Abstract
The molecular mechanism responsible for degenerative process in the nigrostriatal dopaminergic system in Parkinson’s disease (PD) remains unknown. One major advance in this field has been the discovery of several genes associated to familial PD, including alpha synuclein, parkin, LRRK2, etc., thereby providing important insight toward basic research approaches. There is an consensus in neurodegenerative research that mitochon dria dysfunction, protein degradation dysfunction, aggregation of alpha synuclein to neurotoxic oligomers, oxidative and endoplasmic reticulum stress, and neuroinflammation are involved in degeneration of the neuromelanin-containing dopaminergic neurons that are lost in the disease. An update of the mechanisms relating to neurotoxins that are used to produce preclinical models of Parkinson´s disease is presented. 6-Hydroxydopamine, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, and rotenone have been the most wisely used neurotoxins to delve into mechanisms involved in the loss of dopaminergic neurons containing neuromelanin. Neurotoxins generated from dopamine oxidation during neuromelanin formation are likewise reviewed, as this pathway replicates neurotoxin-induced cellular oxidative stress, inactivation of key proteins related to mitochondria and protein degradation dysfunction, and formation of neurotoxic aggregates of alpha synuclein. This survey of neurotoxin modeling—highlighting newer technologies and implicating a variety of processes and pathways related to mechanisms attending PD—is focused on research studies from 2012 to 2014.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
Abbreviations
- Δψm:
-
Mitochondrial membrane potential
- 1MeTIQ:
-
1-Methyl-1,2,3,4-tetrahydroisoquinoline
- 3-Me-N-proTIQ:
-
3-Methyl-N-propargyl-TIQ
- 5-HT:
-
5-Hydroxytryptamine, serotonin
- 6-OHDA:
-
6-Hydroxydopamine
- AIF:
-
Apoptosis-inducing factor
- AMP:
-
Adenosine monophosphate
- AMPK:
-
AMP activated protein kinase
- ASK1:
-
Apoptosis signal-regulating kinase 1
- ATF:
-
Activating transcription factor
- BDNF:
-
Brain-derived neurotrophic factor
- Ca2+ :
-
Calcium ion
- CHOP:
-
C/EBP homologous protein
- COX:
-
Cyclooxygenase
- DA:
-
Dopamine
- DAT:
-
Dopamine transporter
- l-dopa:
-
l-3,4-Dihydroxyphenylalanine
- DOPAC:
-
l-3,4-Dihydroxyphenylacetic acid
- EP1 receptor:
-
Prostaglandin E subtype 1 receptor
- ER:
-
Endoplasmic reticulum
- ERK:
-
Extracellular signal-regulated kinase
- GDNF:
-
Glial-derived neurotrophic factor
- GFAP:
-
Glial fibrillary acidic protein
- GRP78:
-
Glucose regulatory protein 78
- HO-1:
-
Heme oxygenase-1
- Hsp:
-
Heat shock protein
- hUCP2:
-
Human uncoupling protein
- HVA:
-
Homovanillic acid
- IL:
-
Interleukin
- MAPK:
-
Mitogen-activated protein kinase
- MPP+ :
-
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridinium ion
- MPTP:
-
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
- mTOR:
-
Mammalian target of rapamycin
- NADPH:
-
Reduced nicotinamide adenine dinucleotide phosphate
- NOS:
-
Neuronal nitric oxide synthase
- PARP:
-
Poly-ADP-ribose polymerase
- PD:
-
Parkinson’s disease
- p-ERK:
-
Phosphorylated ERK
- PGE:
-
Prostaglandin E
- Pink:
-
PTEN-induced kinase
- PKA:
-
cAMP-dependent protein kinase A
- PPAR:
-
Peroxisome proliferator-activated receptor
- RESP:
-
Regulated endocrine-specific protein
- ROS:
-
Reactive oxygen species
- S1P:
-
Sphingosine-1 phosphate
- S6K1:
-
p70 S6 kinase 1
- SNpc:
-
Pars compacta Substantia nigra
- TH:
-
Tyrosine hydroxylase
- TH-ir:
-
Tyrosine hydroxylase immunoreactivity
- TIQ:
-
1,2,3,4-Tetrahydroisoquinoline
- TNF-α:
-
Tumor necrosis factor- α
- TRAP:
-
TNF receptor-associated protein
- UCHL-1:
-
Ubiquitin carboxy-terminal hydrolase L-1
- VEGFR-2:
-
Vascular endothelial growth factor receptor-2
References
Abbas N, Lücking CB, Ricard S, Dürr A, Bonifati V, De Michele G, Bouley S, Vaughan JR, Gasser T, Marconi R, Broussolle E, Brefel-Courbon C, Harhangi BS, Oostra BA, Fabrizio E, Böhme GA, Pradier L, Wood NW, Filla A, Meco G, Denefle P, Agid Y, Brice A (1999) A wide variety of mutations in the parkin gene are responsible for autosomal recessive parkinsonism in Europe. French Parkinson’s disease Genetics Study Group and the European consortium on genetic susceptibility in Parkinson’s disease. Hum Mol Genet 8:567–574
Aguiar AS Jr, Tristão FS, Amar M, Chevarin C, Lanfumey L, Mongeau R, Corti O, Prediger RD, Raisman-Vozari R (2013) Parkin-knockout mice did not display increased vulnerability to intranasal administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Neurotox Res 24(2):280–287
Aguiar AS Jr, Tristão FS, Amar M, Chevarin C, Glaser V, de Paula MR, Moreira EL, Mongeau R, Lanfumey L, Raisman-Vozari R, Latini A, Prediger RD (2014) Six weeks of voluntary exercise don’t protect C57BL/6 mice against neurotoxicity of MPTP and MPP(+). Neurotox Res 25(2):147–152
Aguirre P, Urrutia P, Tapia V, Villa M, Paris I, Segura-Aguilar J, Núñez MT (2012) The dopamine metabolite aminochrome inhibits mitochondrial complex I and modifies the expression of iron transporters DMT1 and FPN1. Biometals 25:795–803
Ahmad AS, Maruyama T, Narumiya S, Doré S (2013) PGE2 EP1 receptor deletion attenuates 6-OHDA-induced Parkinsonism in mice: old switch, new target. Neurotox Res 23:260–266
Anandhan A, Janakiraman U, Manivasagam T (2012) Theaflavin ameliorates behavioral deficits, biochemical indices and monoamine transporters expression against subacute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model of Parkinson’s disease. Neuroscience 218:257–267
Anandhan A, Essa MM, Manivasagam T (2013) Therapeutic attenuation of neuroinflammation and apoptosis by black tea theaflavin in chronic MPTP/probenecid model of Parkinson’s disease. Neurotox Res 23:166–173
Annese V, Herrero MT, Di Pentima M, Gomez A, Lombardi L, Ros CM, De Pablos V, Fernandez-Villalba E, De Stefano ME (2014) Metalloproteinase-9 contributes to inflammatory glia activation and nigro-striatal pathway degeneration in both mouse and monkey models of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinsonism. Brain Struct Funct. doi:10.1007/s00429-014-0718-8
Antkiewicz-Michaluk L, Wąsik A, Michaluk J (2014) 1-Methyl-1,2,3,4-tetrahydroisoquinoline, an endogenous amine with unexpected mechanism of action: new vistas of therapeutic application. Neurotox Res 25(1):1–12
Archer T, Fredriksson A (2013) The yeast product Milmed enhances the effect of physical exercise on motor performance and dopamine neurochemistry recovery in MPTP-lesioned mice. Neurotox Res 24(3):393–406
Archer T, Palomo T, McArthur R, Fredriksson A (2003) Effects of acute administration of DA agonists on locomotor activity: MPTP versus neonatal intracerebroventricular 6-OHDA treatment. Neurotox Res 5:95–110
Arodin L, Miranda-Vizuete A, Swoboda P, Fernandes AP (2014) Protective effects of the thioredoxin and glutaredoxin systems in dopamine-induced cell death. Free Radic Biol Med 73:328–336
Arriagada A, Paris I, Sanchez de las MJM, Martinez-Alvarado P, Cardenas S, Castañeda P, Graumann R, Perez-Pastene C, Olea-Azar C, Couve E, Herrero MT, Caviedes P, Segura-Aguilar J (2004) On the neurotoxicity of leukoaminochrome o-semiquinone radical derived of dopamine oxidation: mitochondria damage, necrosis and hydroxyl radical formation. Neurobiol Dis 16:468–477
Arsikin K, Kravic-Stevovic T, Jovanovic M, Ristic B, Tovilovic G, Zogovic N, Bumbasirevic V, Trajkovic V, Harhaji-Trajkovic L (2012) Autophagy-dependent and -independent involvement of AMP-activated protein kinase in 6-hydroxydopamine toxicity to SH-SY5Y neuroblastoma cells. Biochim Biophys Acta 1822(11):1826–1836
Ballard PA, Tetrud JW, Langston JW (1985) Permanent human parkinsonism due to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP): seven cases. Neurology 35(7):949–956
Barbiero JK, Santiago RM, Persike DS, da Silva Fernandes MJ, Tonin FS, da Cunha C, Lucio Boschen S, Lima MM, Vital MA (2014a) Neuroprotective effects of peroxisome proliferator-activated receptor alpha and gamma agonists in model of parkinsonism induced by intranigral 1-methyl-4-phenyl-1,2,3,6-tetrahyropyridine. Behav Brain Res 274:390–399
Barbiero JK, Santiago R, Tonin FS, Boschen S, da Silva LM, Werner MF, da Cunha C, Lima MM, Vital MA (2014b) PPAR-α agonist fenofibrate protects against the damaging effects of MPTP in a rat model of Parkinson’s disease. Prog Neuropsychopharmacol Biol Psychiatry 53:35–44
Benskey M, Lee KY, Parikh K, Lookingland KJ, Goudreau JL (2013) Sustained resistance to acute MPTP toxicity by hypothalamic dopamine neurons following chronic neurotoxicant exposure is associated with sustained up-regulation of parkin protein. Neurotoxicology 37:144–153
Berger K, Przedborski S, Cadet JL (1990) Retrograde degeneration of nigrostriatal neurons induced by intrastriatal 6-hydroxydopamine injection in rats. Brain Res Bull 26:301–307
Bernstein AI, O’Malley KL (2013) MPP+-induces PUMA- and p53-dependent, but ATF3-independent cell death. Toxicol Lett 219(2):93–98
Betarbet R, Sherer TB, MacKenzie G, Garcia-Osuna M, Panov AV, Greenamyre JT (2000) Chronic systemic pesticide exposure reproduces features of Parkinson’s disease. Nat Neurosci 3:1301–1306
Bisaglia M, Mammi S, Bubacco L (2007) Kinetic and structural analysis of the early oxidation products of dopamine: analysis of the interactions with alpha-synuclein. J Biol Chem 282:15597–15605
Bisht R, Kaur B, Gupta H, Prakash A (2014) Ceftriaxone mediated rescue of nigral oxidative damage and motor deficits in MPTP model of Parkinson’s disease in rats. Neurotoxicology 44:71–79
Bonifati V, Rizzu P, Squitieri F, Krieger E, Vanacore N, van Swieten JC, Brice A, van Duijn CM, Oostra B, Meco G, Heutink P (2003a) DJ-1(PARK7), a novel gene for autosomal recessive, early onset parkinsonism. Neurol Sci 24:159–160
Bonifati V, Rizzu P, van Baren MJ, Schaap O, Breedveld GJ, Krieger E, Dekker MC, Squitieri F, Ibanez P, Joosse M, van Dongen JW, Vanacore N, van Swieten JC, Brice A, Meco G, van Duijn CM, Oostra BA, Heutink P (2003b) Mutations in the DJ-1 gene associated with autosomal recessive early-onset parkinsonism. Science 299:256–259
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
Bourque M, Morissette M, Di Paolo T (2014) Raloxifene activates G protein-coupled estrogen receptor 1/Akt signaling to protect dopamine neurons in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mice. Neurobiol Aging 35(10):2347–2356
Braak H, Ghebremedhin E, Rüb U, Bratzke H, Del Tredici K (2004) Stages in the development of Parkinson’s disease-related pathology. Cell Tissue Res 318:121–134
Brus R, Jochem J, Nowak P, Adwent M, Boroń D, Brus H, Kostrzewa RM (2012) Effect of pre- and postnatal manganese exposure on brain histamine content in a rodent model of Parkinson’s disease. Neurotox Res 21:143–148
Cannon JR, Greenamyre JT (2010) Neurotoxic in vivo models of Parkinson’s disease, recent advances. Prog Brain Res 184:17–33
Cardenas SP, Perez-Pastene C, Couve E, Segura- Aguilar J (2008) The DT-diaphorase prevent the aggregation of α-synuclein induced for aminochrome. Neurotox Res 13:136
Carrasco E, Casper D, Werner P (2005) Dopaminergic neurotoxicity by 6-OHDA and MPP+: differential requirement for neuronal cyclooxygenase activity. J Neurosci Res 81:121–131
Carrasco E, Casper D, Werner P (2007) PGE(2) receptor EP1 renders dopaminergic neurons selectively vulnerable to low-level oxidative stress and direct PGE(2) neurotoxicity. J Neurosci Res 85:3109–3117
Carta AR, Pisanu A (2013) Modulating microglia activity with PPAR-γ agonists: a promising therapy for Parkinson’s disease? Neurotox Res 23:112–123
Castro-Caldas M, Carvalho AN, Rodrigues E, Henderson CJ, Wolf CR, Rodrigues CM, Gama MJ (2012) Tauroursodeoxycholic acid prevents MPTP-induced dopaminergic cell death in a mouse model of Parkinson’s disease. Mol Neurobiol 46(2):475–486
Chambers JW, Howard S, LoGrasso PV (2013) Blocking c-Jun N-terminal kinase (JNK) translocation to the mitochondria prevents 6-hydroxydopamine-induced toxicity in vitro and in vivo. J Biol Chem 288:1079–1087
Chang CY, Choi DK, Lee DK, Hong YJ, Park EJ (2013) Resveratrol confers protection against rotenone-induced neurotoxicity by modulating myeloperoxidase levels in glial cells. PLoS ONE 8(4):e60654
Chen J, Wang X, Yi X, Wang Y, Liu Q, Ge R (2013a) Induction of KLF4 contributes to the neurotoxicity of MPP+ in M17 cells: a new implication in Parkinson’s disease. J Mol Neurosci 51(1):109–117
Chen T, Zhu J, Zhang C, Huo K, Fei Z, Jiang XF (2013b) Protective effects of SKF-96365, a non-specific inhibitor of SOCE, against MPP+-induced cytotoxicity in PC12 cells: potential role of Homer1. PLoS ONE 8(1):e55601
Chen Y, Ni YY, Liu J, Lu JW, Wang F, Wu XL, Gu MM, Lu ZY, Wang ZG, Ren ZH (2013c) Dopamine receptor 3 might be an essential molecule in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced neurotoxicity. BMC Neurosci 14:76
Chen T, Hou R, Li C, Wu C, Xu S (2015) MPTP/MPP+ suppresses activation of protein C in Parkinson’s disease. J Alzheimers Dis 43:133–142
Chiba K, Trevor A, Castagnoli N Jr (1984) Metabolism of the neurotoxic tertiary amine, MPTP, by brain monoamine oxidase. Biochem Biophys Res Commun 120(2):574–578
Chiba K, Trevor AJ, Castagnoli N Jr (1985) Active uptake of MPP+, a metabolite of MPTP, by brain synaptosomes. Biochem Biophys Res Commun 128(3):1228–1232
Chinta SJ, Rajagopalan S, Ganesan A, Andersen JK (2012) A possible novel anti-inflammatory mechanism for the pharmacological prolyl hydroxylase inhibitor 3,4-dihydroxybenzoate: implications for use as a therapeutic for Parkinson’s disease. Parkinsons Dis 2012:364684
Chinta SJ, Ganesan A, Reis-Rodrigues P, Lithgow GJ, Andersen JK (2013) Anti-inflammatory role of the isoflavone diadzein in lipopolysaccharide-stimulated microglia: implications for Parkinson’s disease. Neurotox Res 23:145–153
Choi WS, Yoon SY, Oh TH, Choi EJ, O’Malley KL, Oh YJ (1999) Two distinct mechanisms are involved in 6-hydroxydopamine- and MPP+-induced dopaminergic neuronal cell death: role of caspases, ROS, and JNK. J Neurosci Res 57(1):86–94
Chung YC, Kim YS, Bok E, Yune TY, Maeng S, Jin BK (2013) MMP-3 contributes to nigrostriatal dopaminergic neuronal loss, BBB damage, and neuroinflammation in an MPTP mouse model of Parkinson’s disease. Mediators Inflamm 2013:370526
Condello S, Currò M, Ferlazzo N, Costa G, Visalli G, Caccamo D, Pisani LR, Costa C, Calabresi P, Ientile R, Pisani F (2013) Protective effects of zonisamide against rotenone-induced neurotoxicity. Neurochem Res 38(12):2631–2639
Costall B, Naylor RJ, Pycock C (1975) The 6-hydroxydopamine rotational model for the detection of dopamine agonist activity: reliability of effect from different locations of 6-hydroxydopamine. J Pharm Pharmacol 27:943–946
Cuervo AM, Stefanis L, Fredenburg R, Lansbury PT, Sulzer D (2004) Impaired degradation of mutant alpha-synuclein by chaperone-mediated autophagy. Science 305:1292–1295
Cuevas C, Huenchuguala S, Muñoz P, Villa M, Paris I, Mannervik B, Segura-Aguilar J (2014) Glutathione transferase-M2-2 secreted from glioblastoma cell protects SH-SY5Y cells from aminochrome neurotoxicity. Neurotox Res. doi:10.1007/s12640-014-9500-1
Cui W, Zhang Z, Li W, Mak S, Hu S, Zhang H, Yuan S, Rong J, Choi TC, Lee SM, Han Y (2012) Unexpected neuronal protection of SU5416 against 1-methyl-4-phenylpyridinium ion-induced toxicity via inhibiting neuronal nitric oxide synthase. PLoS ONE 7(9):e46253
Cui W, Zhang Z, Li W, Hu S, Mak S, Zhang H, Han R, Yuan S, Li S, Sa F, Xu D, Lin Z, Zuo Z, Rong J, Ma ED, Choi TC, Lee SM, Han Y (2013) The anti-cancer agent SU4312 unexpectedly protects against MPP (+) -induced neurotoxicity via selective and direct inhibition of neuronal NOS. Br J Pharmacol 168(5):1201–1214
Dai TL, Zhang C, Peng F, Niu XY, Hu L, Zhang Q, Huang Y, Chen L, Zhang L, Zhu W, Ding YQ, Song NN, Liao M (2014) Depletion of canonical Wnt signaling components has a neuroprotective effect on midbrain dopaminergic neurons in an MPTP-induced mouse model of Parkinson’s disease. Exp Ther Med 8(2):384–390
Dal-Cim T, Molz S, Egea J, Parada E, Romero A, Budni J, Martín de Saavedra MD, del Barrio L, Tasca CI, López MG (2012) Guanosine protects human neuroblastoma SH-SY5Y cells against mitochondrial oxidative stress by inducing heme oxigenase-1 via PI3 K/Akt/GSK-3β pathway. Neurochem Int 61(3):397–404
Deng C, Tao R, Yu SZ, Jin H (2012a) Inhibition of 6-hydroxydopamine-induced endoplasmic reticulum stress by sulforaphane through the activation of Nrf2 nuclear translocation. Mol Med Rep 6:215–219
Deng C, Tao R, Yu SZ, Jin H (2012b) Sulforaphane protects against 6-hydroxydopamine-induced cytotoxicity by increasing expression of heme oxygenase-1 in a PI3 K/Akt-dependent manner. Mol Med Rep 5:847–851
Deng YN, Shi J, Liu J, Qu QM (2013) Celastrol protects human neuroblastoma SH-SY5Y cells from rotenone-induced injury through induction of autophagy. Neurochem Int 63(1):1–9
Denton T, Howard BD (1987) A dopaminergic cell line variant resistant to the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. J Neurochem 49(2):622–630
Dewapriya P, Himaya SW, Li YX, Kim SK (2013) Tyrosol exerts a protective effect against dopaminergic neuronal cell death in in vitro model of Parkinson’s disease. Food Chem 141(2):1147–1157
Di Monte D, Jewell SA, Ekström G, Sandy MS, Smith MT (1986) 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 1-methyl-4-phenylpyridine (MPP+) cause rapid ATP depletion in isolated hepatocytes. Biochem Biophys Res Commun 137(1):310–315
Di Monte DA, Wu EY, Irwin I, Delanney LE, Langston JW (1991) Biotransformation of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in primary cultures of mouse astrocytes. J Pharmacol Exp Ther 258(2):594–600
Dibenedetto D, Rossetti G, Caliandro R, Carloni P (2013) A molecular dynamics simulation-based interpretation of nuclear magnetic resonance multidimensional heteronuclear spectra of α-synuclein dopamine adducts. Biochemistry 52:6672–6683
Dipasquale B, Marini AM, Youle RJ (1991) Apoptosis and DNA degradation induced by 1-methyl-4-phenylpyridinium in neurons. Biochem Biophys Res Commun 181:1442–1448
Dluzen DE, Kefalas G (1996) The effects of intranasal infusion of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) upon catecholamine concentrations within olfactory bulbs and corpus striatum of male mice. Brain Res 741:215–219
Du C, Jin M, Hong Y, Li Q, Wang XH, Xu JM, Wang F, Zhang Y, Jia J, Liu CF, Hu LF (2014) Downregulation of cystathionine β-synthase/hydrogen sulfide contributes to rotenone-induced microglia polarization toward M1 type. Biochem Biophys Res Commun 451(2):239–245
Dun Y, Yang Y, Xiong Z, Feng M, Zhang Y, Wang M, Xiang J, Li G, Ma R (2013) Induction of Dickkopf-1 contributes to the neurotoxicity of MPP+ in PC12 cells via inhibition of the canonical Wnt signaling pathway. Neuropharmacology 67:168–175
Durgadoss L, Nidadavolu P, Valli RK, Saeed U, Mishra M, Seth P, Ravindranath V (2012) Redox modification of Akt mediated by the dopaminergic neurotoxin MPTP, in mouse midbrain, leads to down-regulation of pAkt. FASEB J 26(4):1473–1483
Ebrahimi-Fakhari D, Wahlster L, McLean PJ (2012) Protein degradation pathways in Parkinson’s disease: curse or blessing. Acta Neuropathol 124:153–172
Emmrich JV, Hornik TC, Neher JJ, Brown GC (2013) Rotenone induces neuronal death by microglial phagocytosis of neurons. FEBS J 280(20):5030–5038
Exner N, Lutz AK, Haass C, Winklhofer KF (2012) Mitochondrial dysfunction in Parkinson’s disease: molecular mechanisms and pathophysiological consequences. EMBO J 31:3038–3062
Fan Y, Li J, Zhang YQ, Jiang LH, Zhang YN, Yan CQ (2014) Protein kinase C delta mediated cytotoxicity of 6-Hydroxydopamine via sustained extracellular signal-regulated kinase 1/2 activation in PC12 cells. Neurol Res 36:53–64
Ferreira NR, Mitkovski M, Stühmer W, Pardo LA, Del Bel EA (2012) Ether-à-go-go 1 (Eag1) potassium channel expression in dopaminergic neurons of basal ganglia is modulated by 6-hydroxydopamine lesion. Neurotox Res 21:317–333
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(4):767–785
Fisher BE, Li Q, Nacca A, Salem GJ, Song J, Yip J, Hui JS, Jakowec MW, Petzinger GM (2013) Treadmill exercise elevates striatal dopamine D2 receptor binding potential in patients with early Parkinson’s disease. NeuroReport 24(10):509–514
Fuentes P, Paris I, Nassif M, Caviedes P, Segura-Aguilar J (2007) Inhibition of VMAT-2 and DT-diaphorase induce cell death in a substantia nigra-derived cell line an experimental cell model for dopamine toxicity studies. Chem Res Toxicol 20:776–783
Galindo MF, Solesio ME, Atienzar-Aroca S, Zamora MJ, Jordán Bueso J (2012) Mitochondrial dynamics and mitophagy in the 6-hydroxydopamine preclinical model of Parkinson’s disease. Parkinsons Dis 2012:131058
Gao H, Yang W, Qi Z, Lu L, Duan C, Zhao C, Yang H (2012) DJ-1 protects dopaminergic neurons against rotenone-induced apoptosis by enhancing ERK-dependent mitophagy. J Mol Biol 423(2):232–248
Gao HL, Li C, Nabeka H, Shimokawa T, Saito S, Wang ZY, Cao YM, Matsuda S (2013) Attenuation of MPTP/MPP(+) toxicity in vivo and in vitro by an 18-mer peptide derived from prosaposin. Neuroscience 236:373–393
Garrido-Gil P, Joglar B, Rodriguez-Perez AI, Guerra MJ, Labandeira-Garcia JL (2012) Involvement of PPAR-γ in the neuroprotective and anti-inflammatory effects of angiotensin type 1 receptor inhibition: effects of the receptor antagonist telmisartan and receptor deletion in a mouse MPTP model of Parkinson’s disease. J Neuroinflammation 9:38
Gerecke KM, Jiao Y, Pagala V, Smeyne RJ (2012) Exercise does not protect against MPTP-induced neurotoxicity in BDNF haploinsufficient mice. PLoS ONE 7(8):e43250
Giménez-Cassina A, Lim F, Díaz-Nido J (2012) Chronic inhibition of glycogen synthase kinase-3 protects against rotenone-induced cell death in human neuron-like cells by increasing BDNF secretion. Neurosci Lett 531(2):182–187
Giordano S, Dodson M, Ravi S, Redmann M, Ouyang X, Darley Usmar VM, Zhang J (2014) Bioenergetic adaptation in response to autophagy regulators during rotenone exposure. J Neurochem 131(5):625–633
Glinka Y, Youdim MB (1995) Inhibition of mitochondrial complexes I and IV by 6-hydroxydopamine. Eur J Pharmacol 292:329–332
Glinka Y, Tipton KF, Youdim MB (1996) Nature of inhibition of mitochondrial respiratory complex I by 6-hydroxydopamine. J Neurochem 66:2004–22010
Gołembiowska K, Dziubina A (2012) Effect of adenosine A(2A) receptor antagonists and L-DOPA on hydroxyl radical, glutamate and dopamine in the striatum of 6-OHDA-treated rats. Neurotox Res 21:222–230
Gołembiowska K, Wardas J, Noworyta-Sokołowska K, Kamińska K, Górska A (2013) Effects of adenosine receptor antagonists on the in vivo LPS-induced inflammation model of Parkinson’s disease. Neurotox Res 24:29–40
Gomez-Lazaro M, Galindo MF, Concannon CG, Segura MF, Fernandez-Gomez FJ, Llecha N, Comella JX, Prehn JH, Jordan J (2008) 6-Hydroxydopamine activates the mitochondrial apoptosis pathway through p38 MAPK-mediated, p53-independent activation of Bax and PUMA. J Neurochem 104:1599–1612
Gong L, Zhang QL, Zhang N, Hua WY, Huang YX, Di PW, Huang T, Xu XS, Liu CF, Hu LF, Luo WF (2012) Neuroprotection by urate on 6-OHDA-lesioned rat model of Parkinson’s disease: linking to Akt/GSK3β signaling pathway. J Neurochem 123:876–885
Gunjima K, Tomiyama R, Takakura K, Yamada T, Hashida K, Nakamura Y, Konishi T, Matsugo S, Hori O (2014) 3,4-dihydroxybenzalacetone protects against Parkinson’s disease-related neurotoxin 6-OHDA through Akt/Nrf2/glutathione pathway. J Cell Biochem 115:151–160
Ha JY, Kim JS, Kang YH, Bok E, Kim YS, Son JH (2014) Tnfaip8 l1/Oxi-β binds to FBXW5, increasing autophagy through activation of TSC2 in a Parkinson’s disease model. J Neurochem 129:527–538
Hacioglu G, Seval-Celik Y, Tanriover G, Ozsoy O, Saka-Topcuoglu E, Balkan S, Agar A (2012) Docosahexaenoic acid provides protective mechanism in bilaterally MPTP-lesioned rat model of Parkinson’s disease. Folia Histochem Cytobiol 50(2):228–238
Han XH, Cheng MN, Chen L, Fang H, Wang LJ, Li XT, Qu ZQ (2014) 7,8-Dihydroxyflavone protects PC12 cells against 6-hydroxydopamine-induced cell death through modulating PI3 K/Akt and JNK pathways. Neurosci Lett 581:85–88
Hanrott K, Murray TK, Orfali Z, Ward M, Finlay C, O’Neill MJ, Wonnacott S (2008) Differential activation of PKCdelta in the substantia nigra of rats following striatal or nigral 6-hydroxydopamine lesions. Eur J Neurosci 27:1086–1096
Haque ME, Mount MP, Safarpour F, Abdel-Messih E, Callaghan S, Mazerolle C, Kitada T, Slack RS, Wallace V, Shen J, Anisman H, Park DS (2012) Inactivation of Pink1 gene in vivo sensitizes dopamine-producing neurons to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and can be rescued by autosomal recessive Parkinson disease genes, Parkin or DJ-1. J Biol Chem 287(27):23162–23170
Hara H, Kamiya T, Adachi T (2011) Endoplasmic reticulum stress inducers provide protection against 6-hydroxydopamine-induced cytotoxicity. Neurochem Int 58:35–43
Hashimoto R, Yu J, Koizumi H, Ouchi Y, Okabe T (2012) Ginsenoside Rb1 prevents MPP(+)-induced apoptosis in PC12 cells by stimulating estrogen receptors with consequent activation of ERK1/2, Akt and inhibition of SAPK/JNK, p38 MAPK. Evid Based Complement Alternat Med 2012:693717
Hattori N, Matsumine H, Asakawa S, Kitada T, Yoshino H, Elibol B, Brookes AJ, Yamamura Y, Kobayashi T, Wang M, Yoritaka A, Minoshima S, Shimizu N, Mizuno Y (1998) Point mutations (Thr240Arg and Gln311Stop) [correction of Thr240Arg and Ala311Stop] in the Parkin gene. Biochem Biophys Res Commun 249:754–758
Hauser DN, Hastings TG (2013) Mitochondrial dysfunction and oxidative stress in Parkinson’s disease and monogenic parkinsonism. Neurobiol Dis 51:35–42
Hauser DN, Dukes AA, Mortimer AD, Hastings TG (2013) Dopamine quinone modifies and decreases the abundance of the mitochondrial selenoprotein glutathione peroxidase 4. Free Radic Biol Med 65:419–427
Hong Y, Nie H, Wu D, Wei X, Ding X, Ying W (2014) NAD(+) treatment prevents rotenone-induced apoptosis and necrosis of differentiated PC12 cells. Neurosci Lett 560:46–50
Hongo H, Kihara T, Kume T, Izumi Y, Niidome T, Sugimoto H, Akaike A (2012) Glycogen synthase kinase-3β activation mediates rotenone-induced cytotoxicity with the involvement of microtubule destabilization. Biochem Biophys Res Commun 426(1):94–99
Huang Y, Xu J, Liang M, Hong X, Suo H, Liu J, Yu M, Huang F (2013) RESP18 is involved in the cytotoxicity of dopaminergic neurotoxins in MN9D cells. Neurotox Res 24(2):164–175
Huenchuguala S, Muñoz P, Zavala P, Villa M, Cuevas C, Ahumada U, Graumann R, Nore BF, Couve E, Mannervik B, Paris I, Segura-Aguilar J (2014) Glutathione transferase M2 protects glioblastoma cells against aminochrome toxicity by preventing autophagy and lysosome dysfunction. Autophagy 10:618–630
Hwang CK, Chun HS (2012) Isoliquiritigenin isolated from licorice Glycyrrhiza uralensis prevents 6-hydroxydopamine-induced apoptosis in dopaminergic neurons. Biosci Biotechnol Biochem 76:536–543
Hwang RD, Wiemerslage L, LaBreck CJ, Khan M, Kannan K, Wang X, Zhu X, Lee D, Fridell YW (2014) The neuroprotective effect of human uncoupling protein 2 (hUCP2) requires cAMP-dependent protein kinase in a toxin model of Parkinson’s disease. Neurobiol Dis 69:180–191
Iglesias-González J, Sánchez-Iglesias S, Méndez-Álvarez E, Rose S, Hikima A, Jenner P, Soto-Otero R (2012) Differential toxicity of 6-hydroxydopamine in SH-SY5Y human neuroblastoma cells and rat brain mitochondria: protective role of catalase and superoxide dismutase. Neurochem Res 37:2150–2160
Itier JM, Ibanez P, Mena MA, Abbas N, Cohen-Salmon C, Bohme GA, Laville M, Pratt J, Corti O, Pradier L, Ret G, Joubert C, Periquet M, Araujo F, Negroni J, Casarejos MJ, Canals S, Solano R, Serrano A, Gallego E, Sanchez M, Denefle P, Benavides J, Tremp G, Rooney TA, Brice A, Garcia de Yebenes J (2003) Parkin gene inactivation alters behaviour and dopamine neurotransmission in the mouse. Hum Mol Genet 12:2277–2291
Jantas D, Roman A, Kuśmierczyk J, Lorenc-Koci E, Konieczny J, Lenda T, Lasoń W (2013) The extent of neurodegeneration and neuroprotection in two chemical in vitro models related to Parkinson’s disease is critically dependent on cell culture conditions. Neurotox Res 24(1):41–54
Jantas D, Greda A, Golda S, Korostynski M, Grygier B, Roman A, Pilc A, Lason W (2014) Neuroprotective effects of metabotropic glutamate receptor group II and III activators against MPP(+)-induced cell death in human neuroblastoma SH-SY5Y cells: the impact of cell differentiation state. Neuropharmacology 83:36–53
Javitch JA, Snyder SH (1984) Uptake of MPP(+) by dopamine neurons explains selectivity of parkinsonism-inducing neurotoxin. MPTP. Eur J Pharmacol 106(2):455–456
Javitch JA, D’Amato RJ, Strittmatter SM, Snyder SH (1985) Parkinsonism-inducing neurotoxin, N-methyl-4-phenyl-1,2,3,6 -tetrahydropyridine: uptake of the metabolite N-methyl-4-phenylpyridine by dopamine neurons explains selective toxicity. Proc Natl Acad Sci USA 82(7):2173–2177
Jiang BP, Le L, Xu LJ, Xiao PG (2014) Minocycline inhibits ICAD degradation and the NF-κB activation induced by 6-OHDA in PC12 cells. Brain Res 1586:1–11
Jing X, Shi Q, Bi W, Zeng Z, Liang Y, Wu X, Xiao S, Liu J, Yang L, Tao E (2014) Rifampicin protects PC12 cells from rotenone-induced cytotoxicity by activating GRP78 via PERK-eIF2α-ATF4 pathway. PLoS ONE 9(3):e92110
Jones BC, Miller DB, O’Callaghan JP, Lu L, Unger EL, Alam G, Williams RW (2013) Systems analysis of genetic variation in MPTP neurotoxicity in mice. Neurotoxicology 37:26–34
Jones BC, O’Callaghan JP, Lu L, Williams RW, Alam G, Miller DB (2014) Genetic correlational analysis reveals no association between MPP+ and the severity of striatal dopaminergic damage following MPTP treatment in BXD mouse strains. Neurotoxicol Teratol 45:91–92
Kachergus J, Mata IF, Hulihan M, Taylor JP, Lincoln S, Aasly J, Gibson JM, Ross OA, Lynch T, Wiley J, Payami H, Nutt J, Maraganore DM, Czyzewski K, Styczynska M, Wszolek ZK, Farrer MJ, Toft M (2005) Identification of a novel LRRK2 mutation linked to autosomal dominant parkinsonism: evidence of a common founder across European populations. Am J Hum Genet 76:672–680
Kadar H, Le Douaron G, Amar M, Ferrié L, Figadère B, Touboul D, Brunelle A, Raisman-Vozari R (2014) MALDI mass spectrometry imaging of 1-methyl-4-phenylpyridinium (MPP+) in mouse brain. Neurotox Res 25(1):135–145
Kaidery NA, Banerjee R, Yang L, Smirnova NA, Hushpulian DM, Liby KT, Williams CR, Yamamoto M, Kensler TW, Ratan RR, Sporn MB, Beal MF, Gazaryan IG, Thomas B (2013) Targeting Nrf2-mediated gene transcription by extremely potent synthetic triterpenoids attenuate dopaminergic neurotoxicity in the MPTP mouse model of Parkinson’s disease. Antioxid Redox Signal 18(2):139–157
Kalia LV, Kalia SK, McLean PJ, Lozano AM, Lang AE (2013) α-Synuclein oligomers and clinical implications for Parkinson disease. Ann Neurol 73:155–169
Kamalden TA, Ji D, Osborne NN (2012) Rotenone-induced death of RGC-5 cells is caspase independent, involves the JNK and p38 pathways and is attenuated by specific green tea flavonoids. Neurochem Res 37(5):1091–1101
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
Khan MM, Raza SS, Javed H, Ahmad A, Khan A, Islam F, Safhi MM, Islam F (2012) Rutin protects dopaminergic neurons from oxidative stress in an animal model of Parkinson’s disease. Neurotox Res 22:1–15
Khan MM, Kempuraj D, Thangavel R, Zaheer A (2013) Protection of MPTP-induced neuroinflammation and neurodegeneration. Pycnogenol Neurochem Int 62(4):379–388
Khan MM, Kempuraj D, Zaheer S, Zaheer A (2014a) Glia maturation factor deficiency suppresses 1-methyl-4-phenylpyridinium-induced oxidative stress in astrocytes. J Mol Neurosci 53(4):590–599
Khan MM, Zaheer S, Nehman J, Zaheer A (2014b) Suppression of glia maturation factor expression prevents 1-methyl-4-phenylpyridinium (MPP+)-induced loss of mesencephalic dopaminergic neurons. Neuroscience 277:196–205
Kim HG, Ju MS, Ha SK, Lee H, Lee H, Kim SY, Oh MS (2012a) 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
Kim Y, Li E, Park S (2012b) Insulin-like growth factor-1 inhibits 6-hydroxydopamine-mediated endoplasmic reticulum stress-induced apoptosis via regulation of heme oxygenase-1 and Nrf2 expression in PC12 cells. Int J Neurosci 122:641–649
Kim TW, Cho HM, Choi SY, Suguira Y, Hayasaka T, Setou M, Koh HC, Hwang EM, Park JY, Kang SJ, Kim HS, Kim H, Sun W (2013) (ADP-ribose) polymerase 1 and AMP-activated protein kinase mediate progressive dopaminergic neuronal degeneration in a mouse model of Parkinson’s disease. Cell Death Dis 4:e919
Knaryan VH, Samantaray S, Park S, Azuma M, Inoue J, Banik NL (2014) SNJ-1945, a calpain inhibitor, protects SH-SY5Y cells against MPP(+) and rotenone. J Neurochem 130(2):280–290
Kost GC, Selvaraj S, Lee YB, Kim DJ, Ahn CH, Singh BB (2012) Clavulanic acid inhibits MPP+-induced ROS generation and subsequent loss of dopaminergic cells. Brain Res 1469:129–135
Kostrzewa RM (2014) Survey of selective neurotoxins, section on selective neurotoxins. In: Kostrzewa RM (ed) Handbook of neurotoxicity. Springer, Dordrecht, pp 3–67
Kostrzewa RM, Jacobowitz DM (1974) Pharmacological actions of 6-hydroxydopamine. Pharmacol Rev 26(3):199–288
Kostrzewa RM, Kostrzewa FP (2012) Neonatal 6-hydroxydopamine lesioning enhances quinpirole-induced vertical jumping in rats that were quinpirole primed during postnatal ontogeny. Neurotox Res 21:231–235
Kostrzewa RM, Antkiewicz-Michaluk L, Fornai F (2010) Dopaminergic nerves as targets for neurotoxins. In: Harry J, Tilson H (eds) Neurotoxicology, target organ toxicity series, 3rd edn. Informa Health Care, New York, pp 112–137 ISBN: 9781420054873
Kulich SM, Horbinski C, Patel M, Chu CT (2007) 6-Hydroxydopamine induces mitochondrial ERK activation. Free Radic Biol Med 43:372–383
Kupsch A, Schmidt W, Gizatullina Z, Debska-Vielhaber G, Voges J, Striggow F, Panther P, Schwegler H, Heinze HJ, Vielhaber S, Gellerich FN (2014) 6-Hydroxydopamine impairs mitochondrial function in the rat model of Parkinson’s disease: respirometric, histological, and behavioral analyses. J Neural Transm 121:1245–1257
Kurauchi Y, Hisatsune A, Isohama Y, Sawa T, Akaike T, Katsuki H (2013) Nitric oxide/soluble guanylyl cyclase signaling mediates depolarization-induced protection of rat mesencephalic dopaminergic neurons from MPP+ cytotoxicity. Neuroscience 231:206–215
Kuruvilla KP, Nandhu MS, Paul J, Paulose CS (2013) Oxidative stress mediated neuronal damage in the corpus striatum of 6-hydroxydopamine lesioned Parkinson’s rats: neuroprotection by serotonin, GABA and bone marrow cells supplementation. J Neurol Sci 331:31–37
Kwon SH, Hong SI, Jung YH, Kim MJ, Kim SY, Kim HC, Lee SY, Jang CG (2012) Lonicera japonica THUNB. Protects 6-hydroxydopamine-induced neurotoxicity by inhibiting activation of MAPKs, PI3 K/Akt, and NF-κB in SH-SY5Y cells. Food Chem Toxicol 50:797–807
Kwon SH, Ma SX, Hong SI, Kim SY, Lee SY, Jang CG (2014a) Eucommia ulmoides Oliv. bark. attenuates 6-hydroxydopamine-induced neuronal cell death through inhibition of oxidative stress in SH-SY5Y cells. J Ethnopharmacol 152:173–182
Kwon SH, Ma SX, Lee SY, Jang CG (2014b) Sulfuretin inhibits 6-hydroxydopamine-induced neuronal cell death via reactive oxygen species-dependent mechanisms in human neuroblastoma SH-SY5Y cells. Neurochem Int 74:53–64
Laloux C, Petrault M, Lecointe C, Devos D, Bordet R (2012) Differential susceptibility to the PPAR-γ agonist pioglitazone in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and 6-hydroxydopamine rodent models of Parkinson’s disease. Pharmacol Res 65(5):514–522
Langston JW, Ballard P (1984) Parkinsonism induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP): implications for treatment and the pathogenesis of Parkinson’s disease. Can J Neurol Sci 11(1 Suppl):160–165
Lao CL, Kuo YH, Hsieh YT, Chen JC (2013) Intranasal and subcutaneous administration of dopamine D3 receptor agonists functionally restores nigrostriatal dopamine in MPTP-treated mice. Neurotox Res 24(4):523–531
LaVoie MJ, Ostaszewski BL, Weihofen A, Schlossmacher MG, Selkoe DJ (2005) Dopamine covalently modifies and functionally inactivates parkin. Nat Med 11:1159–1161
Lee EY, Lee JE, Park JH, Shin IC, Koh HC (2012a) Rosiglitazone, a PPAR-γ agonist, protects against striatal dopaminergic neurodegeneration induced by 6-OHDA lesions in the substantia nigra of rats. Toxicol Lett 213:332–344
Lee KW, Zhao X, Im JY, Grosso H, Jang WH, Chan TW, Sonsalla PK, German DC, Ichijo H, Junn E, Mouradian MM (2012b) Apoptosis signal-regulating kinase 1 mediates MPTP toxicity and regulates glial activation. PLoS ONE 7(1):e29935
Leem E, Nam JH, Jeon MT, Shin WH, Won SY, Park SJ, Choi MS, Jin BK, Jung UJ, Kim SR (2012) Naringin protects the nigrostriatal dopaminergic projection through induction of GDNF in a neurotoxin model of Parkinson’s disease. J Nutr Biochem 25:801–806
Lei S, Zavala-Flores L, Garcia-Garcia A, Nandakumar R, Huang Y, Madayiputhiya N, Stanton RC, Dodds ED, Powers R, Franco R (2014) Alterations in energy/redox metabolism induced by mitochondrial and environmental toxins: a specific role for glucose-6-phosphate-dehydrogenase and the pentose phosphate pathway in paraquat toxicity. ACS Chem Biol 9(9):2032–2048
Li DW, Li GR, Lu Y, Liu ZQ, Chang M, Yao M, Cheng W, Hu LS (2013a) α-lipoic acid protects dopaminergic neurons against MPP+-induced apoptosis by attenuating reactive oxygen species formation. Int J Mol Med 32(1):108–114
Li X, Chen W, Zhang L, Liu WB, Fei Z (2013b) Inhibition of store-operated calcium entry attenuates MPP(+)-induced oxidative stress via preservation of mitochondrial function in PC12 cells: involvement of Homer1a. PLoS ONE 8(12):e83638
Li B, Xiao L, Wang ZY, Zheng PS (2014a) Knockdown of STIM1 inhibits 6-hydroxydopamine-induced oxidative stress through attenuating calcium-dependent ER stress and mitochondrial dysfunction in undifferentiated PC12 cells. Free Radic Res 48:758–768
Li D, Liu Q, Jia D, Dou D, Wang X, Kang T (2014b) Protective effect of arctigenin against MPP+ and MPTP-induced neurotoxicity. Planta Med 80(1):48–55
Lin E, Cavanaugh JE, Leak RK, Perez RG, Zigmond MJ (2008) Rapid activation of ERK by 6-hydroxydopamine promotes survival of dopaminergic cells. J Neurosci Res 86:108–117
Lin TK, Cheng CH, Chen SD, Liou CW, Huang CR, Chuang YC (2012) Mitochondrial dysfunction and oxidative stress promote apoptotic cell death in the striatum via cytochrome c/caspase-3 signaling cascade following chronic rotenone intoxication in rats. Int J Mol Sci 13(7):8722–8739
Lin TK, Chen SD, Chuang YC, Lin HY, Huang CR, Chuang JH, Wang PW, Huang ST, Tiao MM, Chen JB, Liou CW (2014) Resveratrol partially prevents rotenone-induced neurotoxicity in dopaminergic SH-SY5Y cells through induction of heme oxygenase-1 dependent autophagy. Int J Mol Sci 15(1):1625–1646
Liu Y, Hu J, Wu J, Zhu C, Hui Y, Han Y, Huang Z, Ellsworth K, Fan W (2012a) α7 nicotinic acetylcholine receptor-mediated neuroprotection against dopaminergic neuron loss in an MPTP mouse model via inhibition of astrocyte activation. J Neuroinflammation 9:98
Liu Y, Hu J, Wu J, Zhu C, Hui Y, Han Y, Huang Z, Ellsworth K, Fan W (2012b) α7 nicotinic acetylcholine receptor-mediated neuroprotection against dopaminergic neuron loss in an MPTP mouse model via inhibition of astrocyte activation. J Neuroinflammation 9:98
Liu K, Shi N, Sun Y, Zhang T, Sun X (2013) Therapeutic effects of rapamycin on MPTP-induced Parkinsonism in mice. Neurochem Res 38(1):201–207
Liu X, Shao R, Li M, Yang G (2014) Edaravone protects neurons in the rat Substantia nigra against 6-hydroxydopamine-induced oxidative stress damage. Cell Biochem Biophys 70(2):1247–1254
Lo YC, Shih YT, Tseng YT, Hsu HT (2012) Neuroprotective effects of San-Huang-Xie-Xin-Tang in the MPP(+)/MPTP models of Parkinson’s disease in vitro and in vivo. Evid Based Complement Alternat Med 2012:501032
Lofrumento DD, Nicolardi G, Cianciulli A, De Nuccio F, La Pesa V, Carofiglio V, Dragone T, Calvello R, Panaro MA (2014) Neuroprotective effects of resveratrol in an MPTP mouse model of Parkinson’s-like disease: possible role of SOCS-1 in reducing pro-inflammatory responses. Innate Immun 20(3):249–260
Lopes FM, Londero GF, de Medeiros LM, da Motta LL, Behr GA, de Oliveira VA, Ibrahim M, Moreira JC, de Oliveira PL, da Rocha JB, Klamt F (2012) Evaluation of the neurotoxic/neuroprotective role of organoselenides using differentiated human neuroblastoma SH-SY5Y cell line challenged with 6-hydroxydopamine. Neurotox Res 22:138–149
Lozano J, Muñoz P, Nore BF, Ledoux S, Segura-Aguilar J (2010) Stable expression of short interfering RNA for DT-diaphorase induces neurotoxicity. Chem Res Toxicol 23:1492–1496
Lu M, Zhao FF, Tang JJ, Su CJ, Fan Y, Ding JH, Bian JS, Hu G (2012) The neuroprotection of hydrogen sulfide against MPTP-induced dopaminergic neuron degeneration involves uncoupling protein 2 rather than ATP-sensitive potassium channels. Antioxid Redox Signal 17(6):849–859
Lu DY, Chen JH, Tan TW, Huang CY, Yeh WL, Hsu HC (2013) Resistin protects against 6-hydroxydopamine-induced cell death in dopaminergic-like MES23.5 cells. J Cell Physiol 228:563–571
Luchtman DW, Meng Q, Wang X, Shao D, Song C (2013) ω-3 fatty acid eicosapentaenoic acid attenuates MPP+-induced neurodegeneration in fully differentiated human SH-SY5Y and primary mesencephalic cells. J Neurochem 124(6):855–868
Lundius EG, Stroth N, Vukojević V, Terenius L, Svenningsson P (2013) Functional GPR37 trafficking protects against toxicity induced by 6-OHDA, MPP+ or rotenone in a catecholaminergic cell line. J Neurochem 124(3):410–417
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 Based Complement Alternat Med 2012:928643
Madathil SK, Karuppagounder SS, Mohanakumar KP (2013) Sodium salicylate protects against rotenone-induced parkinsonism in rats. Synapse 67(8):502–514
Marshall JF, Ungerstedt U (1977) Supersensitivity to apomorphine following destruction of the ascending dopamine neurons: quantification using the rotational model. Eur J Pharmacol 41:361–367
Martin HL, Mounsey RB, Mustafa S, Sathe K, Teismann P (2012) Pharmacological manipulation of peroxisome proliferator-activated receptor γ (PPARγ) reveals a role for anti-oxidant protection in a model of Parkinson’s disease. Exp Neurol 235(2):528–538
Martin HL, Mounsey RB, Sathe K, Mustafa S, Nelson MC, Evans RM, Teismann P (2013) A peroxisome proliferator-activated receptor-δ agonist provides neuroprotection in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of Parkinson’s disease. Neuroscience 240:191–203
Martinez-Vicente M, Vila M (2013) Alpha-synuclein and protein degradation pathways in Parkinson’s disease: a pathological feed-back loop. Exp Neurol 4886(13):00085–00088
Mastroberardino PG, Hoffman EK, Horowitz MP, Betarbet R, Taylor G, Cheng D, Na HM, Gutekunst CA, Gearing M, Trojanowski JQ, Anderson M, Chu CT, Peng J, Greenamyre JT (2009) A novel transferrin/TfR2-mediated mitochondrial iron transport system is disrupted in Parkinson’s disease. Neurobiol Dis 34:417–431
McFarland K, Price DL, Davis CN, Ma JN, Bonhaus DW, Burstein ES, Olsson R (2013) AC-186, a selective nonsteroidal estrogen receptor β agonist, shows gender specific neuroprotection in a Parkinson’s disease rat model. ACS Chem Neurosci 4:1249–1255
Melamed E, Rosenthal J, Youdim MB (1990) Immunity of fetal mice to prenatal administration of the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. J Neurochem 55(4):1427–1431
Mizuno Y, Suzuki K, Sone N, Saitoh T (1987) Inhibition of ATP synthesis by 1-methyl-4-phenylpyridinium ion (MPP+) in isolated mitochondria from mouse brains. Neurosci Lett 81(1–2):204–208
Mochizuki H, Nakamura N, Nishi K, Mizuno Y (1994) Apoptosis is induced by 1-methyl-4-phenylpyridinium ion (MPP+) in ventral mesencephalic-striatal co-culture in rat. Neurosci Lett 170:191–194
Modi G, Voshavar C, Gogoi S, Shah M, Antonio T, Reith ME, Dutta AK (2014) Multifunctional D2/D3 agonist d-520 with high in vivo efficacy: modulator of toxicity of alpha-synuclein aggregates. ACS Chem Neurosci 5:700–717
Moreira CG, Barbiero JK, Ariza D, Dombrowski PA, Sabioni P, Bortolanza M, Da Cunha C, Vital MA, Lima MM (2012) Behavioral, neurochemical and histological alterations promoted by bilateral intranigral rotenone administration: a new approach for an old neurotoxin. Neurotox Res 21(3):291–301
Moreno-Sánchez R, Hernández-Esquivel L, Rivero-Segura NA, Marín-Hernández A, Neuzil J, Ralph SJ, Rodríguez-Enríquez S (2013) Reactive oxygen species are generated by the respiratory complex II-evidence for lack of contribution of the reverse electron flow in complex I. FEBS J 280(3):927–938
Mulcahy P, O’Doherty A, Paucard A, O’Brien T, Kirik D, Dowd E (2012) Development and characterisation of a novel rat model of Parkinson’s disease induced by sequential intranigral administration of AAV-α-synuclein and the pesticide, rotenone. Neuroscience 203:170–179
Mullett SJ, Di Maio R, Greenamyre JT, Hinkle DA (2013) DJ-1 expression modulates astrocyte-mediated protection against neuronal oxidative stress. J Mol Neurosci 49(3):507–511
Mullin S, Schapira A (2013) α-Synuclein and mitochondrial dysfunction in Parkinson’s disease. Mol Neurobiol 47:587–597
Muñoz P, Cardenas S, Huenchuguala S, Briceño A, Couve E, Paris I, Segura-Aguilar J (2015) DT-Diaphorase prevents aminochrome-induced alpha-synuclein oligomer formation and neurotoxicity. Toxicol Sci (in press)
Muñoz P, Huenchuguala S, Paris I, Cuevas C, Villa M, Caviedes P, Segura-Aguilar J, Tizabi Y (2012a) Protective effects of nicotine against aminochrome-induced toxicity in substantia nigra derived cells: implications for Parkinson’s disease. Neurotox Res 22:177–180
Muñoz P, Huenchuguala S, Paris I, Segura-Aguilar J (2012b) Dopamine oxidation and autophagy. Parkinsons Dis 2012:920953
Muñoz P, Paris I, Sanders LH, Greenamyre JT, Segura-Aguilar J (2012c) Overexpression of VMAT-2 and DT-diaphorase protects substantia nigra-derived cells against aminochrome neurotoxicity. Biochim Biophys Acta 1822:1125–1136
Murakami S, Miyazaki I, Sogawa N, Miyoshi K, Asanuma M (2014) Neuroprotective effects of metallothionein against rotenone-induced myenteric neurodegeneration in parkinsonian mice. Neurotox Res 26(3):285–298
Muroyama A, Fujita A, Lv C, Kobayashi S, Fukuyama Y, Mitsumoto Y (2012) Magnolol protects against MPTP/MPP(+)-induced toxicity via inhibition of xxidative stress in in vivo and in vitro models of Parkinson’s disease. Parkinsons Dis 2012:985157
Muthukumaran K, Smith J, Jasra H, Sikorska M, Sandhu JK, Cohen J, Lopatin D, Pandey S (2014) Genetic susceptibility model of Parkinson’s disease resulting from exposure of DJ-1 deficient mice to MPTP: evaluation of neuroprotection by Ubisol-Q10. J Parkinsons Dis 4(3):523–530
Napolitano A, Manini P, d’Ischia M (2011) Oxidation chemistry of catecholamines and neuronal degeneration: an update. Curr Med Chem 18:1832–1845
Nicoletti F, Philippens I, Fagone P, Ahlem CN, Reading CL, Frincke JM, Auci DL (2012) 17α-Ethynyl-androst-5-ene-3β,7β,17β-triol (HE3286) is neuroprotective and reduces motor impairment and neuroinflammation in a murine MPTP model of Parkinson’s disease. Parkinsons Dis. 2012:969418
Noelker C, Morel L, Lescot T, Osterloh A, Alvarez-Fischer D, Breloer M, Henze C, Depboylu C, Skrzydelski D, Michel PP, Dodel RC, Lu L, Hirsch EC, Hunot S (2013) Hartmann A (2013) Toll like receptor 4 mediates cell death in a mouse MPTP model of Parkinson disease. Sci Rep 3:1393
Nopparat C, Porter JE, Ebadi M, Govitrapong P (2014) 1-Methyl-4-phenylpyridinium-induced cell death via autophagy through a Bcl-2/beclin 1 complex-dependent pathway. Neurochem Res 39(2):225–232
Norris EH, Giasson BI, Hodara R, Xu S, Trojanowski JQ, Ischiropoulos H, Lee VM (2005) Reversible inhibition of alpha-synuclein fibrillization by dopaminochrome-mediated conformational alterations. J Biol Chem 280:21212–21219
Obata T, Miyashita M (2013) Protective effect of diltiazem, a L-type calcium channel antagonist, on lysophosphatidylcholine-enhanced hydroxyl radical generation by MPP(+) in rat striatum. Clin Biochem 46:164–166
Oh YM, Jang EH, Ko JH, Kang JH, Park CS, Han SB, Kim JS, Kim KH, Pie JE, Shin DW (2009) Inhibition of 6-hydroxydopamine-induced endoplasmic reticulum stress by l-carnosine in SH-SY5Y cells. Neurosci Lett 459(1):7–10
Ojha RP, Rastogi M, Devi BP, Agrawal A, Dubey GP (2012) Neuroprotective effect of curcuminoids against inflammation-mediated dopaminergic neurodegeneration in the MPTP model of Parkinson’s disease. J Neuroimmune Pharmacol 7:609–618
Padiglia A, Medda R, Lorrai A, Biggio G, Sanna E, Floris G (1997) Modulation of 6-hydroxydopamine oxidation by various proteins. Biochem Pharmacol 53:1065–1068
Pal R, Monroe TO, Palmieri M, Sardiello M, Rodney GG (2014) Rotenone induces neurotoxicity through Rac1-dependent activation of NADPH oxidase in SHSY-5Y cells. FEBS Lett 588(3):472–481
Pandi-Perumal SR, BaHammam AS, Brown GM, Spence DW, Bharti VK, Kaur C, Hardeland R, Cardinali DP (2013) Melatonin antioxidative defense: therapeutical implications for aging and neurodegenerative processes. Neurotox Res 23:267–300
Papadeas ST, Breese GR (2014) 6-Hydroxydopamine lesioning of dopamine neurons in neonatal and adult rats induces age-dependent consequences. In: Kostrzewa RM (ed) Handbook of neurotoxicity. Springer, London, pp 133–198
Paris I, Perez-Pastene C, Cardenas S, Iturriaga-Vasquez P, Muñoz P, Couve E, Caviedes P, Segura-Aguilar J (2010) Aminochrome induces disruption of actin, alpha-, and beta-tubulin cytoskeleton networks in substantia-nigra-derived cell line. Neurotox Res 18:82–92
Paris I, Muñoz P, Huenchuguala S, Couve E, Sanders LH, Greenamyre JT, Caviedes P, Segura-Aguilar J (2011) Autophagy protects against aminochrome-induced cell death in substantia nigra-derived cell line. Toxicol Sci 121:376–388
Park G, Park YJ, Yang HO, Oh MS (2013a) Ropinirole protects against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity in mice via anti-apoptotic mechanism. Pharmacol Biochem Behav 104:163–168
Park HJ, Park KH, Shin KS, Lee MK (2013b) The roles of cyclic AMP-ERK-Bad signaling pathways on 6-hydroxydopamine-induced cell survival and death in PC12 cells. Toxicol In Vitro 27:2233–2241
Pasquali L, Caldarazzo-Ienco Fornai F (2014) MPTP neurotoxicity: actions, mechanisms, and animal modeling of Parkinson’s disease. In: Kostrzewa RM (ed) Handbook of neurotoxicity. Springer, Heidelberg, pp 237–275
Patel MY, Panchal HV, Ghribi O, Benzeroual KE (2012) The neuroprotective effect of fisetin in the MPTP model of Parkinson’s disease. J Parkinsons Dis 2:287–302
Patil SP, Jain PD, Sancheti JS, Ghumatkar PJ, Tambe R, Sathaye S (2014a) Neuroprotective and neurotrophic effects of Apigenin and Luteolin in MPTP induced parkinsonism in mice. Neuropharmacology 86:192–202
Patil SP, Jain PD, Ghumatkar PJ, Tambe R, Sathaye S (2014b) Neuroprotective effect of metformin in MPTP-induced Parkinson’s disease in mice. Neuroscience 277:747–754
Philippens IH, Wubben JA, Finsen B, ‘t Hart BA (2013) Oral treatment with the NADPH oxidase antagonist apocynin mitigates clinical and pathological features of parkinsonism in the MPTP marmoset model. J Neuroimmune Pharmacol 8(3):715–726
Pisanu A, Lecca D, Mulas G, Wardas J, Simbula G, Spiga S, Carta AR (2014) Dynamic changes in pro- and anti-inflammatory cytokines in microglia after PPAR-γ agonist neuroprotective treatment in the MPTPp mouse model of progressive Parkinson’s disease. Neurobiol Dis 71:280–291
Polymeropoulos MH, Lavedan C, Leroy E, Ide SE, Dehejia A, Dutra A, Pike B, Root H, Rubenstein J, Boyer R, Stenroos ES, Chandrasekharappa S, Athanassiadou A, Papapetropoulos T, Johnson WG, Lazzarini AM, Duvoisin RC, Di Iorio G, Golbe LI, Nussbaum RL (1997) Mutation in the alpha-synuclein gene identified in families with Parkinson’s disease. Science 276:2045–2047
Prediger RD, Aguiar AS Jr, Matheus FC, Walz R, Antoury L, Raisman-Vozari R, Doty RL (2012) Intranasal administration of neurotoxicants in animals: support for the olfactory vector hypothesis of Parkinson’s disease. Neurotox Res 21(1):90–116
Przedborski S, Vila M (2001) MPTP: A review of its mechanisms of neurotoxicity. Clin Neurosci Res 1:407–418
Pyo JH, Jeong YK, Yeo S, Lee JH, Jeong MY, Kim SH, Choi YG, Lim S (2013) Neuroprotective effect of trans-cinnamaldehyde on the 6-hydroxydopamine-induced dopaminergic injury. Biol Pharm Bull 36:1928–1935
Pyszko J, Strosznajder JB (2014) Sphingosine kinase 1 and sphingosine-1-phosphate in oxidative stress evoked by 1-methyl-4-phenylpyridinium (MPP+) in human dopaminergic neuronal cells. Mol Neurobiol 50(1):38–48
Qualls Z, Brown D, Ramlochansingh C, Hurley LL, Tizabi Y (2014) Protective effects of curcumin against rotenone and salsolinol-induced toxicity: implications for Parkinson’s disease. Neurotox Res 25(1):81–89
Radad K, Hassanein K, Moldzio R, Rausch WD (2013) Vascular damage mediates neuronal and non-neuronal pathology following short and long-term rotenone administration in Sprague-Dawley rats. Exp Toxicol Pathol 65(1–2):41–47
Ramirez A, Heimbach A, Gründemann J, Stiller B, Hampshire D, Cid LP, Goebel I, Mubaidin AF, Wriekat AL, Roeper J, Al-Din A, Hillmer AM, Karsak M, Liss B, Woods CG, Behrens MI, Kubisch C (2006) Hereditary parkinsonism with dementia is caused by mutations in ATP13A2, encoding a lysosomal type 5 P-type ATPase. Nat Genet 38:1184–1191
Redman PT, Jefferson BS, Ziegler CB, Mortensen OV, Torres GE, Levitan ES, Aizenman E (2006) A vital role for voltage-dependent potassium channels in dopamine transporter -mediated 6-hydroxydopamine neurotoxicity. Neuroscience 143:1–6
Rescigno A, Porcu MC, Sanjust E, Rinaldi AC, Rinaldi A (1995) Inhibitory effect of NAD(P)H:quinone oxidoreductase on autoxidation of 6-hydroxydopa and 6-hydroxydopamine. Biochem Arch 11:161–169
Riachi NJ, Arora PK, Sayre LM, Harik SI (1988) Potent neurotoxic fluorinated 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine analogs as potential probes in models of Parkinson disease. J Neurochem 50(4):1319–1321
Rohn TT (2012) Targeting alpha-synuclein for the treatment of Parkinson’s disease. CNS Neurol Disord: Drug Targets 11:174–179
Sai T, Uchida K, Nakayama H (2013a) Acute toxicity of MPTP and MPP(+) in the brain of embryo and newborn mice. Exp Toxicol Pathol 65(1–2):113–119
Sai Y, Chen J, Ye F, Zhao Y, Zou Z, Cao J, Dong Z (2013b) Dopamine release suppression dependent on an increase of intracellular Ca(2+) contributed to rotenone-induced neurotoxicity in PC12 cells. J Toxicol Pathol 26(2):149–157
Saitoh K, Abe K, Chiba T, Katagiri N, Saitoh T, Horiguchi Y, Nojima H, Taguchi K (2013) Properties of 3-methyl-TIQ and 3-methyl-N-propargyl-TIQ for preventing MPTP-induced parkinsonism-like symptoms in mice. Pharmacol Rep 65(5):1204–1212
Sanders LH, Greenamyre JT (2013) Oxidative damage to macromolecules in human Parkinson disease and the rotenone model. Free Radic Biol Med 62:111–120
Santra S, Xu L, Shah M, Johnson M, Dutta A (2013) D-512 and D-440 as novel multifunctional dopamine agonists: characterization of neuroprotection properties and evaluation of in vivo efficacy in a Parkinson’s disease animal model. ACS Chem Neurosci 4(10):1382–1392
Sathe K, Maetzler W, Lang JD, Mounsey RB, Fleckenstein C, Martin HL, Schulte C, Mustafa S, Synofzik M, Vukovic Z, Itohara S, Berg D, Teismann P (2012) S100B is increased in Parkinson’s disease and ablation protects against MPTP-induced toxicity through the RAGE and TNF-α pathway. Brain 135(Pt 11):3336–3347
Sathiya S, Ranju V, Kalaivani P, Priya RJ, Sumathy H, Sunil AG, Babu CS (2013) Telmisartan attenuates MPTP induced dopaminergic degeneration and motor dysfunction through regulation of α-synuclein and neurotrophic factors (BDNF and GDNF) expression in C57BL/6 J mice. Neuropharmacology 73:98–110
Segura-Aguilar J, Lind C (1989) On the mechanism of Mn3+ induced neurotoxicity of dopamine: prevention of quinone derived oxygen toxicity by DT-diaphorase and superoxide dismutase. Chem Biol Interact 72:309–324
Segura-Aguilar J, Paris I, (2014) Mechanisms of dopamine oxidation and Parkinson’s disease, In: Kostrzewa RM, (ed) Handbook of neurotoxicity, Springer New York, Heidelberg, pp 865–883. ISBN 978-1-4614-5835-7 (print); ISBN 978-1-4614-5836-4 (eBook); ISBN 978-1-4614-7458-6 (print and electronic bundle)
Segura-Aguilar J, Baez S, Widersten M, Welch CJ, Mannervik B (1997) Human class Mu glutathione transferases, in particular isoenzyme M2-2, catalyze detoxication of the dopamine metabolite aminochrome. J Biol Chem 272:5727–5731
Segura-Aguilar J, Metodiewa D, Welch C (1998) Metabolic activation of dopamine o-quinones to o-semiquinones by NADPH cytochrome P450 reductase may play an important role in oxidative stress and apoptotic effects. Biochim Biophys Acta 1381:1–6
Segura-Aguilar J, Paris I, Muñoz P, Ferrari E, Zecca L, Zucca FA (2014) Protective and toxic roles of dopamine in Parkinson’s disease. J Neurochem 129:898–915
Shah M, Rajagopalan S, Xu L, Voshavar C, Shurubor Y, Beal F, Andersen JK, Dutta AK (2014) The high-affinity D2/D3 agonist D512 protects PC12 cells from 6-OHDA-induced apoptotic cell death and rescues dopaminergic neurons in the MPTP mouse model of Parkinson’s disease. J Neurochem 131(1):74–85
Shin DI, Oh YJ (2014) Tumor necrosis factor-associated protein 1 (TRAP1) is released from the mitochondria following 6-hydroxydopamine treatment. Exp Neurobiol 23:65–76
Shrivastava P, Vaibhav K, Tabassum R, Khan A, Ishrat T, Khan MM, Ahmad A, Islam F, Safhi MM, Islam F (2013) Anti-apoptotic and anti-inflammatory effect of Piperine on 6-OHDA induced Parkinson’s rat model. J Nutr Biochem 24:680–687
Shukla A, Mohapatra TM, Parmar D, Seth K (2014) Neuroprotective potentials of neurotrophin rich olfactory ensheathing cell’s conditioned media against 6OHDA-induced oxidative damage. Free Radic Res 48:560–571
Sikorska M, Lanthier P, Miller H, Beyers M, Sodja C, Zurakowski B, Gangaraju S, Pandey S, Sandhu JK (2014) Nanomicellar formulation of coenzyme Q10 (Ubisol-Q10) effectively blocks ongoing neurodegeneration in the mouse 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model: potential use as an adjuvant treatment in Parkinson’s disease. Neurobiol Aging 35(10):2329–2346
Simola N, Morelli M, Carta AR (2007) The 6-hydroxydopamine model of Parkinson’s disease. Neurotox Res 11:151–167
Siow TY, Chen CC, Wan N, Chow KP, Chang C (2013) In vivo evidence of increased nNOS activity in acute MPTP neurotoxicity: a functional pharmacological MRI study. Biomed Res Int 2013:964034
Solesio ME, Prime TA, Logan A, Murphy MP, Del Mar Arroyo-Jimenez M, Jordán J, Galindo MF (2013) The mitochondria-targeted anti-oxidant MitoQ reduces aspects of mitochondrial fission in the 6-OHDA cell model of Parkinson’s disease. Biochim Biophys Acta 1832:174–182
Song JX, Shaw PC, Wong NS, Sze CW, Yao XS, Tang CW, Tong Y, Zhang YB (2012) Chrysotoxine, a novel bibenzyl compound selectively antagonizes MPP+, but not rotenone, neurotoxicity in dopaminergic SH-SY5Y cells. Neurosci Lett 521(1):76–81
Sonia Angeline M, Chaterjee P, Anand K, Ambasta RK, Kumar P (2012) Rotenone-induced parkinsonism elicits behavioral impairments and differential expression of parkin, heat shock proteins and caspases in the rat. Neuroscience 220:291–301
Sonia Angeline M, Sarkar A, Anand K, Ambasta RK, Kumar P (2013) Sesamol and naringenin reverse the effect of rotenone-induced PD rat model. Neuroscience 254:379–394
Soto-Otero R, Méndez-Alvarez E, Hermida-Ameijeiras A, Muñoz-Patiño AM, Labandeira-Garcia JL (2000) Autoxidation and neurotoxicity of 6-hydroxydopamine in the presence of some antioxidants: potential implication in relation to the pathogenesis of Parkinson’s disease. J Neurochem 74:1605–1612
Spittau B, Zhou X, Ming M, Krieglstein K (2012) IL6 protects MN9D cells and midbrain dopaminergic neurons from MPP+-induced neurodegeneration. Neuromolecular Med 14(4):317–327
St Laurent R, O’Brien LM, Ahmad ST (2013) Sodium butyrate improves locomotor impairment and early mortality in a rotenone-induced Drosophila model of Parkinson’s disease. Neuroscience 246:382–390
Sterky FH, Hoffman AF, Milenkovic D, Bao B, Paganelli A, Edgar D, Wibom R, Lupica CR, Olson L, Larsson NG (2012) Altered dopamine metabolism and increased vulnerability to MPTP in mice with partial deficiency of mitochondrial complex I in dopamine neurons. Hum Mol Genet 21:1078–1089
Sun X, Liu J, Crary JF, Malagelada C, Sulzer D, Greene LA, Levy OA (2013) ATF4 protects against neuronal death in cellular Parkinson’s disease models by maintaining levels of parkin. J Neurosci 33(6):2398–2407
Sun X, Xiong Z, Zhang Y, Meng Y, Xu G, Xia Z, Li J, Zhang R, Ke Z, Xia Z, Hu Y (2012) Harpagoside attenuates MPTP/MPP induced dopaminergic neurodegeneration and movement disorder via elevating glial cell line-derived neurotrophic factor. J Neurochem 120:1072–1083
Sung YH, Kim SC, Hong HP, Park CY, Shin MS, Kim CJ, Seo JH, Kim DY, Kim DJ, Cho HJ (2012) Treadmill exercise ameliorates dopaminergic neuronal loss through suppressing microglial activation in Parkinson’s disease mice. Life Sci 91(25–26):1309–1316
Swanson CR, Du E, Johnson DA, Johnson JA, Emborg ME (2013) Neuroprotective properties of a novel non-thiazoledinedione partial PPAR-γ agonist against MPTP. PPAR Res. 2013:582809
Swarnkar S, Goswami P, Kamat PK, Gupta S, Patro IK, Singh S, Nath C (2012a) Rotenone-induced apoptosis and role of calcium: a study on Neuro-2a cells. Arch Toxicol 86(9):1387–1397
Swarnkar S, Singh S, Goswami P, Mathur R, Patro IK, Nath C (2012b) Astrocyte activation: a key step in rotenone induced cytotoxicity and DNA damage. Neurochem Res 37(10):2178–2189
Tamilselvam K, Braidy N, Manivasagam T, Essa MM, Prasad NR, Karthikeyan S, Thenmozhi AJ, Selvaraju S, Guillemin GJ (2013) Neuroprotective effects of hesperidin, a plant flavanone, on rotenone-induced oxidative stress and apoptosis in a cellular model for Parkinson’s disease. Oxid Med Cell Longev 2013:102741
Tang XQ, Zhuang YY, Fan LL, Fang HR, Zhou CF, Zhang P, Hu B (2012) Involvement of K(ATP)/PI (3)K/AKT/Bcl-2 pathway in hydrogen sulfide-induced neuroprotection against the toxicity of 1-methy-4-phenylpyridinium ion. J Mol Neurosci 46(2):442–449
Tasaki Y, Yamamoto J, Omura T, Noda T, Kamiyama N, Yoshida K, Satomi M, Sakaguchi T, Asari M, Ohkubo T, Shimizu K, Matsubara K (2012) Oxicam structure in non-steroidal anti-inflammatory drugs is essential to exhibit Akt-mediated neuroprotection against 1-methyl-4-phenyl pyridinium-induced cytotoxicity. Eur J Pharmacol 676(1–3):57–63
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
Teng L, Kou C, Lu C, Xu J, Xie J, Lu J, Liu Y, Wang Z, Wang D (2014) Involvement of the ERK pathway in the protective effects of glycyrrhizic acid against the MPP+-induced apoptosis of dopaminergic neuronal cells. Int J Mol Med 34(3):742–748
Thakur P, Nehru B (2013) Anti-inflammatory properties rather than anti-oxidant capability is the major mechanism of neuroprotection by sodium salicylate in a chronic rotenone model of Parkinson’s disease. Neuroscience 231:420–431
Thakur P, Nehru B (2014a) Inhibition of neuroinflammation and mitochondrial dysfunctions by carbenoxolone in the rotenone model of Parkinson’s disease. Mol Neurobiol. doi:10.1007/s12035-014-8769-7
Thakur P, Nehru B (2014b) Long-term heat shock proteins (HSPs) induction by carbenoxolone improves hallmark features of Parkinson’s disease in a rotenone-based model. Neuropharmacology 79:190–200
Thoenen H, Tranzer JP (1968) Chemical sympathectomy by selective destruction of adrenergic nerve endings with 6-Hydroxydopamine. Naunyn Schmiedebergs Arch Exp Pathol Pharmakol 261:271–288
Tian LL, Wang XJ, Sun YN, Li CR, Xing YL, Zhao HB, Duan M, Zhou Z, Wang SQ (2008) Salvianolic acid B, an antioxidant from Salvia miltiorrhiza, prevents 6-hydroxydopamine induced apoptosis in SH-SY5Y cells. Int J Biochem Cell Biol 40:409–422
Tobón-Velasco JC, Limón-Pacheco JH, Orozco-Ibarra M, Macías-Silva M, Vázquez-Victorio G, Cuevas E, Ali SF, Cuadrado A, Pedraza-Chaverrí J, Santamaría A (2013) 6-OHDA-induced apoptosis and mitochondrial dysfunction are mediated by early modulation of intracellular signals and interaction of Nrf2 and NF-κB factors. Toxicology 304:109–119
Tolosa A, Zhou X, Spittau B, Krieglstein K (2013) Establishment of a survival and toxic cellular model for Parkinson’s disease from chicken mesencephalon. Neurotox Res 24:119–129
Toulouse A, Collins GC, Sullivan AM (2012) Neurotrophic effects of growth/differentiation factor 5 in a neuronal cell line. Neurotox Res 21:256–265
Tovilovic G, Zogovic N, Soskic V, Schrattenholz A, Kostic-Rajacic S, Misirkic-Marjanovic M, Janjetovic K, Vucicevic L, Arsikin K, Harhaji-Trajkovic L, Trajkovic V (2013) Arylpiperazine-mediated activation of Akt protects SH-SY5Y neuroblastoma cells from 6-hydroxydopamine-induced apoptotic and autophagic death. Neuropharmacology 72:224–235
Toy WA, Petzinger GM, Leyshon BJ, Akopian GK, Walsh JP, Hoffman MV, Vučković MG, Jakowec MW (2014) Treadmill exercise reverses dendritic spine loss in direct and indirect striatal medium spiny neurons in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson’s disease. Neurobiol Dis 63:201–209
Tristão FS, Amar M, Latrous I, Del-Bel EA, Prediger RD, Raisman-Vozari R (2014) Evaluation of nigrostriatal neurodegeneration and neuroinflammation following repeated intranasal 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration in mice, an experimental model of Parkinson’s disease. Neurotox Res 25(1):24–32
Tse DC, McCreery RL, Adams RN (1976) Potential oxidative pathways of brain catecholamines. J Med Chem 19:37–40
Ungerstedt U (1971) Post synaptic supersensitivity after 6-hydroxydopamine induced degeneration of the nigrostriatal dopamine system. Acta Physiol Scand 367:69–93
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, González-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
Van Laar VS, Mishizen AJ, Cascio M, Hastings TG (2009) Proteomic identification of dopamine-conjugated proteins from isolated rat brain mitochondria and SH-SY5Y cells. Neurobiol Dis 34:487–500
Verhave PS, Jongsma MJ, Van Den Berg RM, Vanwersch RA, Smit AB, Philippens IH (2012) Neuroprotective effects of riluzole in early phase Parkinson’s disease on clinically relevant parameters in the marmoset MPTP model. Neuropharmacology 62(4):1700–1707
Villa M, Muñoz P, Ahumada-Castro U, Paris I, Jiménez A, Martínez I, Sevilla F, Segura-Aguilar J (2013) One-electron reduction of 6-hydroxydopamine quinone is essential in 6-hydroxydopamine neurotoxicity. Neurotox Res 24(1):94–101
Villar-Cheda B, Dominguez-Meijide A, Joglar B, Rodriguez-Perez AI, Guerra MJ, Labandeira-Garcia JL (2012) Involvement of microglial RhoA/Rho-kinase pathway activation in the dopaminergic neuron death. Role of angiotensin via angiotensin type 1 receptors. Neurobiol Dis 47:268–279
Walsh S, Gavin A, Wyatt S, O’Connor C, Keeshan K, Nolan YM, O’Keeffe GW, Sullivan AM (2014) Knockdown of interleukin-1 receptor 1 is not neuroprotective in the 6-hydroxydopamine striatal lesion rat model of Parkinson’s disease. Int J Neurosci 125(1):70–77
Wang R, Ma Z, Wang J, Xie J (2012) L-type Cav1.2 calcium channel is involved in 6-hydroxydopamine-induced neurotoxicity in rats. Neurotox Res 21:266–270
Wang HM, Zhang T, Li Q, Huang JK, Chen RF, Sun XJ (2013a) Inhibition of glycogen synthase kinase-3β by lithium chloride suppresses 6-hydroxydopamine-induced inflammatory response in primary cultured astrocytes. Neurochem Int 63:345–353
Wang YH, Yu HT, Pu XP, Du GH (2013b) Baicalein prevents 6-hydroxydopamine-induced mitochondrial dysfunction in SH-SY5Y cells via inhibition of mitochondrial oxidation and up-regulation of DJ-1 protein expression. Molecules 18:14726–14738
Wang H, Zhang Z, Huang J, Zhang P, Xiong N, Wang T (2014a) The contribution of Cdc2 in rotenone-induced G2/M arrest and caspase-3-dependent apoptosis. J Mol Neurosci 53(1):31–40
Wang L, Wang R, Jin M, Huang Y, Liu A, Qin J, Chen M, Wen S, Pi R, Shen W (2014b) Carvedilol attenuates 6-hydroxydopamine-induced cell death in PC12 cells: involvement of Akt and Nrf2/ARE pathways. Neurochem Res 39:1733–1740
Wang S, He H, Chen L, Zhang W, Zhang X, Chen J (2014c) Protective effects of salidroside in the MPTP/MPP+-induced model of Parkinson’s disease through ROS-NO-related mitochondrion pathway. Mol Neurobiol. doi:10.1007/s12035-014-8755-0
Weetman JL, Wong MB, Sharry S, Rcom-H’cheo-Gauthier A, Gai WP, Meedeniya A, Pountney DL (2013) Increased SUMO-1 expression in the unilateral rotenone-lesioned mouse model of Parkinson’s disease. Neurosci Lett 544:119–124
Wei L, Sun C, Lei M, Li G, Yi L, Luo F, Li Y, Ding L, Liu Z, Li S, Xu P (2013) Activation of Wnt/β-catenin pathway by exogenous Wnt1 protects SH-SY5Y cells against 6-hydroxydopamine toxicity. J Mol Neurosci 49:105–115
Westlund KN, Denney RM, Kochersperger LM, Rose RM, Abell CW (1985) Distinct monoamine oxidase A and B populations in primate brain. Science 230(4722):181–183
Whitehead RE, Ferrer JV, Javitch JA, Justice JB (2001) Reaction of oxidized dopamine with endogenous cysteine residues in the human dopamine transporter. J Neurochem 76:1242–1251
Wiemerslage L, Schultz BJ, Ganguly A, Lee D (2013) Selective degeneration of dopaminergic neurons by MPP(+) and its rescue by D2 autoreceptors in Drosophila primary culture. J Neurochem 126(4):529–540
Williams A (1984) MPTP parkinsonism. Br Med J 289:1401–1402
Williams A (1986) MPTP toxicity: clinical features. J Neural Transm Suppl 20:5–9
Williamson TP, Johnson DA, Johnson JA (2012) Activation of the Nrf2-ARE pathway by siRNA knockdown of Keap1 reduces oxidative stress and provides partial protection from MPTP-mediated neurotoxicity. Neurotoxicology 33(3):272–279
Wolfgang S, Beat U (1991) Placental toxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in mice. Toxicology 67:63–74
Wolters ECh, Braak H (2006) Parkinson’s disease: premotor clinico-pathological correlations. J Neural Transm Suppl 70:309–319
Wong MB, Goodwin J, Norazit A, Meedeniya AC, Richter-Landsberg C, Gai WP, Pountney DL (2013) SUMO-1 is associated with a subset of lysosomes in glial protein aggregate diseases. Neurotox Res 23(1):1–21
Wu EY, Smith MT, Bellomo G, Di Monte D (1990) Relationships between the mitochondrial transmembrane potential, ATP concentration, and cytotoxicity in isolated rat hepatocytes. Arch Biochem Biophys 282(2):358–362
Wu DD, Huang L, Zhang L, Wu LY, Li YC, Feng L (2012) LLDT-67 attenuates MPTP-induced neurotoxicity in mice by up-regulating NGF expression. Acta Pharmacol Sin 33:1187–1194
Wu F, Wang Z, Gu JH, Ge JB, Liang ZQ, Qin ZH (2013a) p38(MAPK)/p53-Mediated Bax induction contributes to neurons degeneration in rotenone-induced cellular and rat models of Parkinson’s disease. Neurochem Int 63(3):133–140
Wu L, Tian YY, Shi JP, Xie W, Shi JQ, Lu J, Zhang YD (2013b) Inhibition of endoplasmic reticulum stress is involved in the neuroprotective effects of candesartan cilexitil in the rotenone rat model of Parkinson’s disease. Neurosci Lett 548:50–55
Wu L, Luo N, Zhao HR, Gao Q, Lu J, Pan Y, Shi JP, Tian YY, Zhang YD (2014) Salubrinal protects against rotenone-induced SH-SY5Y cell death via ATF4-parkin pathway. Brain Res 1549:52–62
Xie L, Tiong CX, Bian JS (2012) Hydrogen sulfide protects SH-SY5Y cells against 6-hydroxydopamine-induced endoplasmic reticulum stress. Am J Physiol Cell Physiol 303(1):C81–C91
Xiong R, Siegel D, Ross D (2014) Quinone-induced protein handling changes: implications for major protein handling systems in quinone-mediated toxicity. Toxicol Appl Pharmacol 14:00306–00308
Xu Y, Stokes AH, Roskoski R Jr, Vrana KE (1998) Dopamine, in the presence of tyrosinase, covalently modifies and inactivates tyrosine hydroxylase. J Neurosci Res 54:691–697
Xu L, Li W, Lin D, Zhang H, Zou F (2013a) Role of calcium dyshomeostasis in 1-methyl-4-phenylpyridinium ion-induced apoptosis of human neuroblastoma SH-SY5Y cells. Nan Fang Yi Ke Da Xue Xue Bao 33(4):479–485 Chinese
Xu X, Gao W, Dou S, Cheng B (2013b) Simvastatin inhibited the apoptosis of PC12 cells induced by 1-methyl-4-phenylpyridinium ion via inhibiting reactive oxygen species production. Cell Mol Neurobiol 33:69–73
Xu YQ, Long L, Yan JQ, Wei L, Pan MQ, Gao HM, Zhou P, Liu M, Zhu CS, Tang BS, Wang Q (2013c) Simvastatin induces neuroprotection in 6-OHDA-lesioned PC12 via the PI3 K/AKT/caspase 3 pathway and anti-inflammatory responses. CNS Neurosci Ther 19:170–177
Xu DP, Zhang K, Zhang ZJ, Sun YW, Guo BJ, Wang YQ, Hoi PM, Han YF, Lee SM (2014a) A novel tetramethylpyrazine bis-nitrone (TN-2) protects against 6-hydroxyldopamine-induced neurotoxicity via modulation of the NF-κB and the PKCα/PI3-K/Akt pathways. Neurochem Int 78C:76–85
Xu Y, Liu C, Chen S, Ye Y, Guo M, Ren Q, Liu L, Zhang H, Xu C, Zhou Q, Huang S, Chen L (2014b) Activation of AMPK and inactivation of Akt result in suppression of mTOR-mediated S6K1 and 4E-BP1 pathways leading to neuronal cell death in in vitro models of Parkinson’s disease. Cell Signal 26:1680–1689
Yan J, Sun J, Huang L, Fu Q, Du G (2014) Simvastatin prevents neuroinflammation by inhibiting N-methyl-d-aspartic acid receptor 1 in 6-hydroxydopamine-treated PC12 cells. J Neurosci Res 92:634–640
Yap YW, Chen MJ, Peng ZF, Manikandan J, Ng JM, Llanos RM, La Fontaine S, Beart PM, Cheung NS (2013) Gene expression profiling of rotenone-mediated cortical neuronal death: evidence for inhibition of ubiquitin-proteasome system and autophagy-lysosomal pathway, and dysfunction of mitochondrial and calcium signaling. Neurochem Int 62(5):653–663
Ye Q, Huang B, Zhang X, Zhu Y, Chen X (2012a) Astaxanthin protects against MPP(+)-induced oxidative stress in PC12 cells via the HO-1/NOX2 axis. BMC Neurosci 13:156
Ye Q, Ye L, Xu X, Huang B, Zhang X, Zhu Y, Chen X (2012b) Epigallocatechin-3-gallate suppresses 1-methyl-4-phenyl-pyridine-induced oxidative stress in PC12 cells via the SIRT1/PGC-1α signaling pathway. BMC Complement Altern Med 12:82
Ye Q, Zhang X, Huang B, Zhu Y, Chen X (2013) Astaxanthin suppresses MPP(+)-induced oxidative damage in PC12 cells through a Sp1/NR1 signaling pathway. Mar Drugs 11(4):1019–1034
Yi F, He X, Wang D (2013) Lycopene protects against MPP(+)-induced cytotoxicity by maintaining mitochondrial function in SH-SY5Y cells. Neurochem Res 38(8):1747–1757
Yong-Kee CJ, Sidorova E, Hanif A, Perera G, Nash JE (2012a) Mitochondrial dysfunction precedes other sub-cellular abnormalities in an in vitro model linked with cell death in Parkinson’s disease. Neurotox Res 21:185–194
Yong-Kee CJ, Warre R, Monnier PP, Lozano AM, Nash JE (2012b) Evidence for synergism between cell death mechanisms in a cellular model of neurodegeneration in Parkinson’s disease. Neurotox Res 22:355–364
Youn JK, Kim DW, Kim ST, Park SY, Yeo EJ, Choi YJ, Lee HR, Kim DS, Cho SW, Han KH, Park J, Eum WS, Hwang HS, Choi SY (2014) PEP-1-HO-1 prevents MPTP-induced degeneration of dopaminergic neurons in a Parkinson’s disease mouse model. BMB Rep 47(10):569–574
Yu X, Li X, Jiang G, Wang X, Chang HC, Hsu WH, Li Q (2013) Isradipine prevents rotenone-induced intracellular calcium rise that accelerates senescence in human neuroblastoma SH-SY5Y cells. Neuroscience 246:243–253
Yürekli VA, Gürler S, Nazıroğlu M, Uğuz AC, Koyuncuoğlu HR (2013) Zonisamide attenuates MPP+-induced oxidative toxicity through modulation of Ca2+ signaling and caspase-3 activity in neuronal PC12 cells. Cell Mol Neurobiol 33(2):205–212
Zafar KS, Siegel D, Ross D (2006) A potential role for cyclized quinones derived from dopamine, DOPA, and 3,4-dihydroxyphenylacetic acid in proteasomal inhibition. Mol Pharmacol 70:1079–1086
Zaminelli T, Gradowski RW, Bassani TB, Barbiero JK, Santiago RM, Maria-Ferreira D, Baggio CH, Vital MA (2014) Antidepressant and antioxidative effect of ibuprofen in the rotenone model of Parkinson’s disease. Neurotox Res 26(4):351–362
Zare K, Eidi A, Roghani M, Rohani AH (2015) The neuroprotective potential of sinapic acid in the 6-hydroxydopamine-induced hemi-parkinsonian rat. Metab Brain Dis 30:205–213
Zawada WM, Banninger GP, Thornton J, Marriott B, Cantu D, Rachubinski AL, Das M, Griffin WS, Jones SM (2011) Generation of reactive oxygen species in 1-methyl-4-phenylpyridinium (MPP+) treated dopaminergic neurons occurs as an NADPH oxidase-dependent two-wave cascade. J Neuroinflammation 8:129
Zecca L, Fariello R, Riederer P, Sulzer D, Gatti A, Tampellini D (2002) The absolute concentration of nigral neuromelanin, assayed by a new sensitive method, increases throughout the life and is dramatically decreased in Parkinson’s disease. FEBS Lett 510:216–220
Zhai A, Zhu X, Wang X, Chen R, Wang H (2013) Secalonic acid A protects dopaminergic neurons from 1-methyl-4-phenylpyridinium (MPP+)-induced cell death via the mitochondrial apoptotic pathway. Eur J Pharmacol 713(1–3):58–67
Zhang L, Ding W, Sun H, Zhou Q, Huang J, Li X, Xie Y, Chen J (2012) Salidroside protects PC12 cells from MPP+-induced apoptosis via activation of the PI3 K/Akt pathway. Food Chem Toxicol 50(8):2591–2597
Zhang S, Xue ZF, Huang LP, Fang RM, He YP, Li L, Fang YQ (2013) Dynamic expressions of Beclin 1 and tyrosine hydroxylase in different areas of 6-hydroxydopamine-induced Parkinsonian rats. Cell Mol Neurobiol 33:973–981
Zhou ZD, Lim TM (2009) Dopamine (DA) induced irreversible proteasome inhibition via DA derived quinones. Free Radic Res 43:417–430
Zhou H, Zhang F, Chen SH, Zhang D, Wilson B, Hong JS, Gao HM (2012) Rotenone activates phagocyte NADPH oxidase by binding to its membrane subunit gp91phox. Free Radic Biol Med 52(2):303–313
Zhou J, Qu XD, Li ZY, Wei-Ji, Liu Q, Ma YH, He JJ (2014) Salvianolic acid B attenuates toxin-induced neuronal damage via Nrf2-dependent glial cells-mediated protective activity in Parkinson’s disease models. PLoS ONE 9(7):e101668
Zhu G, Wang X, Wu S, Li Q (2012a) Involvement of activation of PI3 K/Akt pathway in the protective effects of puerarin against MPP+-induced human neuroblastoma SH-SY5Y cell death. Neurochem Int 60(4):400–408
Zhu JH, Gusdon AM, Cimen H, Van Houten B, Koc E, Chu CT (2012b) Impaired mitochondrial biogenesis contributes to depletion of functional mitochondria in chronic MPP+ toxicity: dual roles for ERK1/2. Cell Death Dis 24(3):e312
Zhu Q, Wang J, Zhang Y, Sun S (2012c) Mechanisms of MPP+-induced PC12 cell apoptosis via reactive oxygen species. J Huazhong Univ Sci Technolog Med Sci 32:861–866
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Segura-Aguilar, J., Kostrzewa, R.M. Neurotoxin Mechanisms and Processes Relevant to Parkinson’s Disease: An Update. Neurotox Res 27, 328–354 (2015). https://doi.org/10.1007/s12640-015-9519-y
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12640-015-9519-y