Login Register Cart 0
Generic placeholder image

CNS & Neurological Disorders - Drug Targets

Editor-in-Chief

ISSN (Print): 1871-5273
ISSN (Online): 1996-3181

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Mini-Review Article

Clinical Benefits of Therapeutic Interventions Targeting Mitochondria in Parkinson’s Disease Patients

Author(s): Matteo Ciocca* and Chiara Pizzamiglio

Volume 23, Issue 5, 2024

Published on: 06 April, 2023

Page: [554 - 561] Pages: 8

DOI: 10.2174/1871527322666230330122444

open access plus

conference banner
Abstract

Parkinson’s disease is the second most common neurodegenerative disease. Mitochondrial dysfunction has been associated with neurodegeneration in Parkinson’s disease, and several treatments targeting mitochondria have been tested in these patients to delay disease progression and tackle disease symptoms. Herein, we review available data from randomised, double-blind clinical studies that have investigated the role of compounds targeting mitochondria in idiopathic Parkinson’s disease patients, with a view of providing patients and clinicians with a comprehensive and practical paper that can inform therapeutic interventions in this group of people. A total of 9 compounds have been tested in randomized clinical trials, but only exenatide has shown some promising neuroprotective and symptomatic effects. However, whether this evidence can be translated into daily clinical practice still needs to be confirmed. In conclusion, targeting mitochondrial dysfunction in Parkinson’s disease is a promising therapeutic approach, although only one compound has shown a positive effect on Parkinson’s disease progression and symptoms. New compounds have been investigated in animal models, and their efficacy needs to be confirmed in humans through robust, randomised, double-blind clinical trials.

Keywords: Parkinson’s disease, treatment, mitochondria, supplements, neuroprotection, oxidative stress, mitochondrial dysfunction.

« Previous Next »
Graphical Abstract

[1]
Khatter AS, Kurth MC, Brewer MA, et al. Prevalence of tremor and Parkinson’s disease. Parkinsonism Relat Disord 1996; 2(4): 205-8.
[http://dx.doi.org/10.1016/S1353-8020(96)00027-2] [PMID: 18591041]
[2]
Balestrino R, Schapira AHV. Parkinson disease. Eur J Neurol 2020; 27(1): 27-42.
[http://dx.doi.org/10.1111/ene.14108] [PMID: 31631455]
[3]
Spillantini MG, Schmidt ML, Lee VMY, Trojanowski JQ, Jakes R, Goedert M. α-Synuclein in Lewy bodies. Nature 1997; 388(6645): 839-40.
[http://dx.doi.org/10.1038/42166] [PMID: 9278044]
[4]
Bernheimer H, Birkmayer W, Hornykiewicz O, Jellinger K, Seitelberger F. Brain dopamine and the syndromes of Parkinson and Huntington Clinical, morphological and neurochemical correlations. J Neurol Sci 1973; 20(4): 415-55.
[http://dx.doi.org/10.1016/0022-510X(73)90175-5] [PMID: 4272516]
[5]
Blesa J, Trigo-Damas I, Quiroga-Varela A, Jackson-Lewis VR. Oxidative stress and Parkinson’s disease. Front Neuroanat 2015; 9: 91.
[http://dx.doi.org/10.3389/fnana.2015.00091] [PMID: 26217195]
[6]
Dias V, Junn E, Mouradian MM. The role of oxidative stress in Parkinson’s disease. J Parkinsons Dis 2013; 3(4): 461-91.
[http://dx.doi.org/10.3233/JPD-130230] [PMID: 24252804]
[7]
Guo C, Sun L, Chen X, Zhang D. Oxidative stress, mitochondrial damage and neurodegenerative diseases. Neural Regen Res 2013; 8(21): 2003-14.
[http://dx.doi.org/10.3969/j.issn.1673-5374.2013.21.009] [PMID: 25206509]
[8]
Chen C, Turnbull DM, Reeve AK. Mitochondrial dysfunction in Parkinson’s disease—cause or consequence? Biology 2019; 8(2): 38.
[http://dx.doi.org/10.3390/biology8020038] [PMID: 31083583]
[9]
Park JS, Davis RL, Sue CM. Mitochondrial dysfunction in parkinson’s disease: New mechanistic insights and therapeutic perspectives. Curr Neurol Neurosci Rep 2018; 18(5): 21.
[http://dx.doi.org/10.1007/s11910-018-0829-3] [PMID: 29616350]
[10]
Grünewald A, Kumar KR, Sue CM. New insights into the complex role of mitochondria in Parkinson’s disease. Prog Neurobiol 2019; 177: 73-93.
[http://dx.doi.org/10.1016/j.pneurobio.2018.09.003] [PMID: 30219247]
[11]
Liss B, Striessnig J. The potential of l-type calcium channels as a drug target for neuroprotective therapy in Parkinson’s Disease. Annu Rev Pharmacol Toxicol 2019; 59(1): 263-89.
[http://dx.doi.org/10.1146/annurev-pharmtox-010818-021214] [PMID: 30625283]
[12]
Kieburtz K, Tilley BC, Elm JJ, et al. Effect of creatine monohydrate on clinical progression in patients with Parkinson disease: A randomized clinical trial. JAMA 2015; 313(6): 584-93.
[http://dx.doi.org/10.1001/jama.2015.120] [PMID: 25668262]
[13]
Rajendran PR, Thompson RE, Reich SG. The use of alternative therapies by patients with Parkinson’s disease. Neurology 2001; 57(5): 790-4.
[http://dx.doi.org/10.1212/WNL.57.5.790] [PMID: 11552005]
[14]
Wang Y, Xie C, Wang WW, et al. Epidemiology of complementary and alternative medicine use in patients with Parkinson’s disease. J Clin Neurosci 2013; 20(8): 1062-7.
[http://dx.doi.org/10.1016/j.jocn.2012.10.022] [PMID: 23815871]
[15]
Gonzalez-Rodriguez P, Zampese E, Surmeier DJ. Disease mechanisms as Subtypes: Mitochondrial and bioenergetic dysfunction. Handb Clin Neurol 2023; 193: 53-66.
[http://dx.doi.org/10.1016/B978-0-323-85555-6.00007-2] [PMID: 36803823]
[16]
Legati A, Ghezzi D. Parkinson’s Disease, Parkinsonisms, and Mitochondria: The role of nuclear and mitochondrial DNA. Curr Neurol Neurosci Rep 2023. (E-pub ahead of print).
[http://dx.doi.org/10.1007/s11910-023-01260-8] [PMID: 36881253]
[17]
Rabin ML, Stevens-Haas C, Havrilla E, et al. Complementary therapies for parkinson’s disease: What’s promoted, rationale, potential risks and benefits. Mov Disord Clin Pract 2015; 2(3): 205-12.
[http://dx.doi.org/10.1002/mdc3.12170] [PMID: 30363487]
[18]
Ciulla M, Marinelli L, Cacciatore I, Stefano AD. Role of dietary supplements in the management of Parkinson’s Disease. Biomolecules 2019; 9(7): 271.
[http://dx.doi.org/10.3390/biom9070271] [PMID: 31295842]
[19]
Onaolapo OJ, Odeniyi AO, Onaolapo AY. Parkinson’s Disease: Is there a role for dietary and herbal supplements? CNS Neurol Disord Drug Targets 2021; 20(4): 343-65.
[http://dx.doi.org/10.2174/1871527320666210218082954] [PMID: 33602107]
[20]
Hang L, Basil AH, Lim KL. Nutraceuticals in Parkinson’s Disease. Neuromolecular Med 2016; 18(3): 306-21.
[http://dx.doi.org/10.1007/s12017-016-8398-6] [PMID: 27147525]
[21]
Mantle D, Hargreaves IP. Mitochondrial dysfunction and neurodegenerative disorders: Role of nutritional supplementation. Int J Mol Sci 2022; 23(20): 12603.
[http://dx.doi.org/10.3390/ijms232012603] [PMID: 36293457]
[22]
Garrido-Maraver J, Cordero MD, Oropesa-Avila M, et al. Clinical applications of coenzyme Q₁₀. Front Biosci 2014; 19(4): 619-33.
[http://dx.doi.org/10.2741/4231] [PMID: 24389208]
[23]
Crane FL. Biochemical functions of coenzyme Q10. J Am Coll Nutr 2001; 20(6): 591-8.
[http://dx.doi.org/10.1080/07315724.2001.10719063] [PMID: 11771674]
[24]
Shults CW, Oakes D, Kieburtz K, et al. Effects of coenzyme Q10 in early Parkinson disease: evidence of slowing of the functional decline. Arch Neurol 2002; 59(10): 1541-50.
[http://dx.doi.org/10.1001/archneur.59.10.1541] [PMID: 12374491]
[25]
Müller T, Büttner T, Gholipour AF, Kuhn W. Coenzyme Q10 supplementation provides mild symptomatic benefit in patients with Parkinson’s disease. Neurosci Lett 2003; 341(3): 201-4.
[http://dx.doi.org/10.1016/S0304-3940(03)00185-X] [PMID: 12697283]
[26]
Storch A, Jost WH, Vieregge P, et al. Randomized, double-blind, placebo-controlled trial on symptomatic effects of coenzyme Q(10) in Parkinson disease. Arch Neurol 2007; 64(7): 938-44.
[http://dx.doi.org/10.1001/archneur.64.7.nct60005] [PMID: 17502459]
[27]
Beal MF, Oakes D, Shoulson I, et al. A randomized clinical trial of high-dosage coenzyme Q10 in early Parkinson disease: No evidence of benefit. JAMA Neurol 2014; 71(5): 543-52.
[http://dx.doi.org/10.1001/jamaneurol.2014.131] [PMID: 24664227]
[28]
Yoritaka A, Kawajiri S, Yamamoto Y, et al. Randomized, double-blind, placebo-controlled pilot trial of reduced coenzyme Q10 for Parkinson’s disease. Parkinsonism Relat Disord 2015; 21(8): 911-6.
[http://dx.doi.org/10.1016/j.parkreldis.2015.05.022] [PMID: 26054881]
[29]
Li Z, Wang P, Yu Z, et al. The effect of creatine and coenzyme q10 combination therapy on mild cognitive impairment in Parkinson’s disease. Eur Neurol 2015; 73(3-4): 205-11.
[http://dx.doi.org/10.1159/000377676] [PMID: 25792086]
[30]
Snow BJ, Rolfe FL, Lockhart MM, et al. A double-blind, placebo-controlled study to assess the mitochondria-targeted antioxidant MitoQ as a disease-modifying therapy in Parkinson’s disease. Mov Disord 2010; 25(11): 1670-4.
[http://dx.doi.org/10.1002/mds.23148] [PMID: 20568096]
[31]
Monti DA, Zabrecky G, Kremens D, et al. N‐Acetyl cysteine is associated with dopaminergic improvement in Parkinson’s Disease. Clin Pharmacol Ther 2019; 106(4): 884-90.
[http://dx.doi.org/10.1002/cpt.1548] [PMID: 31206613]
[32]
Schwarzschild MA, Schwid SR, Marek K, et al. Serum urate as a predictor of clinical and radiographic progression in Parkinson disease. Arch Neurol 2008; 65(6): 716-23.
[http://dx.doi.org/10.1001/archneur.2008.65.6.nct70003] [PMID: 18413464]
[33]
Parkinson Study Group. DATATOP: A multicenter controlled clinical trial in early Parkinson’s disease. Arch Neurol 1989; 46(10): 1052-60.
[http://dx.doi.org/10.1001/archneur.1989.00520460028009] [PMID: 2508608]
[34]
Schwarzschild MA, Ascherio A, Beal MF, et al. Inosine to increase serum and cerebrospinal fluid urate in Parkinson disease: A randomized clinical trial. JAMA Neurol 2014; 71(2): 141-50.
[http://dx.doi.org/10.1001/jamaneurol.2013.5528] [PMID: 24366103]
[35]
Bluett B, Togasaki DM, Mihaila D, et al. Effect of urate-elevating inosine on early parkinson disease progression. JAMA 2021; 326(10): 926-39.
[http://dx.doi.org/10.1001/jama.2021.10207] [PMID: 34519802]
[36]
Lautrup S, Sinclair DA, Mattson MP, Fang EF. NAD+ in brain aging and neurodegenerative disorders. Cell Metab 2019; 30(4): 630-55.
[http://dx.doi.org/10.1016/j.cmet.2019.09.001] [PMID: 31577933]
[37]
Conze D, Brenner C, Kruger CL. Safety and metabolism of long-term administration of NIAGEN (Nicotinamide Riboside Chloride) in a randomized, double-blind, placebo-controlled clinical trial of healthy overweight adults. Sci Rep 2019; 9(1): 9772.
[http://dx.doi.org/10.1038/s41598-019-46120-z] [PMID: 31278280]
[38]
Brakedal B, Dölle C, Riemer F, et al. The NADPARK study: A randomized phase I trial of nicotinamide riboside supplementation in Parkinson’s disease. Cell Metab 2022; 34(3): 396-407.e6.
[http://dx.doi.org/10.1016/j.cmet.2022.02.001] [PMID: 35235774]
[39]
Bagheri H, Ghasemi F, Barreto GE, Rafiee R, Sathyapalan T, Sahebkar A. Effects of curcumin on mitochondria in neurodegenerative diseases. Biofactors 2020; 46(1): 5-20.
[http://dx.doi.org/10.1002/biof.1566] [PMID: 31580521]
[40]
Ghodsi H, Rahimi HR, Aghili SM, Saberi A, Shoeibi A. Evaluation of curcumin as add-on therapy in patients with Parkinson’s disease: A pilot randomized, triple-blind, placebo-controlled trial. Clin Neurol Neurosurg 2022; 218: 107300.
[http://dx.doi.org/10.1016/j.clineuro.2022.107300] [PMID: 35636380]
[41]
Mortiboys H, Furmston R, Bronstad G, Aasly J, Elliott C, Bandmann O. UDCA exerts beneficial effect on mitochondrial dysfunction in LRRK2G2019S carriers and in vivo. Neurology 2015; 85(10): 846-52.
[http://dx.doi.org/10.1212/WNL.0000000000001905] [PMID: 26253449]
[42]
Qi H, Shen D, Jiang C, Wang H, Chang M. Ursodeoxycholic acid protects dopaminergic neurons from oxidative stress via regulating mitochondrial function, autophagy, and apoptosis in MPTP/MPP+-induced Parkinson’s disease. Neurosci Lett 2021; 741: 135493.
[http://dx.doi.org/10.1016/j.neulet.2020.135493] [PMID: 33181233]
[43]
Sathe AG, Tuite P, Chen C, et al. Pharmacokinetics, safety, and tolerability of orally administered ursodeoxycholic acid in patients with Parkinson’s disease-a pilot study. J Clin Pharmacol 2020; 60(6): 744-50.
[http://dx.doi.org/10.1002/jcph.1575] [PMID: 32052462]
[44]
Payne T, Sassani M, Buckley E, et al. Ursodeoxycholic acid as a novel disease-modifying treatment for Parkinson’s disease: Protocol for a two-centre, randomised, double-blind, placebo-controlled trial, The ‘UP’ study. BMJ Open 2020; 10(8): e038911.
[http://dx.doi.org/10.1136/bmjopen-2020-038911] [PMID: 32759251]
[45]
Froiland K, Koszewski W, Hingst J, Kopecky L. Nutritional supplement use among college athletes and their sources of information. Int J Sport Nutr Exerc Metab 2004; 14(1): 104-20.
[http://dx.doi.org/10.1123/ijsnem.14.1.104] [PMID: 15129934]
[46]
Bender A, Koch W, Elstner M, et al. Creatine supplementation in Parkinson disease: A placebo-controlled randomized pilot trial. Neurology 2006; 67(7): 1262-4.
[http://dx.doi.org/10.1212/01.wnl.0000238518.34389.12] [PMID: 17030762]
[47]
Simon DK, Wu C, Tilley BC, et al. Caffeine and progression of Parkinson Disease. Clin Neuropharmacol 2015; 38(5): 163-9.
[http://dx.doi.org/10.1097/WNF.0000000000000102] [PMID: 26366971]
[48]
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(1): 19.
[http://dx.doi.org/10.1186/1742-2094-5-19] [PMID: 18492290]
[49]
Aviles-Olmos I, Dickson J, Kefalopoulou Z, et al. Exenatide and the treatment of patients with Parkinson’s disease. J Clin Invest 2013; 123(6): 2730-6.
[http://dx.doi.org/10.1172/JCI68295] [PMID: 23728174]
[50]
Athauda D, Maclagan K, Skene SS, et al. Exenatide once weekly versus placebo in Parkinson’s disease: A randomised, double-blind, placebo-controlled trial. Lancet 2017; 390(10103): 1664-75.
[http://dx.doi.org/10.1016/S0140-6736(17)31585-4] [PMID: 28781108]
[51]
Athauda D, Maclagan K, Budnik N, 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.
[http://dx.doi.org/10.3233/JPD-181329] [PMID: 29843254]
[52]
Athauda D, Maclagan K, Budnik N, et al. Post hoc analysis of the Exenatide-PD trial-Factors that predict response. Eur J Neurosci 2019; 49(3): 410-21.
[http://dx.doi.org/10.1111/ejn.14096] [PMID: 30070753]
[53]
Vijiaratnam N, Girges C, Auld G, et al. Exenatide once weekly over 2 years as a potential disease-modifying treatment for Parkinson’s disease: protocol for a multicentre, randomised, double blind, parallel group, placebo controlled, phase 3 trial: The ‘Exenatide-PD3’ study. BMJ Open 2021; 11(5): e047993.
[http://dx.doi.org/10.1136/bmjopen-2020-047993] [PMID: 34049922]
[54]
NINDS Exploratory Trials. in Parkinson Disease (NET-PD) FS-ZONE Investigators. Pioglitazone in early Parkinson’s disease: A phase 2, multicentre, double-blind, randomised trial. Lancet Neurol 2015; 14(8): 795-803.
[http://dx.doi.org/10.1016/S1474-4422(15)00144-1] [PMID: 26116315]
[55]
Parkinson Study Group STEADY-PD III Investigators. Isradipine versus placebo in early Parkinson Disease. Ann Intern Med 2020; 172(9): 591-8.
[http://dx.doi.org/10.7326/M19-2534] [PMID: 32227247]
[56]
Venuto CS, Yang L, Javidnia M, Oakes D, James SD, Simuni T. Isradipine plasma pharmacokinetics and exposure–response in early Parkinson’s disease. Ann Clin Transl Neurol 2021; 8(3): 603-12.
[http://dx.doi.org/10.1002/acn3.51300] [PMID: 33460320]
[57]
Surmeier DJ, Nguyen JT, Lancki N, et al. Re‐analysis of the STEADY‐PD II trial-evidence for slowing the progression of Parkinson’s Disease. Mov Disord 2022; 37(2): 334-42.
[http://dx.doi.org/10.1002/mds.28850] [PMID: 34766657]

Rights & Permissions Print Cite
Article Metrics
64
1
Wayfinder Image
© 2024 Bentham Science Publishers | Privacy Policy