Skip to main content

Neuroprotective strategies to prevent and treat Parkinson’s disease based on its pathophysiological mechanism

Archives of Pharmacal Research volume 40, pages 1117–1128 (2017)Cite this article

Abstract

Parkinson’s disease (PD) is the second most common progressive neurodegenerative disease after Alzheimer’s disease. PD exhibits clinical symptoms that include tremors, rigidity, and bradykinesia. Many drugs are available to treat PD, such as, l-dopa, COMT inhibitor, MAO-B inhibitor, and dopamine agonists, but these drugs simply compensate for dopamine loss in PD, and therefore, cannot completely suppress its symptoms or progression. Although the causes of PD are not clearly understood, common pathophysiological pathways, such as, oxidative stress, mitochondrial dysfunction, and neuroinflammation are considered to be etiological factors, and thus, many treatments and interventions have been developed to target these pathophysiological factors. This review describes the neuroprotective strategies devised based on current understanding of the pathophysiological mechanisms of PD.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

43,34 €

Price includes VAT (Finland)
Tax calculation will be finalised during checkout.

References

  • Alvira D, Yeste-Velasco M, Folch J, Verdaguer E, Canudas AM, Pallas M, Camins A (2007) Comparative analysis of the effects of resveratrol in two apoptotic models: inhibition of complex I and potassium deprivation in cerebellar neurons. Neuroscience 147:746–756

    CAS  PubMed  Article  Google Scholar 

  • Antunes MS, Goes AT, Boeira SP, Prigol M, Jesse CR (2014) Protective effect of hesperidin in a model of Parkinson’s disease induced by 6-hydroxydopamine in aged mice. Nutrition 30:1415–1422

    CAS  PubMed  Article  Google Scholar 

  • Arun S, Liu L, Donmez G (2016) Mitochondrial biology and neurological diseases. Curr Neuropharmacol 14:143–154

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Assaf F, Fishbein M, Gafni M, Keren O, Sarne Y (2011) Pre- and post-conditioning treatment with an ultra-low dose of Delta9-tetrahydrocannabinol (THC) protects against pentylenetetrazole (PTZ)-induced cognitive damage. Behav Brain Res 220:194–201

    CAS  PubMed  Article  Google Scholar 

  • Baluchnejadmojarad T, Rabiee N, Zabihnejad S, Roghani M (2017) Ellagic acid exerts protective effect in intrastriatal 6-hydroxydopamine rat model of Parkinson’s disease: possible involvement of ERbeta/Nrf2/HO-1 signaling. Brain Res 1662:23–30

    CAS  PubMed  Article  Google Scholar 

  • Biskup S, Moore DJ (2006) Detrimental deletions: mitochondria, aging and Parkinson’s disease. BioEssays 28:963–967

    CAS  PubMed  Article  Google Scholar 

  • Blanchet J, Longpre F, Bureau G, Morissette M, Dipaolo T, Bronchti G, Martinoli MG (2008) Resveratrol, a red wine polyphenol, protects dopaminergic neurons in MPTP-treated mice. Prog Neuropsychopharmacol Biol Psychiatry 32:1243–1250

    CAS  PubMed  Article  Google Scholar 

  • Blesa J, Trigo-Damas I, Quiroga-Varela A, Jackson-Lewis VR (2015) Oxidative stress and Parkinson’s disease. Front Neuroanat 9:91

    PubMed  PubMed Central  Google Scholar 

  • Block ML, Hong JS (2007) Chronic microglial activation and progressive dopaminergic neurotoxicity. Biochem Soc Trans 35:1127–1132

    CAS  PubMed  Article  Google Scholar 

  • Blum D, Torch S, Lambeng N, Nissou M, Benabid AL, Sadoul R, Verna JM (2001) Molecular pathways involved in the neurotoxicity of 6-OHDA, dopamine and MPTP: contribution to the apoptotic theory in Parkinson’s disease. Prog Neurobiol 65:135–172

    CAS  PubMed  Article  Google Scholar 

  • Bournival J, Plouffe M, Renaud J, Provencher C, Martinoli MG (2012) Quercetin and sesamin protect dopaminergic cells from MPP+-induced neuroinflammation in a microglial (N9)-neuronal (PC12) coculture system. Oxid Med Cell Longev 2012:921941

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  • Boveris A, Navarro A (2008) Systemic and mitochondrial adaptive responses to moderate exercise in rodents. Free Radic Biol Med 44:224–229

    CAS  PubMed  Article  Google Scholar 

  • Brochard V, Combadiere B, Prigent A, Laouar Y, Perrin A, Beray-Berthat V, Bonduelle O, Alvarez-Fischer D, Callebert J, Launay JM, Duyckaerts C, Flavell RA, Hirsch EC, Hunot S (2009) Infiltration of CD4+ lymphocytes into the brain contributes to neurodegeneration in a mouse model of Parkinson disease. J Clin Invest 119:182–192

    CAS  PubMed  Google Scholar 

  • Cacabelos R (2017) Parkinson’s disease: from pathogenesis to pharmacogenomics. Int J Mol Sci 18:551

    PubMed Central  Article  Google Scholar 

  • Cadet JL, Brannock C (1998) Free radicals and the pathobiology of brain dopamine systems. Neurochem Int 32:117–131

    CAS  PubMed  Article  Google Scholar 

  • Calabrese EJ, Bachmann KA, Bailer AJ, Bolger PM, Borak J, Cai L, Cedergreen N, Cherian MG, Chiueh CC, Clarkson TW, Cook RR, Diamond DM, Doolittle DJ, Dorato MA, Duke SO, Feinendegen L, Gardner DE, Hart RW, Hastings KL, Hayes AW, Hoffmann GR, Ives JA, Jaworowski Z, Johnson TE, Jonas WB, Kaminski NE, Keller JG, Klaunig JE, Knudsen TB, Kozumbo WJ, Lettieri T, Liu SZ, Maisseu A, Maynard KI, Masoro EJ, Mcclellan RO, Mehendale HM, Mothersill C, Newlin DB, Nigg HN, Oehme FW, Phalen RF, Philbert MA, Rattan SI, Riviere JE, Rodricks J, Sapolsky RM, Scott BR, Seymour C, Sinclair DA, Smith-Sonneborn J, Snow ET, Spear L, Stevenson DE, Thomas Y, Tubiana M, Williams GM, Mattson MP (2007) Biological stress response terminology: integrating the concepts of adaptive response and preconditioning stress within a hormetic dose-response framework. Toxicol Appl Pharmacol 222:122–128

    CAS  PubMed  Article  Google Scholar 

  • Cannon JR, Keep RF, Hua Y, Richardson RJ, Schallert T, Xi G (2005) Thrombin preconditioning provides protection in a 6-hydroxydopamine Parkinson’s disease model. Neurosci Lett 373:189–194

    CAS  PubMed  Article  Google Scholar 

  • Cao Q, Qin L, Huang F, Wang X, Yang L, Shi H, Wu H, Zhang B, Chen Z, Wu X (2017) Amentoflavone protects dopaminergic neurons in MPTP-induced Parkinson’s disease model mice through PI3K/Akt and ERK signaling pathways. Toxicol Appl Pharmacol 319:80–90

    PubMed  Article  Google Scholar 

  • Chan YC, Suzuki M, Yamamoto S (1997) Dietary, anthropometric, hematological and biochemical assessment of the nutritional status of centenarians and elderly people in Okinawa, Japan. J Am Coll Nutr 16:229–235

    CAS  PubMed  Article  Google Scholar 

  • Chen RW, Saunders PA, Wei H, Li Z, Seth P, Chuang DM (1999) Involvement of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and p53 in neuronal apoptosis: evidence that GAPDH is upregulated by p53. J Neurosci 19:9654–9662

    CAS  PubMed  Google Scholar 

  • Chen ZH, Yoshida Y, Saito Y, Niki E (2005) Adaptation to hydrogen peroxide enhances PC12 cell tolerance against oxidative damage. Neurosci Lett 383:256–259

    CAS  PubMed  Article  Google Scholar 

  • Chen HQ, Jin ZY, Wang XJ, Xu XM, Deng L, Zhao JW (2008) Luteolin protects dopaminergic neurons from inflammation-induced injury through inhibition of microglial activation. Neurosci Lett 448:175–179

    CAS  PubMed  Article  Google Scholar 

  • Chen Z, Jalabi W, Shpargel KB, Farabaugh KT, Dutta R, Yin X, Kidd GJ, Bergmann CC, Stohlman SA, Trapp BD (2012) Lipopolysaccharide-induced microglial activation and neuroprotection against experimental brain injury is independent of hematogenous TLR4. J Neurosci 32:11706–11715

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Choi JS, Choi KM, Lee CK (2011) Caloric restriction improves efficiency and capacity of the mitochondrial electron transport chain in Saccharomyces cerevisiae. Biochem Biophys Res Commun 409:308–314

    CAS  PubMed  Article  Google Scholar 

  • Cohen AD, Tillerson JL, Smith AD, Schallert T, Zigmond MJ (2003) Neuroprotective effects of prior limb use in 6-hydroxydopamine-treated rats: possible role of GDNF. J Neurochem 85:299–305

    CAS  PubMed  Article  Google Scholar 

  • Colman RJ, Anderson RM, Johnson SC, Kastman EK, Kosmatka KJ, Beasley TM, Allison DB, Cruzen C, Simmons HA, Kemnitz JW, Weindruch R (2009) Caloric restriction delays disease onset and mortality in rhesus monkeys. Science 325:201–204

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Colman RJ, Beasley TM, Kemnitz JW, Johnson SC, Weindruch R, Anderson RM (2014) Caloric restriction reduces age-related and all-cause mortality in rhesus monkeys. Nat Commun 5:3557

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  • Cotman CW, Berchtold NC, Christie LA (2007) Exercise builds brain health: key roles of growth factor cascades and inflammation. Trends Neurosci 30:464–472

    CAS  PubMed  Article  Google Scholar 

  • Danielson SR, Andersen JK (2008) Oxidative and nitrative protein modifications in Parkinson’s disease. Free Radic Biol Med 44:1787–1794

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • De Lau LM, Breteler MM (2006) Epidemiology of Parkinson’s disease. Lancet Neurol 5:525–535

    PubMed  Article  Google Scholar 

  • De Rijk MC, Tzourio C, Breteler MM, Dartigues JF, Amaducci L, Lopez-Pousa S, Manubens-Bertran JM, Alperovitch A, Rocca WA (1997) Prevalence of parkinsonism and Parkinson’s disease in Europe: the EUROPARKINSON Collaborative Study. European Community Concerted Action on the Epidemiology of Parkinson’s disease. J Neurol Neurosurg Psychiatry 62:10–15

    PubMed  PubMed Central  Article  Google Scholar 

  • Deas E, Plun-Favreau H, Wood NW (2009) PINK1 function in health and disease. EMBO Mol Med 1:152–165

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Denny AP, Behari M (1999) Motor fluctuations in Parkinson’s disease. J Neurol Sci 165:18–23

    CAS  PubMed  Article  Google Scholar 

  • Duan W, Mattson MP (1999) Dietary restriction and 2-deoxyglucose administration improve behavioral outcome and reduce degeneration of dopaminergic neurons in models of Parkinson’s disease. J Neurosci Res 57:195–206

    CAS  PubMed  Article  Google Scholar 

  • Duzel E, Van Praag H, Sendtner M (2016) Can physical exercise in old age improve memory and hippocampal function? Brain 139:662–673

    PubMed  PubMed Central  Article  Google Scholar 

  • Elkins GR (2017) Parkinson's disease. Springer, NY

    Google Scholar 

  • Erickson KI, Voss MW, Prakash RS, Basak C, Szabo A, Chaddock L, Kim JS, Heo S, Alves H, White SM, Wojcicki TR, Mailey E, Vieira VJ, Martin SA, Pence BD, Woods JA, Mcauley E, Kramer AF (2011) Exercise training increases size of hippocampus and improves memory. Proc Natl Acad Sci USA 108:3017–3022

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Factor SA (2008) Current status of symptomatic medical therapy in Parkinson’s disease. Neurotherapeutics 5:164–180

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Federico A, Cardaioli E, Da Pozzo P, Formichi P, Gallus GN, Radi E (2012) Mitochondria, oxidative stress and neurodegeneration. J Neurol Sci 322:254–262

    CAS  PubMed  Article  Google Scholar 

  • Filomeni G, Graziani I, De Zio D, Dini L, Centonze D, Rotilio G, Ciriolo MR (2012) Neuroprotection of kaempferol by autophagy in models of rotenone-mediated acute toxicity: possible implications for Parkinson’s disease. Neurobiol Aging 33:767–785

    CAS  PubMed  Article  Google Scholar 

  • Fleming SM, Espay AJ (2014) Cinnamon in a mouse model of PD: Khasnavis S, Pahan K. Cinnamon protects dopaminergic neurons in a mouse model of Parkinson’s disease. J Neuroimmune Pharmacol 2014;9:569-581. Mov Disord 29:1466

    PubMed  Article  Google Scholar 

  • Franco-Iborra S, Vila M, Perier C (2016) The Parkinson disease mitochondrial hypothesis: where are we at? Neuroscientist 22:266–277

    CAS  PubMed  Article  Google Scholar 

  • Gaballah HH, Zakaria SS, Elbatsh MM, Tahoon NM (2016) Modulatory effects of resveratrol on endoplasmic reticulum stress-associated apoptosis and oxido-inflammatory markers in a rat model of rotenone-induced Parkinson’s disease. Chem Biol Interact 251:10–16

    CAS  PubMed  Article  Google Scholar 

  • Gandhi S, Wood-Kaczmar A, Yao Z, Plun-Favreau H, Deas E, Klupsch K, Downward J, Latchman DS, Tabrizi SJ, Wood NW, Duchen MR, Abramov AY (2009) PINK1-associated Parkinson’s disease is caused by neuronal vulnerability to calcium-induced cell death. Mol Cell 33:627–638

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Gandhi S, Vaarmann A, Yao Z, Duchen MR, Wood NW, Abramov AY (2012) Dopamine induced neurodegeneration in a PINK1 model of Parkinson’s disease. PLoS ONE 7:e37564

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Gao X, Cassidy A, Schwarzschild MA, Rimm EB, Ascherio A (2012a) Habitual intake of dietary flavonoids and risk of Parkinson disease. Neurology 78:1138–1145

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Gao X, Simon KC, Schwarzschild MA, Ascherio A (2012b) Prospective study of statin use and risk of Parkinson disease. Arch Neurol 69:380–384

    PubMed  PubMed Central  Article  Google Scholar 

  • Goldman SM, Tanner CM, Oakes D, Bhudhikanok GS, Gupta A, Langston JW (2006) Head injury and Parkinson’s disease risk in twins. Ann Neurol 60:65–72

    PubMed  Article  Google Scholar 

  • Golpich M, Rahmani B, Mohamed Ibrahim N, Dargahi L, Mohamed Z, Raymond AA, Ahmadiani A (2015) Preconditioning as a potential strategy for the prevention of Parkinson’s disease. Mol Neurobiol 51:313–330

    CAS  PubMed  Article  Google Scholar 

  • Griffioen KJ, Rothman SM, Ladenheim B, Wan R, Vranis N, Hutchison E, Okun E, Cadet JL, Mattson MP (2013) Dietary energy intake modifies brainstem autonomic dysfunction caused by mutant alpha-synuclein. Neurobiol Aging 34:928–935

    CAS  PubMed  Article  Google Scholar 

  • Grundlingh J, Dargan PI, El-Zanfaly M, Wood DM (2011) 2,4-dinitrophenol (DNP): a weight loss agent with significant acute toxicity and risk of death. J Med Toxicol 7:205–212

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Hald A, Lotharius J (2005) Oxidative stress and inflammation in Parkinson’s disease: is there a causal link? Exp Neurol 193:279–290

    CAS  PubMed  Article  Google Scholar 

  • Hamidi GA, Faraji A, Zarmehri HA, Haghdoost-Yazdi H (2012) Prolonged hyperoxia preconditioning attenuates behavioral symptoms of 6-hydroxydopamine-induced Parkinsonism. Neurol Res 34:636–642

    CAS  PubMed  Article  Google Scholar 

  • Han JM, Lee YJ, Lee SY, Kim EM, Moon Y, Kim HW, Hwang O (2007) Protective effect of sulforaphane against dopaminergic cell death. J Pharmacol Exp Ther 321:249–256

    CAS  PubMed  Article  Google Scholar 

  • Hancock DB, Martin ER, Vance JM, Scott WK (2008) Nitric oxide synthase genes and their interactions with environmental factors in Parkinson’s disease. Neurogenetics 9:249–262

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Hatano T, Kubo S, Sato S, Hattori N (2009) Pathogenesis of familial Parkinson’s disease: new insights based on monogenic forms of Parkinson’s disease. J Neurochem 111:1075–1093

    CAS  PubMed  Article  Google Scholar 

  • Heetun ZS, Quigley EM (2012) Gastroparesis and Parkinson’s disease: a systematic review. Parkinsonism Relat Disord 18:433–440

    PubMed  Article  Google Scholar 

  • Hernan MA, Takkouche B, Caamano-Isorna F, Gestal-Otero JJ (2002) A meta-analysis of coffee drinking, cigarette smoking, and the risk of Parkinson’s disease. Ann Neurol 52:276–284

    PubMed  Article  Google Scholar 

  • Hickey E, Shi H, Van Arsdell G, Askalan R (2011) Lipopolysaccharide-induced preconditioning against ischemic injury is associated with changes in toll-like receptor 4 expression in the rat developing brain. Pediatr Res 70:10–14

    CAS  PubMed  Article  Google Scholar 

  • Hirsch EC (1993) Does oxidative stress participate in nerve cell death in Parkinson’s disease? Eur Neurol 33(Suppl 1):52–59

    PubMed  Google Scholar 

  • Hirsch EC, Breidert T, Rousselet E, Hunot S, Hartmann A, Michel PP (2003) The role of glial reaction and inflammation in Parkinson’s disease. Ann N Y Acad Sci 991:214–228

    CAS  PubMed  Article  Google Scholar 

  • Holmer HK, Keyghobadi M, Moore C, Menashe RA, Meshul CK (2005) Dietary restriction affects striatal glutamate in the MPTP-induced mouse model of nigrostriatal degeneration. Synapse 57:100–112

    CAS  PubMed  Article  Google Scholar 

  • Howitz KT, Bitterman KJ, Cohen HY, Lamming DW, Lavu S, Wood JG, Zipkin RE, Chung P, Kisielewski A, Zhang LL, Scherer B, Sinclair DA (2003) Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature 425:191–196

    CAS  PubMed  Article  Google Scholar 

  • Im AR, Kim YH, Uddin MR, Chae S, Lee HW, Kim YS, Lee MY (2013) Betaine protects against rotenone-induced neurotoxicity in PC12 cells. Cell Mol Neurobiol 33:625–635

    CAS  PubMed  Article  Google Scholar 

  • Jiang J, Zuo Y, Gu Z (2013) Rapamycin protects the mitochondria against oxidative stress and apoptosis in a rat model of Parkinson’s disease. Int J Mol Med 31:825–832

    CAS  PubMed  Article  Google Scholar 

  • Karlsson O, Lindquist NG (2013) Melanin affinity and its possible role in neurodegeneration. J Neural Transm (Vienna) 120:1623–1630

    CAS  Article  Google Scholar 

  • Karuppagounder SS, Madathil SK, Pandey M, Haobam R, Rajamma U, Mohanakumar KP (2013) Quercetin up-regulates mitochondrial complex-I activity to protect against programmed cell death in rotenone model of Parkinson’s disease in rats. Neuroscience 236:136–148

    CAS  PubMed  Article  Google Scholar 

  • Kavitha M, Nataraj J, Essa MM, Memon MA, Manivasagam T (2013) Mangiferin attenuates MPTP induced dopaminergic neurodegeneration and improves motor impairment, redox balance and Bcl-2/Bax expression in experimental Parkinson’s disease mice. Chem Biol Interact 206:239–247

    CAS  PubMed  Article  Google Scholar 

  • Khan MM, Ahmad A, Ishrat T, Khan MB, Hoda MN, Khuwaja G, Raza SS, Khan A, Javed H, Vaibhav K, Islam F (2010) Resveratrol attenuates 6-hydroxydopamine-induced oxidative damage and dopamine depletion in rat model of Parkinson’s disease. Brain Res 1328:139–151

    CAS  PubMed  Article  Google Scholar 

  • Khan MM, Raza SS, Javed H, Ahmad A, Khan A, Islam F, Safhi MM (2012) Rutin protects dopaminergic neurons from oxidative stress in an animal model of Parkinson’s disease. Neurotox Res 22:1–15

    PubMed  Article  CAS  Google Scholar 

  • Kim Y, Park J, Kim S, Song S, Kwon SK, Lee SH, Kitada T, Kim JM, Chung J (2008) PINK1 controls mitochondrial localization of Parkin through direct phosphorylation. Biochem Biophys Res Commun 377:975–980

    CAS  PubMed  Article  Google Scholar 

  • Kim HG, Ju MS, Ha SK, Lee H, Kim SY, Oh MS (2012) Acacetin protects dopaminergic cells against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced neuroinflammation in vitro and in vivo. Biol Pharm Bull 35:1287–1294

    CAS  PubMed  Article  Google Scholar 

  • Kim GH, Kim JE, Rhie SJ, Yoon S (2015) The Role of Oxidative Stress in Neurodegenerative Diseases. Exp Neurobiol 24:325–340

    PubMed  PubMed Central  Article  Google Scholar 

  • Lee HJ, Cho HS, Park E, Kim S, Lee SY, Kim CS, Kim DK, Kim SJ, Chun HS (2008) Rosmarinic acid protects human dopaminergic neuronal cells against hydrogen peroxide-induced apoptosis. Toxicology 250:109–115

    CAS  PubMed  Article  Google Scholar 

  • Lee E, Park HR, Ji ST, Lee Y, Lee J (2014) Baicalein attenuates astroglial activation in the 1-methyl-4-phenyl-1,2,3,4-tetrahydropyridine-induced Parkinson’s disease model by downregulating the activations of nuclear factor-kappaB, ERK, and JNK. J Neurosci Res 92:130–139

    CAS  PubMed  Article  Google Scholar 

  • Lee Y, Chun HJ, Lee KM, Jung YS, Lee J (2015a) Silibinin suppresses astroglial activation in a mouse model of acute Parkinson’s disease by modulating the ERK and JNK signaling pathways. Brain Res 1627:233–242

    CAS  PubMed  Article  Google Scholar 

  • Lee Y, Park HR, Chun HJ, Lee J (2015b) Silibinin prevents dopaminergic neuronal loss in a mouse model of Parkinson’s disease via mitochondrial stabilization. J Neurosci Res 93:755–765

    CAS  PubMed  Article  Google Scholar 

  • Lee Y, Heo G, Lee KM, Kim AH, Chung KW, Im E, Chung HY, Lee J (2017) Neuroprotective effects of 2,4-dinitrophenol in an acute model of Parkinson’s disease. Brain Res 1663:184–193

    CAS  PubMed  Article  Google Scholar 

  • Li FQ, Wang T, Pei Z, Liu B, Hong JS (2005) Inhibition of microglial activation by the herbal flavonoid baicalein attenuates inflammation-mediated degeneration of dopaminergic neurons. J Neural Transm (Vienna) 112:331–347

    CAS  Article  Google Scholar 

  • Lin MT, Beal MF (2006) Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature 443:787–795

    CAS  PubMed  Article  Google Scholar 

  • Liu K, Shi N, Sun Y, Zhang T, Sun X (2013) Therapeutic effects of rapamycin on MPTP-induced Parkinsonism in mice. Neurochem Res 38:201–207

    CAS  PubMed  Article  Google Scholar 

  • Lopes UG, Erhardt P, Yao R, Cooper GM (1997) p53-dependent induction of apoptosis by proteasome inhibitors. J Biol Chem 272:12893–12896

    CAS  PubMed  Article  Google Scholar 

  • Lou H, Jing X, Wei X, Shi H, Ren D, Zhang X (2014) Naringenin protects against 6-OHDA-induced neurotoxicity via activation of the Nrf2/ARE signaling pathway. Neuropharmacology 79:380–388

    CAS  PubMed  Article  Google Scholar 

  • Lv C, Hong T, Yang Z, Zhang Y, Wang L, Dong M, Zhao J, Mu J, Meng Y (2012) Effect of quercetin in the 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine-induced mouse model of Parkinson’s disease. Evid Complement Altern Med 2012:928643

    Google Scholar 

  • Ma ZG, Wang J, Jiang H, Liu TW, Xie JX (2007) Myricetin reduces 6-hydroxydopamine-induced dopamine neuron degeneration in rats. NeuroReport 18:1181–1185

    CAS  PubMed  Article  Google Scholar 

  • Magalingam KB, Radhakrishnan A, Haleagrahara N (2013) Rutin, a bioflavonoid antioxidant protects rat pheochromocytoma (PC-12) cells against 6-hydroxydopamine (6-OHDA)-induced neurotoxicity. Int J Mol Med 32:235–240

    CAS  PubMed  Article  Google Scholar 

  • Magalingam KB, Radhakrishnan A, Haleagrahara N (2014) Protective effects of flavonol isoquercitrin, against 6-hydroxy dopamine (6-OHDA)-induced toxicity in PC12 cells. BMC Res Notes 7:49

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  • Maggio R, Barbier P, Corsini GU (1995) Apomorphine continuous stimulation in Parkinson’s disease: receptor desensitization as a possible mechanism of reduced motor response. J Neural Transm Suppl 45:133–136

    CAS  PubMed  Google Scholar 

  • Malagelada C, Jin ZH, Jackson-Lewis V, Przedborski S, Greene LA (2010) Rapamycin protects against neuron death in in vitro and in vivo models of Parkinson’s disease. J Neurosci 30:1166–1175

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Massano J, Bhatia KP (2012) Clinical approach to Parkinson’s disease: features, diagnosis, and principles of management. Cold Spring Harb Perspect Med 2:a008870

    PubMed  PubMed Central  Article  Google Scholar 

  • Mattison JA, Roth GS, Beasley TM, Tilmont EM, Handy AM, Herbert RL, Longo DL, Allison DB, Young JE, Bryant M, Barnard D, Ward WF, Qi W, Ingram DK, De Cabo R (2012) Impact of caloric restriction on health and survival in rhesus monkeys from the NIA study. Nature 489:318–321

    CAS  PubMed  Article  Google Scholar 

  • Mcnaught KS, Olanow CW, Halliwell B, Isacson O, Jenner P (2001) Failure of the ubiquitin-proteasome system in Parkinson’s disease. Nat Rev Neurosci 2:589–594

    CAS  PubMed  Article  Google Scholar 

  • Merritt JR, Rhodes JS (2015) Mouse genetic differences in voluntary wheel running, adult hippocampal neurogenesis and learning on the multi-strain-adapted plus water maze. Behav Brain Res 280:62–71

    PubMed  Article  Google Scholar 

  • Minault P, Madigand M, Sabouraud O (1981) Pallidostriatal necrosis after Hymenoptera sting. Parkinsonian syndrome. Nouv Presse Med 10:3725–3726

    CAS  PubMed  Google Scholar 

  • Mochizuki H, Goto K, Mori H, Mizuno Y (1996) Histochemical detection of apoptosis in Parkinson’s disease. J Neurol Sci 137:120–123

    CAS  PubMed  Article  Google Scholar 

  • Muller T (2015) Catechol-O-methyltransferase inhibitors in Parkinson’s disease. Drugs 75:157–174

    PubMed  Article  CAS  Google Scholar 

  • Mythri RB, Bharath MM (2012) Curcumin: a potential neuroprotective agent in Parkinson’s disease. Curr Pharm Des 18:91–99

    CAS  PubMed  Article  Google Scholar 

  • Nagatsu T, Mogi M, Ichinose H, Togari A (2000) Cytokines in Parkinson’s disease. J Neural Transm Suppl 58:143–151

    Google Scholar 

  • Napolitano A, Del Dotto P, Petrozzi L, Dell’agnello G, Bellini G, Gambaccini G, Bonuccelli U (1999) Pharmacokinetics and pharmacodynamics of l-Dopa after acute and 6-week tolcapone administration in patients with Parkinson’s disease. Clin Neuropharmacol 22:24–29

    CAS  PubMed  Article  Google Scholar 

  • Navarro A, Boveris A (2009) Brain mitochondrial dysfunction and oxidative damage in Parkinson’s disease. J Bioenerg Biomembr 41:517–521

    CAS  PubMed  Article  Google Scholar 

  • Nie G, Cao Y, Zhao B (2002) Protective effects of green tea polyphenols and their major component, (-)-epigallocatechin-3-gallate (EGCG), on 6-hydroxydopamine-induced apoptosis in PC12 cells. Redox Rep 7:171–177

    CAS  PubMed  Article  Google Scholar 

  • Nussbaum RL, Ellis CE (2003) Alzheimer’s disease and Parkinson’s disease. N Engl J Med 348:1356–1364

    CAS  PubMed  Article  Google Scholar 

  • Pan MH, Lai CS, Ho CT (2010) Anti-inflammatory activity of natural dietary flavonoids. Food Funct 1:15–31

    CAS  PubMed  Article  Google Scholar 

  • Patten DA, Germain M, Kelly MA, Slack RS (2010) Reactive oxygen species: stuck in the middle of neurodegeneration. J Alzheimers Dis 20(Suppl 2):S357–367

    PubMed  Article  CAS  Google Scholar 

  • Perier C, Bove J, Wu DC, Dehay B, Choi DK, Jackson-Lewis V, Rathke-Hartlieb S, Bouillet P, Strasser A, Schulz JB, Przedborski S, Vila M (2007) Two molecular pathways initiate mitochondria-dependent dopaminergic neurodegeneration in experimental Parkinson’s disease. Proc Natl Acad Sci USA 104:8161–8166

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Piccoli C, Sardanelli A, Scrima R, Ripoli M, Quarato G, D’aprile A, Bellomo F, Scacco S, De Michele G, Filla A, Iuso A, Boffoli D, Capitanio N, Papa S (2008) Mitochondrial respiratory dysfunction in familiar parkinsonism associated with PINK1 mutation. Neurochem Res 33:2565–2574

    CAS  PubMed  Article  Google Scholar 

  • Poewe W, Mahlknecht P (2009) The clinical progression of Parkinson’s disease. Parkinsonism Relat Disord 15(Suppl 4):S28–32

    PubMed  Article  Google Scholar 

  • Poole AC, Thomas RE, Andrews LA, Mcbride HM, Whitworth AJ, Pallanck LJ (2008) The PINK1/Parkin pathway regulates mitochondrial morphology. Proc Natl Acad Sci USA 105:1638–1643

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Qiu G, Spangler EL, Wan R, Miller M, Mattson MP, So KF, De Cabo R, Zou S, Ingram DK (2012) Neuroprotection provided by dietary restriction in rats is further enhanced by reducing glucocortocoids. Neurobiol Aging 33:2398–2410

    CAS  PubMed  Article  Google Scholar 

  • Quigney DJ, Gorman AM, Samali A (2003) Heat shock protects PC12 cells against MPP+ toxicity. Brain Res 993:133–139

    CAS  PubMed  Article  Google Scholar 

  • Quinn N (1995) Drug treatment of Parkinson’s disease. BMJ 310:575–579

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Radad K, Moldzio R, Rausch WD (2015) Rapamycin protects dopaminergic neurons against rotenone-induced cell death in primary mesencephalic cell culture. Folia Neuropathol 53:250–261

    PubMed  Article  Google Scholar 

  • Rajeswari A (2006) Curcumin protects mouse brain from oxidative stress caused by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Eur Rev Med Pharmacol Sci 10:157–161

    CAS  PubMed  Google Scholar 

  • Ramsey CP, Tansey MG (2014) A survey from 2012 of evidence for the role of neuroinflammation in neurotoxin animal models of Parkinson’s disease and potential molecular targets. Exp Neurol 256:126–132

    CAS  PubMed  Article  Google Scholar 

  • Ravenstijn PG, Drenth HJ, O’neill MJ, Danhof M, De Lange EC (2012) Evaluation of blood-brain barrier transport and CNS drug metabolism in diseased and control brain after intravenous l-DOPA in a unilateral rat model of Parkinson’s disease. Fluids Barriers CNS 9:4

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Rinne UK, Bracco F, Chouza C, Dupont E, Gershanik O, Marti Masso JF, Montastruc JL, Marsden CD (1998) Early treatment of Parkinson’s disease with cabergoline delays the onset of motor complications. Results of a double-blind levodopa controlled trial. The PKDS009 Study Group. Drugs 55(Suppl 1):23–30

    CAS  PubMed  Article  Google Scholar 

  • Robakis D, Fahn S (2015) Defining the role of the monoamine oxidase-B inhibitors for Parkinson’s disease. CNS Drugs 29:433–441

    CAS  PubMed  Article  Google Scholar 

  • Rojas P, Montes P, Rojas C, Serrano-Garcia N, Rojas-Castaneda JC (2012) Effect of a phytopharmaceutical medicine, Ginko biloba extract 761, in an animal model of Parkinson’s disease: therapeutic perspectives. Nutrition 28:1081–1088

    CAS  PubMed  Article  Google Scholar 

  • Salat D, Tolosa E (2013) Levodopa in the treatment of Parkinson’s disease: current status and new developments. J Parkinsons Dis 3:255–269

    CAS  PubMed  Google Scholar 

  • Schapira AH (2008) Mitochondria in the aetiology and pathogenesis of Parkinson’s disease. Lancet Neurol 7:97–109

    CAS  PubMed  Article  Google Scholar 

  • Schneider P, Tschopp J (2000) Apoptosis induced by death receptors. Pharm Acta Helv 74:281–286

    CAS  PubMed  Article  Google Scholar 

  • Schuler M, Green DR (2001) Mechanisms of p53-dependent apoptosis. Biochem Soc Trans 29:684–688

    CAS  PubMed  Article  Google Scholar 

  • Shavali S, Brown-Borg HM, Ebadi M, Porter J (2008) Mitochondrial localization of alpha-synuclein protein in alpha-synuclein overexpressing cells. Neurosci Lett 439:125–128

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Shin MS, Kim TW, Lee JM, Ji ES, Lim BV (2017) Treadmill exercise alleviates nigrostriatal dopaminergic loss of neurons and fibers in rotenone-induced Parkinson rats. J Exerc Rehabil 13:30–35

    PubMed  PubMed Central  Article  Google Scholar 

  • Speakman JR, Mitchell SE (2011) Caloric restriction. Mol Aspects Med 32:159–221

    CAS  PubMed  Article  Google Scholar 

  • Stocchi F, Torti M, Fossati C (2016) Advances in dopamine receptor agonists for the treatment of Parkinson’s disease. Expert Opin Pharmacother 17:1889–1902

    CAS  PubMed  Article  Google Scholar 

  • Stojkovska I, Wagner BM, Morrison BE (2015) Parkinson’s disease and enhanced inflammatory response. Exp Biol Med (Maywood) 240:1387–1395

    CAS  Article  Google Scholar 

  • Strathearn KE, Yousef GG, Grace MH, Roy SL, Tambe MA, Ferruzzi MG, Wu QL, Simon JE, Lila MA, Rochet JC (2014) Neuroprotective effects of anthocyanin- and proanthocyanidin-rich extracts in cellular models of Parkinsons disease. Brain Res 1555:60–77

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Sulzer D (2007) Multiple hit hypotheses for dopamine neuron loss in Parkinson’s disease. Trends Neurosci 30:244–250

    CAS  PubMed  Article  Google Scholar 

  • Tai KK, Truong DD (2002) Activation of adenosine triphosphate-sensitive potassium channels confers protection against rotenone-induced cell death: therapeutic implications for Parkinson’s disease. J Neurosci Res 69:559–566

    CAS  PubMed  Article  Google Scholar 

  • Tansey MG, Mccoy MK, Frank-Cannon TC (2007) Neuroinflammatory mechanisms in Parkinson’s disease: potential environmental triggers, pathways, and targets for early therapeutic intervention. Exp Neurol 208:1–25

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Tarozzi A, Morroni F, Merlicco A, Hrelia S, Angeloni C, Cantelli-Forti G, Hrelia P (2009) Sulforaphane as an inducer of glutathione prevents oxidative stress-induced cell death in a dopaminergic-like neuroblastoma cell line. J Neurochem 111:1161–1171

    CAS  PubMed  Article  Google Scholar 

  • Tatton WG, Chalmers-Redman R, Brown D, Tatton N (2003) Apoptosis in Parkinson’s disease: signals for neuronal degradation. Ann Neurol 53(Suppl 3):S61–S70 discussion S70-62

    CAS  PubMed  Article  Google Scholar 

  • Taylor JM, Main BS, Crack PJ (2013) Neuroinflammation and oxidative stress: co-conspirators in the pathology of Parkinson’s disease. Neurochem Int 62:803–819

    CAS  PubMed  Article  Google Scholar 

  • Teixeira MD, Souza CM, Menezes AP, Carmo MR, Fonteles AA, Gurgel JP, Lima FA, Viana GS, Andrade GM (2013) Catechin attenuates behavioral neurotoxicity induced by 6-OHDA in rats. Pharmacol Biochem Behav 110:1–7

    CAS  PubMed  Article  Google Scholar 

  • Tian YY, An LJ, Jiang L, Duan YL, Chen J, Jiang B (2006) Catalpol protects dopaminergic neurons from LPS-induced neurotoxicity in mesencephalic neuron-glia cultures. Life Sci 80:193–199

    CAS  PubMed  Article  Google Scholar 

  • Tillerson JL, Caudle WM, Reveron ME, Miller GW (2003) Exercise induces behavioral recovery and attenuates neurochemical deficits in rodent models of Parkinson’s disease. Neuroscience 119:899–911

    CAS  PubMed  Article  Google Scholar 

  • Tsang AH, Chung KK (2009) Oxidative and nitrosative stress in Parkinson’s disease. Biochim Biophys Acta 1792:643–650

    CAS  PubMed  Article  Google Scholar 

  • Valente EM, Abou-Sleiman PM, Caputo V, Muqit MM, Harvey K, Gispert S, Ali Z, Del Turco D, Bentivoglio AR, Healy DG, Albanese A, Nussbaum R, Gonzalez-Maldonado R, Deller T, Salvi S, Cortelli P, Gilks WP, Latchman DS, Harvey RJ, Dallapiccola B, Auburger G, Wood NW (2004) Hereditary early-onset Parkinson’s disease caused by mutations in PINK1. Science 304:1158–1160

    CAS  PubMed  Article  Google Scholar 

  • Wang YH, Yu HT, Pu XP, Du GH (2014) Myricitrin alleviates methylglyoxal-induced mitochondrial dysfunction and AGEs/RAGE/NF-kappaB pathway activation in SH-SY5Y cells. J Mol Neurosci 53:562–570

    CAS  PubMed  Article  Google Scholar 

  • Weihofen A, Thomas KJ, Ostaszewski BL, Cookson MR, Selkoe DJ (2009) Pink1 forms a multiprotein complex with Miro and Milton, linking Pink1 function to mitochondrial trafficking. Biochemistry 48:2045–2052

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Weintraub D, Comella CL, Horn S (2008) Parkinson’s disease–Part 1: pathophysiology, symptoms, burden, diagnosis, and assessment. Am J Manag Care 14:S40–48

    PubMed  Google Scholar 

  • White WB, Salzman P, Schwid SR (2008) Transtelephonic home blood pressure to assess the monoamine oxidase-B inhibitor rasagiline in Parkinson disease. Hypertension 52:587–593

    CAS  PubMed  Article  Google Scholar 

  • Xiang H, Kinoshita Y, Knudson CM, Korsmeyer SJ, Schwartzkroin PA, Morrison RS (1998) Bax involvement in p53-mediated neuronal cell death. J Neurosci 18:1363–1373

    CAS  PubMed  Google Scholar 

  • Xiao-Qing T, Jun-Li Z, Yu C, Jian-Qiang F, Pei-Xi C (2005) Hydrogen peroxide preconditioning protects PC12 cells against apoptosis induced by dopamine. Life Sci 78:61–66

    PubMed  Article  CAS  Google Scholar 

  • Yang Y, Gehrke S, Imai Y, Huang Z, Ouyang Y, Wang JW, Yang L, Beal MF, Vogel H, Lu B (2006) Mitochondrial pathology and muscle and dopaminergic neuron degeneration caused by inactivation of Drosophila Pink1 is rescued by Parkin. Proc Natl Acad Sci USA 103:10793–10798

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Yi F, He X, Wang D (2013) Lycopene protects against MPP(+)-induced cytotoxicity by maintaining mitochondrial function in SH-SY5Y cells. Neurochem Res 38:1747–1757

    CAS  PubMed  Article  Google Scholar 

  • Zecca L, Shima T, Stroppolo A, Goj C, Battiston GA, Gerbasi R, Sarna T, Swartz HM (1996) Interaction of neuromelanin and iron in substantia nigra and other areas of human brain. Neuroscience 73:407–415

    CAS  PubMed  Article  Google Scholar 

  • Zhang ZT, Cao XB, Xiong N, Wang HC, Huang JS, Sun SG, Wang T (2010) Morin exerts neuroprotective actions in Parkinson disease models in vitro and in vivo. Acta Pharmacol Sin 31:900–906

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Zhang K, Ma Z, Wang J, Xie A, Xie J (2011) Myricetin attenuated MPP(+)-induced cytotoxicity by anti-oxidation and inhibition of MKK4 and JNK activation in MES23.5 cells. Neuropharmacology 61:329–335

    CAS  PubMed  Article  Google Scholar 

  • Zheng LT, Ock J, Kwon BM, Suk K (2008) Suppressive effects of flavonoid fisetin on lipopolysaccharide-induced microglial activation and neurotoxicity. Int Immunopharmacol 8:484–494

    CAS  PubMed  Article  Google Scholar 

  • Zhou HF, Liu XY, Niu DB, Li FQ, He QH, Wang XM (2005) Triptolide protects dopaminergic neurons from inflammation-mediated damage induced by lipopolysaccharide intranigral injection. Neurobiol Dis 18:441–449

    CAS  PubMed  Article  Google Scholar 

Download references

Acknowledgement

This research was supported by the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT & Future Planning (MSIP) (Grant No. 2009-0083538). This work was also supported by the Basic Science Research Program through NRF funded by the Ministry of Education (Grant No. NRF-2016R1D1A3B03933222).

Author information

Affiliations

  1. Department of Pharmacy, College of Pharmacy, Molecular Inflammation Research Center for Aging Intervention, Pusan National University, Busan, 609-735, Republic of Korea

    Yujeong Lee & Jaewon Lee

  2. Department of Pharmacy, College of Pharmacy, Sunchon National University, Sunchon, 57922, Republic of Korea

    Min-Sun Kim

Authors
  1. Yujeong Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Min-Sun Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jaewon Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Min-Sun Kim or Jaewon Lee.

Ethics declarations

Conflict of interest

The authors have no potential conflict of interest to declare.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Lee, Y., Kim, MS. & Lee, J. Neuroprotective strategies to prevent and treat Parkinson’s disease based on its pathophysiological mechanism. Arch. Pharm. Res. 40, 1117–1128 (2017). https://doi.org/10.1007/s12272-017-0960-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12272-017-0960-8

Keywords

  • Parkinson’s disease
  • Pathophysiological pathway
  • Phytochemicals
  • Oxidative stress
  • Mitochondrial dysfunction
  • Neuroinflammation
  • Adaptive cellular stress response