJ, Einzinger U, et al. Expression and 1,4-dihydropyridine-binding properties of brain L-type calcium channel isoforms. Mol Pharmacol. 2009;75:407–14.
Fitton A, Benfield P. Isradipine. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in cardiovascular disease. Drugs. 1990;40:31–74.
Ilijic E, Guzman JN, Surmeier DJ. The L-type channel antagonist isradipine is neuroprotective in a mouse model of Parkinson’s disease. Neurobiol Dis. 2011;43:364–71.
Simuni T, Borushko E, Avram MJ, Miskevics S, Martel A, Zadikoff C, et al. Tolerability of isradipine in early Parkinson’s disease: a pilot dose escalation study. Mov Disord. 2010;25:2863–6.
Parkinson Study Group. Phase II safety, tolerability, and dose selection study of isradipine as a potential disease-modifying intervention in early Parkinson’s disease (STEADY-PD). Mov Disord. 2013;28:1823–31.
Kang S, Cooper G, Dunne SF, Dusel B, Luan C-H, Surmeier DJ, et al. CaV1.3-selective L-type calcium channel antagonists as potential new therapeutics for Parkinson’s disease. Nat. Commun. 2012;3:1146.
Chen H, Mosley TH, Alonso A, Huang X. Plasma Urate and Parkinson’s disease in the atherosclerosis risk in communities (ARIC) Study. Am J Epidemiol. 2009;169:1064–9.
de Lau LML, Koudstaal PJ, Hofman A, Breteler MMB. Serum uric acid levels and the risk of Parkinson disease. Ann Neurol. 2005;58:797–800.
De Vera M, Rahman MM, Rankin J, Kopec J, Gao X, Choi H. Gout and the risk of parkinson’s disease: a cohort study. Arthritis Rheum. 2008;59:1549–54.
Weisskopf MG, O’Reilly E, Chen H, Schwarzschild MA, Ascherio A. Plasma urate and risk of Parkinson’s disease. Am J Epidemiol. 2007;166:561–7.
Facheris MF, Hicks AA, Minelli C, Hagenah JM, Kostic V, Campbell S, et al. Variation in the uric acid transporter gene SLC2A9 and its association with AAO of Parkinson’s disease. J Mol Neurosci. 2011;43:246–50.
González-Aramburu I, Sánchez-Juan P, Jesús S, Gorostidi A, Fernández-Juan E, Carrillo F, et al. Genetic variability related to serum uric acid concentration and risk of Parkinson’s disease. Mov Disord. 2013;28:1737–40.
Alonso A, Rodríguez LAG, Logroscino G, Hernán MA. Gout and risk of Parkinson disease: a prospective study. Neurology. 2007;69:1696–700.
Gao X, O’Reilly ÉJ, Schwarzschild MA, Ascherio A. Prospective study of plasma urate and risk of Parkinson disease in men and women. Neurology. 2016;86:520–6.
O’Reilly EJ, Gao X, Weisskopf MG, Chen H, Schwarzschild MA, Spiegelman D, et al. Plasma Urate and Parkinson’s Disease in Women. Am J Epidemiol. 2010;172:666–70.
Cortese M, Riise T, Engeland A, Ascherio A, Bjørnevik K. Urate and the risk of Parkinson’s disease in men and women. Disord: Parkinsonism Relat; 2018.
Ascherio A, LeWitt PA, Xu K, Eberly S, Watts A, Matson WR, et al. Urate as a predictor of the rate of clinical decline in Parkinson disease. Arch Neurol. 2009;66:1460–8.
Duan W, Ladenheim B, Cutler RG, Kruman II, Cadet JL, Mattson MP. Dietary folate deficiency and elevated homocysteine levels endanger dopaminergic neurons in models of Parkinson’s disease. J Neurochem. 2002;80:101–10.
Gong L, Zhang Q-L, Zhang N, Hua W-Y, Huang Y-X, Di P-W, et al. Neuroprotection by urate on 6-OHDA-lesioned rat model of Parkinson’s disease: linking to Akt/GSK3β signaling pathway. J Neurochem. 2012;123:876–85.
Zhang N, Shu H-Y, Huang T, Zhang Q-L, Li D, Zhang G-Q, et al. Nrf2 Signaling Contributes to the Neuroprotective Effects of Urate against 6-OHDA Toxicity. Finkelstein DI, editor. PLoS One. 2014;9:e100286.
Schwarzschild MA, Ascherio A, Beal MF, Cudkowicz ME, Curhan GC, Hare JM, et al. Inosine to increase serum and cerebrospinal fluid urate in Parkinson disease: a randomized clinical trial. JAMA Neurol. 2014;71:141–50.
Grayson PC, Kim SY, LaValley M, Choi HK. Hyperuricemia and incident hypertension: a systematic review and meta-analysis. Arthritis Care Res. 2011;63:102–10.
Iwaki H, Ando R, Miyaue N, Tada S, Tsujii T, Yabe H, et al. One year safety and efficacy of inosine to increase the serum urate level for patients with Parkinson’s disease in Japan. J Neurol Sci. 2017;383:75–8.
Exner N, Lutz AK, Haass C, Winklhofer KF. Mitochondrial dysfunction in Parkinson’s disease: molecular mechanisms and pathophysiological consequences. EMBO J. 2012;31:3038–62.
Miura T, Ouchida R, Yoshikawa N, Okamoto K, Makino Y, Nakamura T, et al. Functional modulation of the glucocorticoid receptor and suppression of NF-kappaB-dependent transcription by ursodeoxycholic acid. J Biol Chem. 2001;276:47371–8.
Lapenna D, Ciofani G, Festi D, Neri M, Pierdomenico SD, Giamberardino MA, et al. Antioxidant properties of ursodeoxycholic acid. Biochem Pharmacol. 2002;64:1661–7.
Ved R, Saha S, Westlund B, Perier C, Burnam L, Sluder A, et al. Similar Patterns of mitochondrial vulnerability and rescue induced by genetic modification of α-synuclein, parkin, and DJ-1 in Caenorhabditis elegans. J Biol Chem. 2005;280:42655–68.
Duan W-M, Rodrigues CMP, Zhao L-R, Steer CJ, Low WC, Rodrigures CMP. Tauroursodeoxycholic acid improves the survival and function of nigral transplants in a rat model of Parkinson’s disease. Cell Transplant. 2002;11:195–205.
Abdelkader NF, Safar MM, Salem HA. Ursodeoxycholic acid ameliorates apoptotic cascade in the rotenone model of Parkinson’s disease: modulation of mitochondrial perturbations. Mol Neurobiol. 2016;53:810–7.
Chun HS, Low WC. Ursodeoxycholic acid suppresses mitochondria-dependent programmed cell death induced by sodium nitroprusside in SH-SY5Y cells. Toxicology. 2012;292:105–12.
Parry GJ, Rodrigues CMP, Aranha MM, Hilbert SJ, Davey C, Kelkar P, et al. Safety, tolerability, and cerebrospinal fluid penetration of ursodeoxycholic acid in patients with amyotrophic lateral sclerosis. Clin Neuropharmacol. 2010;33:17–21.
Kotb MA. Molecular mechanisms of ursodeoxycholic acid toxicity & side effects: ursodeoxycholic acid freezes regeneration & induces hibernation mode. Int J Mol Sci. 2012;13:8882–914.
Castro-Caldas M, Carvalho AN, Rodrigues E, Henderson CJ, Wolf CR, Rodrigues CMP, et al. Tauroursodeoxycholic acid prevents MPTP-induced dopaminergic cell death in a mouse model of Parkinson’s disease. Mol Neurobiol. 2012;46:475–86.
Moreira S, Fonseca I, Nunes MJ, Rosa A, Lemos L, Rodrigues E, et al. Nrf2 activation by tauroursodeoxycholic acid in experimental models of Parkinson’s disease. Exp Neurol. 2017;295:77–87.
Rosa AI, Duarte-Silva S, Silva-Fernandes A, Nunes MJ, Carvalho AN, Rodrigues E, et al. Tauroursodeoxycholic acid improves motor symptoms in a mouse model of Parkinson’s disease. Mol Neurobiol. 2018. https://doi.org/10.1007/s12035-018-1062-4.
Elia AE, Lalli S, Monsurrò MR, Sagnelli A, Taiello AC, Reggiori B, et al. Tauroursodeoxycholic acid in the treatment of patients with amyotrophic lateral sclerosis. Eur J Neurol. 2016;23:45–52.
Takanashi M, Mochizuki H, Yokomizo K, Hattori N, Mori H, Yamamura Y, et al. Iron accumulation in the substantia nigra of autosomal recessive juvenile parkinsonism (ARJP). Parkinsonism Relat Disord. 2001;7:311–4.
Han Y-H, Lee J-H, Kang B-M, Mun C-W, Baik S-K, Shin Y, et al. Topographical differences of brain iron deposition between progressive supranuclear palsy and parkinsonian variant multiple system atrophy. J Neurol Sci. 2013;325:29–35.
Walter U. Transcranial sonography in brain disorders with trace metal accumulation. Int Rev Neurobiol. 2010;90:166–78.
Bartzokis G, Cummings JL, Markham CH, Marmarelis PZ, Treciokas LJ, Tishler TA, et al. MRI evaluation of brain iron in earlier- and later-onset Parkinson’s disease and normal subjects. Magn Reson Imaging. 1999;17:213–22.
Oakley AE, Collingwood JF, Dobson J, Love G, Perrott HR, Edwardson JA, et al. Individual dopaminergic neurons show raised iron levels in Parkinson disease. Neurology. 2007;68:1820–5.
Zucca FA, Segura-Aguilar J, Ferrari E, Muñoz P, Paris I, Sulzer D, et al. Interactions of iron, dopamine and neuromelanin pathways in brain aging and Parkinson’s disease. Prog Neurobiol. 2017;155:96–119.
Zhang W, Phillips K, Wielgus AR, Liu J, Albertini A, Zucca FA, et al. Neuromelanin activates microglia and induces degeneration of dopaminergic neurons: implications for progression of Parkinson’s disease. Neurotox Res. 2011;19:63–72.
Febbraro F, Giorgi M, Caldarola S, Loreni F, Romero-Ramos M. α-synuclein expression is modulated at the translational level by iron. NeuroReport. 2012;23:576–80.
Dixon SJ, Lemberg KM, Lamprecht MR, Skouta R, Zaitsev EM, Gleason CE, et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell. 2012;149:1060–72.
Dusek P, Schneider SA, Aaseth J. Iron chelation in the treatment of neurodegenerative diseases. J Trace Elem Med Biol. 2016;38:81–92.
Sun Y, Pham AN, Waite TD. Mechanism underlying the effectiveness of deferiprone in alleviating Parkinson’s disease symptoms. ACS Chem. 2018;9:1118–27.
Sohn Y-S, Mitterstiller A-M, Breuer W, Weiss G, Cabantchik ZI. Rescuing iron-overloaded macrophages by conservative relocation of the accumulated metal. Br J Pharmacol. 2011;164:406–18.
Devos D, Moreau C, Devedjian JC, Kluza J, Petrault M, Laloux C, et al. Targeting chelatable iron as a therapeutic modality in Parkinson’s disease. Antioxid Redox Signal. 2014;21:195–210.
Zhu Y, Wang B, Tao K, Yang H, Wang Y, Zhou T, et al. Iron accumulation and microglia activation contribute to substantia nigra hyperechogenicity in the 6-OHDA-induced rat model of Parkinson’s disease. Parkinsonism Relat Disord. 2017;36:76–82.
Workman DG, Tsatsanis A, Lewis FW, Boyle JP, Mousadoust M, Hettiarachchi NT, et al. Protection from neurodegeneration in the 6-hydroxydopamine (6-OHDA) model of Parkinson’s with novel 1-hydroxypyridin-2-one metal chelators. Metallomics. 2015;7:867–76.
Carboni E, Tatenhorst L, Tönges L, Barski E, Dambeck V, Bähr M, et al. Deferiprone rescues behavioral deficits induced by mild iron exposure in a mouse model of alpha-synuclein aggregation. Neuromolecular. 2017;19:309–21.
Grolez G, Moreau C, Sablonnière B, Garçon G, Devedjian J-C, Meguig S, et al. Ceruloplasmin activity and iron chelation treatment of patients with Parkinson’s disease. BMC Neurol. 2015;15:74.
Martin-Bastida A, Ward RJ, Newbould R, Piccini P, Sharp D, Kabba C, et al. Brain iron chelation by deferiprone in a phase 2 randomised double-blinded placebo controlled clinical trial in Parkinson’s disease. Sci Rep. 2017;7:1398.
Miyajima H, Takahashi Y, Kamata T, Shimizu H, Sakai N, Gitlin JD. Use of desferrioxamine in the treatment of aceruloplasminemia. Ann Neurol. 1997;41:404–7.
Sangchot P, Sharma S, Chetsawang B, Porter J, Govitrapong P, Ebadi M. Deferoxamine attenuates iron-induced oxidative stress and prevents mitochondrial aggregation and α-synuclein translocation in SK-N-SH cells in culture. Dev Neurosci. 2002;24:143–53.
Sian-Hülsmann J, Mandel S, Youdim MBH, Riederer P. The relevance of iron in the pathogenesis of Parkinson’s disease. J Neurochem. 2011;118:939–57.
Elincx-Benizri S, Glik A, Merkel D, Arad M, Freimark D, Kozlova E, et al. Clinical experience with deferiprone treatment for Friedreich Ataxia. J Child Neurol. 2016;31:1036–40.
De Pablo-Fernandez E, Goldacre R, Pakpoor J, Noyce AJ, Warner TT. Association between diabetes and subsequent Parkinson disease: a record-linkage cohort study. Neurology. 2018;91:e139–42.
Cereda E, Barichella M, Pedrolli C, Klersy C, Cassani E, Caccialanza R, et al. Diabetes and risk of Parkinson’s disease: a systematic review and meta-analysis. Diabetes Care. 2011;34:2614–23.
Bosco D, Plastino M, Cristiano D, Colica C, Ermio C, De Bartolo M, et al. Dementia is associated with insulin resistance in patients with Parkinson’s disease. J Neurol Sci. 2012;315:39–43.
Kotagal V, Albin RL, Müller MLTM, Koeppe RA, Frey KA, Bohnen NI. Diabetes is associated with postural instability and gait difficulty in Parkinson disease. Parkinsonism Relat Disord. 2013;19:522–6.
Choi J-Y, Jang E-H, Park C-S, Kang J-H. Enhanced susceptibility to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine neurotoxicity in high-fat diet-induced obesity. Free Radic Biol Med. 2005;38:806–16.
Morris JK, Zhang H, Gupte AA, Bomhoff GL, Stanford JA, Geiger PC. Measures of striatal insulin resistance in a 6-hydroxydopamine model of Parkinson’s disease. Brain Res. 2008;1240:185–95.
Wang L, Zhai Y-Q, Xu L-L, Qiao C, Sun X-L, Ding J-H, et al. Metabolic inflammation exacerbates dopaminergic neuronal degeneration in response to acute MPTP challenge in type 2 diabetes mice. Exp Neurol. 2014;251:22–9.
Athauda D, Foltynie T. Insulin resistance and Parkinson’s disease: a new target for disease modification? Prog Neurobiol. 2016;145–146:98–120.
Bassil F, Canron M-H, Vital A, Bezard E, Fernagut P-O, Meissner WG. Brain insulin resistance in Parkinson’s disease [abstract]. Mov Disord. 2017;32(suppl 2). http://www.mdsabstracts.org/abstract/brain-insulin-resistance-in-parkinsons-disease/. Accessed 24 July 2018.
Sekar S, Taghibiglou C. Elevated nuclear phosphatase and tensin homolog (PTEN) and altered insulin signaling in substantia nigral region of patients with Parkinson’s disease. Neurosci Lett. 2018;666:139–43.
Gao S, Duan C, Gao G, Wang X, Yang H. Alpha-synuclein overexpression negatively regulates insulin receptor substrate 1 by activating mTORC1/S6K1 signaling. Int J Biochem Cell Biol. 2015;64:25–33.
Parkes DG, Mace KF, Trautmann ME. Discovery and development of exenatide: the first antidiabetic agent to leverage the multiple benefits of the incretin hormone, GLP-1. Expert Opin Drug Discov. 2013;8:219–44.
Perry T, Haughey NJ, Mattson MP, Egan JM, Greig NH. Protection and reversal of excitotoxic neuronal damage by glucagon-like peptide-1 and exendin-4. J Pharmacol Exp Ther. 2002;302:881–8.
Kim S, Moon M, Park S. Exendin-4 protects dopaminergic neurons by inhibition of microglial activation and matrix metalloproteinase-3 expression in an animal model of Parkinson’s disease. J Endocrinol. 2009;202:431–9.
Harkavyi A, Abuirmeileh A, Lever R, Kingsbury AE, Biggs CS, Whitton PS. Glucagon-like peptide 1 receptor stimulation reverses key deficits in distinct rodent models of Parkinson’s disease. J Neuroinflammation. 2008;5:19.
Yun SP, Kam T-I, Panicker N, Kim S, Oh Y, Park J-S, et al. Block of A1 astrocyte conversion by microglia is neuroprotective in models of Parkinson’s disease. Nat Med. 2018;1.
Ventorp F, Bay-Richter C, Nagendra AS, Janelidze S, Matsson VS, Lipton J, et al. Exendin-4 treatment improves LPS-induced depressive-like behavior without affecting pro-inflammatory cytokines. J Parkinsons Dis. 2017;7:263–73.
Fan R, Li X, Gu X, Chan JCN, Xu G. Exendin-4 protects pancreatic beta cells from human islet amyloid polypeptide-induced cell damage: potential involvement of AKT and mitochondria biogenesis. Diabetes Obes Metab. 2010;12(9):815–24.
Perry T, Lahiri DK, Chen D, Zhou J, Shaw KTY, Egan JM, et al. A novel neurotrophic property of glucagon-like peptide 1: a promoter of nerve growth factor-mediated differentiation in PC12 cells. J Pharmacol Exp Ther. 2002;300:958–66.
Bertilsson G, Patrone C, Zachrisson O, Andersson A, Dannaeus K, Heidrich J, et al. Peptide hormone exendin-4 stimulates subventricular zone neurogenesis in the adult rodent brain and induces recovery in an animal model of Parkinson’s disease. J Neurosci Res. 2008;86:326–38.
Bomba M, Granzotto A, Castelli V, Massetti N, Silvestri E, Canazoniero E, et al. Exenatide exerts cognitive effects by modulating the BDNF-TrkB neurotrophic axis in adult mice. Neurobiol Aging. 2018;64:33–43.
Athauda D, Foltynie T. The glucagon-like peptide 1 (GLP) receptor as a therapeutic target in Parkinson’s disease: mechanisms of action. Drug Discov Today. 2016;21:802–18.
Aviles-Olmos I, Dickson J, Kefalopoulou Z, Djamshidian A, Ell P, Soderlund T, et al. Exenatide and the treatment of patients with Parkinson’s disease. J Clin Invest. 2013;123:2730–6.
Aviles-Olmos I, Dickson J, Kefalopoulou Z, Djamshidian A, Kahan J, Fmedsci PE, et al. Motor and cognitive advantages persist 12 months after exenatide exposure in Parkinson’s disease. J Parkinsons Dis. 2014;4:337–44.
Athauda D, Maclagan K, Skene SS, Bajwa-Joseph M, Letchford D, Chowdhury K, et al. Exenatide once weekly versus placebo in Parkinson’s disease: a randomised, double-blind, placebo-controlled trial. Lancet. 2017;390:1664–75.
Athauda D, Maclagan K, Budnik N, Zampedri L, Hibbert S, Skene SS, et al. What effects might exenatide have on non-motor symptoms in Parkinson’s disease: a post hoc analysis. J Parkinsons Dis. 2018;8(2):247–58.
Feng P, Zhang X, Li D, Ji C, Yuan Z, Wang R, et al. Two novel dual GLP-1/GIP receptor agonists are neuroprotective in the MPTP mouse model of Parkinson’s disease. Neuropharmacology. 2018;133:385–94.
Yuan Z, Li D, Feng P, Xue G, Ji C, Li G, et al. A novel GLP-1/GIP dual agonist is more effective than liraglutide in reducing inflammation and enhancing GDNF release in the MPTP mouse model of Parkinson’s disease. Eur J Pharmacol. 2017;812:82–90.
Badawi GA, Abd El Fattah MA, Zaki HF, El Sayed MI. Sitagliptin and liraglutide reversed nigrostriatal degeneration of rodent brain in rotenone-induced Parkinson’s disease. Inflammopharmacology. 2017;25:369–82.
Liu W, Jalewa J, Sharma M, Li G, Li L, Hölscher C. Neuroprotective effects of lixisenatide and liraglutide in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson’s disease. Neuroscience. 2015;303:42–50.
Gejl M, Gjedde A, Egefjord L, Møller A, Hansen SB, Rodell AB, et al. In Alzheimer’s Disease, Six-Month Treatment with GLP-1 Analogue Prevents Decline of Brain Glucose Metabolism: Randomized, Placebo-Controlled, Double-Blind Clinical Trial. Front Aging Neurosci. 2016.
Trujillo JM, Nuffer W, Ellis SL. GLP-1 receptor agonists: a review of head-to-head clinical studies. Ther Adv Endocrinol Metab SAGE Publications. 2015;6:19–28.
Christensen M, Sparre-Ulrich AH, Hartmann B, Grevstad U, Rosenkilde MM, Holst JJ, et al. Transfer of liraglutide from blood to cerebrospinal fluid is minimal in patients with type 2 diabetes. Int J Obes. 2015;39:1651–4.
Imam SZ, Zhou Q, Yamamoto A, Valente AJ, Ali SF, Bains M, et al. Novel regulation of parkin function through c-Abl-mediated tyrosine phosphorylation: implications for Parkinson’s disease. J Neurosci. 2011;31:157–63.
Ko HS, Lee Y, Shin J-H, Karuppagounder SS, Gadad BS, Koleske AJ, et al. Phosphorylation by the c-Abl protein tyrosine kinase inhibits parkin’s ubiquitination and protective function. Proc Natl Acad Sci. 2010;107:16691–6.
Hebron ML, Lonskaya I. Moussa CE-H. Nilotinib reverses loss of dopamine neurons and improves motor behavior via autophagic degradation of -synuclein in Parkinson’s disease models. Hum Mol Genet. 2013;22:3315–28.
Hantschel O, Superti-Furga G. Regulation of the c-Abl and Bcr-Abl tyrosine kinases. Nat Rev Mol Cell Biol. 2004;5:33–44.
Tanabe A, Yamamura Y, Kasahara J, Morigaki R, Kaji R, Goto S. A novel tyrosine kinase inhibitor AMN107 (nilotinib) normalizes striatal motor behaviors in a mouse model of Parkinson’s disease. Front Cell Neurosci. 2014;8:50.
Karuppagounder SS, Brahmachari S, Lee Y, Dawson VL, Dawson TM, Ko HS. The c-Abl inhibitor, Nilotinib, protects dopaminergic neurons in a preclinical animal model of Parkinson’s disease. Sci Rep. 2015;4:4874.
Pagan F, Hebron M, Valadez EH, Torres-Yaghi Y, Huang X, Mills RR, et al. Nilotinib effects in Parkinson’s disease and Dementia with Lewy bodies. J Parkinsons Dis IOS Press. 2016;6:503–17.
Wyse RK, Brundin P, Sherer TB. Nilotinib—differentiating the Hope from the Hype. J Parkinsons Dis. 2016;6:519–22.
Lee S, Kim S, Park YJ, Yun SP, Kwon S-H, Kim D, et al. The c-Abl inhibitor, Radotinib HCl, is neuroprotective in a preclinical Parkinson’s disease mouse model. Hum Mol Genet. 2018;27(13):2344–56. https://doi.org/10.1093/hmg/ddy143.
Carroll CB, Wyse RKH. Simvastatin as a potential disease-modifying therapy for patients with Parkinson’s disease: rationale for clinical trial, and current progress. J Parkinsons Dis. 2017;7:545–68.
Roy A, Pahan K. Prospects of statins in Parkinson disease. Neuroscience. 2011;17:244–55.
Tong H, Zhang X, Meng X, Lu L, Mai D, Qu S. Simvastatin inhibits activation of NADPH oxidase/p38 MAPK pathway and enhances expression of antioxidant protein in Parkinson disease models. Front Mol Neurosci. 2018;11:165.
Yan J, Sun J, Huang L, Fu Q, Du G. Simvastatin prevents neuroinflammation by inhibiting N-methyl-d-aspartic acid receptor 1 in 6-hydroxydopamine-treated PC12 cells. J Neurosci Res. 2014;92:634–40.
Kumar A, Sharma N, Gupta A, Kalonia H, Mishra J. Neuroprotective potential of atorvastatin and simvastatin (HMG-CoA reductase inhibitors) against 6-hydroxydopamine (6-OHDA) induced Parkinson-like symptoms. Brain Res. 2012;1471:13–22.
Ghosh A, Roy A, Matras J, Brahmachari S, Gendelman HE, Pahan K. Simvastatin inhibits the activation of p21ras and prevents the loss of dopaminergic neurons in a mouse model of Parkinson’s disease. J Neurosci. 2009;29:13543–56.
Selley ML. Simvastatin prevents 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced striatal dopamine depletion and protein tyrosine nitration in mice. Brain Res. 2005;1037:1–6.
Bykov K, Yoshida K, Weisskopf MG, Gagne JJ. Confounding of the association between statins and Parkinson disease: systematic review and meta-analysis. Pharmacoepidemiol Drug Saf. 2017;26:294–300.
Lang AE, Espay AJ. Disease modification in Parkinson’s disease: current approaches, challenges, and future considerations. Mov Disord. 2018;33:660–77.
Colca JR, VanderLugt JT, Adams WJ, Shashlo A, McDonald WG, Liang J, et al. Clinical proof-of-concept study with MSDC-0160, a prototype mTOT-modulating insulin sensitizer. Clin Pharmacol Ther. 2013;93:352–9.
Mittal S, Bjørnevik K, Im DS, Flierl A, Dong X, Locascio JJ, et al. β2-Adrenoreceptor is a regulator of the α-synuclein gene driving risk of Parkinson’s disease. Science. American Association for the. Adv Sci. 2017;357:891–8.
Qian L, Wu H, Chen S-H, Zhang D, Ali SF, Peterson L, et al. β2-adrenergic receptor activation prevents rodent dopaminergic neurotoxicity by inhibiting microglia via a novel signaling pathway. J. Immunol. 2011;186:4443–54.
Shah RC, Matthews DC, Andrews RD, Capuano AW, Fleischman DA, VanderLugt JT, et al. An evaluation of MSDC-0160, a prototype mTOT modulating insulin sensitizer, in patients with mild Alzheimer’s disease. Curr Alzheimer Res. 2014;11:564–73.
Ghosh A, Tyson T, George S, Hildebrandt EN, Steiner JA, Madaj Z, et al. Mitochondrial pyruvate carrier regulates autophagy, inflammation, and neurodegeneration in experimental models of Parkinson’s disease. Sci Transl Med. 2016;8:368ra174.
Pan J, Xiao Q, Sheng C-Y, Hong Z, Yang H-Q, Wang G, et al. Blockade of the translocation and activation of c-Jun N-terminal kinase 3 (JNK3) attenuates dopaminergic neuronal damage in mouse model of Parkinson’s disease. Neurochem Int. 2009;54:418–25.
Clark J, Clore EL, Zheng K, Adame A, Masliah E, Simon DK. Oral N-acetyl-cysteine attenuates loss of dopaminergic terminals in alpha-synuclein overexpressing mice. PLoS One. 2010;5:e12333.
Monti DA, Zabrecky G, Kremens D, Liang T-W, Wintering NA, Cai J, et al. N-acetyl cysteine may support dopamine neurons in Parkinson’s disease: preliminary clinical and cell line data. PLoS One. 2016;11:e0157602.
Holmay MJ, Terpstra M, Coles LD, Mishra U, Ahlskog M, Öz G, et al. N-acetylcysteine boosts brain and blood glutathione in Gaucher and Parkinson diseases. Clin Neuropharmacol. 2013;36:103–6.
Coles LD, Tuite PJ, Öz G, Mishra UR, Kartha RV, Sullivan KM, et al. Repeated-dose oral N-acetylcysteine in Parkinson’s disease: pharmacokinetics and effect on brain glutathione and oxidative stress. J Clin Pharmacol. 2018;58:158–67.