Therapeutic Approaches to Non-Motor Symptoms of Parkinson's Disease:
A Current Update on Preclinical Evidence

Poornima   D.E.   Weerasinghe-Mudiyanselage; Sohi      Kang; Joong-Sun      Kim; Changjong      Moon
Abstract

Despite being classified as a movement disorder, Parkinson’s disease (PD) is characterized by a wide range of non-motor symptoms that significantly affect the patients' quality of life. However, clear evidence-based therapy recommendations for non-motor symptoms of PD are uncommon. Animal models of PD have previously been shown to be useful for advancing the knowledge and treatment of motor symptoms. However, these models may provide insight into and assess therapies for non-motor symptoms in PD. This paper highlights non-motor symptoms in preclinical models of PD and the current position regarding preclinical therapeutic approaches for these non-motor symptoms. This information may be relevant for designing future preclinical investigations of therapies for nonmotor symptoms in PD.
Keywords: Non-motor symptoms, Parkinson’s disease, patients' quality of life, preclinical models, therapeutics
Graphical Abstract

[1]
de Lau, L.M.L.; Breteler, M.M.B. Epidemiology of Parkinson’s disease. Lancet Neurol.,  2006, 5(6), 525-535.
 [http://dx.doi.org/10.1016/S1474-4422(06)70471-9] [PMID: 16713924]

[2]
Lee, H.M.; Koh, S.B. Many Faces of Parkinson’s disease: Non-motor symptoms of Parkinson’s disease. J. Mov. Disord.,  2015, 8(2), 92-97.
 [http://dx.doi.org/10.14802/jmd.15003] [PMID: 26090081]

[3]
Poewe, W.; Seppi, K.; Tanner, C.M.; Halliday, G.M.; Brundin, P.; Volkmann, J.; Schrag, A.E.; Lang, A.E. Parkinson disease. Nat. Rev. Dis. Primers,  2017, 3(1), 17013.
 [http://dx.doi.org/10.1038/nrdp.2017.13] [PMID: 28332488]

[4]
Homayoun, H. Parkinson disease. Ann. Intern. Med.,  2018, 169(5), ITC33-ITC48.
 [http://dx.doi.org/10.7326/AITC201809040] [PMID: 30178019]

[5]
Armstrong, M.J.; Okun, M.S. Diagnosis and treatment of Parkinson disease. JAMA,  2020, 323(6), 548-560.
 [http://dx.doi.org/10.1001/jama.2019.22360] [PMID: 32044947]

[6]
Titova, N.; Chaudhuri, K.R. Non‐motor Parkinson disease: new concepts and personalised management. Med. J. Aust.,  2018, 208(9), 404-409.
 [http://dx.doi.org/10.5694/mja17.00993] [PMID: 29764353]

[7]
Gustafsson, H.; Nordström, A.; Nordström, P. Depression and subsequent risk of Parkinson disease: A nationwide cohort study. Neurology,  2015, 84(24), 2422-2429.
 [http://dx.doi.org/10.1212/WNL.0000000000001684] [PMID: 25995056]

[8]
Aarsland, D.; Creese, B.; Politis, M.; Chaudhuri, K.R.; ffytche, D.H.; Weintraub, D.; Ballard, C. Cognitive decline in Parkinson disease. Nat. Rev. Neurol.,  2017, 13(4), 217-231.
 [http://dx.doi.org/10.1038/nrneurol.2017.27] [PMID: 28257128]

[9]
Saredakis, D.; Collins-Praino, L.E.; Gutteridge, D.S.; Stephan, B.C.M.; Keage, H.A.D. Conversion to MCI and dementia in Parkinson’s disease: a systematic review and meta-analysis. Parkinsonism Relat. Disord.,  2019, 65, 20-31.
 [http://dx.doi.org/10.1016/j.parkreldis.2019.04.020] [PMID: 31109727]

[10]
Hobson, P.; Meara, J. Mild cognitive impairment in Parkinson’s disease and its progression onto dementia: a 16-year outcome evaluation of the Denbighshire cohort. Int. J. Geriatr. Psychiatry,  2015, 30(10), 1048-1055.
 [http://dx.doi.org/10.1002/gps.4261] [PMID: 25676160]

[11]
Nicoletti, A.; Luca, A.; Baschi, R.; Cicero, C.E.; Mostile, G.; Davì, M.; Pilati, L.; Restivo, V.; Zappia, M.; Monastero, R. Incidence of mild cognitive impairment and dementia in Parkinson’s disease: The Parkinson’s disease cognitive impairment study. Front. Aging Neurosci.,  2019, 11, 21.
 [http://dx.doi.org/10.3389/fnagi.2019.00021] [PMID: 30800065]

[12]
Chaudhuri, K.R.; Prieto-Jurcynska, C.; Naidu, Y.; Mitra, T.; Frades-Payo, B.; Tluk, S.; Ruessmann, A.; Odin, P.; Macphee, G.; Stocchi, F.; Ondo, W.; Sethi, K.; Schapira, A.H.V.; Castrillo, J.C.M.; Martinez-Martin, P. The nondeclaration of nonmotor symptoms of Parkinson’s disease to health care professionals: An international study using the nonmotor symptoms questionnaire. Mov. Disord.,  2010, 25(6), 704-709.
 [http://dx.doi.org/10.1002/mds.22868] [PMID: 20437539]

[13]
Wolters, E.C.; Francot, C.M.J.E. Mental dysfunction in Parkinson’s disease. Parkinsonism Relat. Disord.,  1998, 4(3), 107-112.
 [http://dx.doi.org/10.1016/S1353-8020(98)00022-4] [PMID: 18591098]

[14]
Pantcheva, P.; Reyes, S.; Hoover, J.; Kaelber, S.; Borlongan, C.V. Treating non-motor symptoms of Parkinson’s disease with transplantation of stem cells. Expert Rev. Neurother.,  2015, 15(10), 1231-1240.
 [http://dx.doi.org/10.1586/14737175.2015.1091727] [PMID: 26394528]

[15]
Chaudhuri, K.R.; Schapira, A.H.V. Non-motor symptoms of Parkinson’s disease: dopaminergic pathophysiology and treatment. Lancet Neurol.,  2009, 8(5), 464-474.
 [http://dx.doi.org/10.1016/S1474-4422(09)70068-7] [PMID: 19375664]

[16]
Honig, H.; Antonini, A.; Martinez-Martin, P.; Forgacs, I.; Faye, G.C.; Fox, T.; Fox, K.; Mancini, F.; Canesi, M.; Odin, P.; Chaudhuri, K.R. Intrajejunal levodopa infusion in Parkinson’s disease: A pilot multicenter study of effects on nonmotor symptoms and quality of life. Mov. Disord.,  2009, 24(10), 1468-1474.
 [http://dx.doi.org/10.1002/mds.22596] [PMID: 19425079]

[17]
Fox, S.H.; Brotchie, J.M.; Lang, A.E. Non-dopaminergic treatments in development for Parkinson’s disease. Lancet Neurol.,  2008, 7(10), 927-938.
 [http://dx.doi.org/10.1016/S1474-4422(08)70214-X] [PMID: 18848312]

[18]
Remy, P.; Doder, M.; Lees, A.; Turjanski, N.; Brooks, D. Depression in Parkinson’s disease: loss of dopamine and noradrenaline innervation in the limbic system. Brain,  2005, 128(6), 1314-1322.
 [http://dx.doi.org/10.1093/brain/awh445] [PMID: 15716302]

[19]
Song, J.; Shen, B.; Yang, Y.J.; Liu, F.; Zhao, J.; Tang, Y.L.; Chen, C.; Ding, Z.T.; An, Y.; Wu, J.J.; Sun, Y.M.; Wang, J. Non-motor symptoms in Parkinson’s disease patients with Parkin mutations: more depression and less executive dysfunction. J. Mol. Neurosci.,  2020, 70(2), 246-253.
 [http://dx.doi.org/10.1007/s12031-019-01444-3] [PMID: 31927768]

[20]
Chen, W.; Kang, W.Y.; Chen, S.; Wang, Y.; Xiao, Q.; Wang, G.; Liu, J.; Chen, S.D. Hyposmia correlates with SNCA variant and non-motor symptoms in Chinese patients with Parkinson’s disease. Parkinsonism Relat. Disord.,  2015, 21(6), 610-614.
 [http://dx.doi.org/10.1016/j.parkreldis.2015.03.021] [PMID: 25921825]

[21]
Gaig, C.; Vilas, D.; Infante, J.; Sierra, M.; García-Gorostiaga, I.; Buongiorno, M.; Ezquerra, M.; Martí, M.J.; Valldeoriola, F.; Aguilar, M.; Calopa, M.; Hernandez-Vara, J.; Tolosa, E. Nonmotor symptoms in LRRK2 G2019S associated Parkinson’s disease. PLoS One,  2014, 9(10), e108982.
 [http://dx.doi.org/10.1371/journal.pone.0108982] [PMID: 25330404]

[22]
Swan, M.; Doan, N.; Ortega, R.A.; Barrett, M.; Nichols, W.; Ozelius, L.; Soto-Valencia, J.; Boschung, S.; Deik, A.; Sarva, H.; Cabassa, J.; Johannes, B.; Raymond, D.; Marder, K.; Giladi, N.; Miravite, J.; Severt, W.; Sachdev, R.; Shanker, V.; Bressman, S.; Saunders-Pullman, R. Neuropsychiatric characteristics of GBA-associated Parkinson disease. J. Neurol. Sci.,  2016, 370, 63-69.
 [http://dx.doi.org/10.1016/j.jns.2016.08.059] [PMID: 27772789]

[23]
Castrioto, A.; Thobois, S.; Carnicella, S.; Maillet, A.; Krack, P. Emotional manifestations of PD: Neurobiological basis. Mov. Disord.,  2016, 31(8), 1103-1113.
 [http://dx.doi.org/10.1002/mds.26587] [PMID: 27041545]

[24]
Zhang, J.F.; Wang, X.X.; Feng, Y.; Fekete, R.; Jankovic, J.; Wu, Y.C. Impulse control disorders in Parkinson’s disease: Epidemiology, pathogenesis and therapeutic strategies. Front. Psychiatry,  2021, 12, 635494.
 [http://dx.doi.org/10.3389/fpsyt.2021.635494] [PMID: 33633615]

[25]
Aquino, C.C.; Fox, S.H. Clinical spectrum of levodopa-induced complications. Mov. Disord.,  2015, 30(1), 80-89.
 [http://dx.doi.org/10.1002/mds.26125] [PMID: 25488260]

[26]
Vijayakumar, D.; Jankovic, J. Drug-Induced Dyskinesia, Part 1: Treatment of levodopa-induced dyskinesia. Drugs,  2016, 76(7), 759-777.
 [http://dx.doi.org/10.1007/s40265-016-0566-3] [PMID: 27091215]

[27]
Jankovic, J.; Tan, E.K. Parkinson’s disease: etiopathogenesis and treatment. J. Neurol. Neurosurg. Psychiatry,  2020, 91(8), 795-808.
 [http://dx.doi.org/10.1136/jnnp-2019-322338] [PMID: 32576618]

[28]
Ko, W.K.D.; Camus, S.M.; Li, Q.; Yang, J.; McGuire, S.; Pioli, E.Y.; Bezard, E. An evaluation of istradefylline treatment on Parkinsonian motor and cognitive deficits in 1-methyl-4-phenyl- 1,2,3,6-tetrahydropyridine (MPTP)-treated macaque models. Neuropharmacology, 2016, 110(Pt A), 48-58.
 [http://dx.doi.org/10.1016/j.neuropharm.2016.07.012] [PMID: 27424102]

[29]
Kasai, S.; Yoshihara, T.; Lopatina, O.; Ishihara, K.; Higashida, H. Selegiline ameliorates depression-like behavior in mice lacking the CD157/BST1 gene, a risk factor for Parkinson’s disease. Front. Behav. Neurosci.,  2017, 11, 75.
 [http://dx.doi.org/10.3389/fnbeh.2017.00075] [PMID: 28515684]

[30]
Dallé, E.; Daniels, W.M.U.; Mabandla, M.V. Long-term treatment with fluvoxamine decreases nonmotor symptoms and dopamine depletion in a postnatal stress rat model of Parkinson’s disease. Oxid. Med. Cell. Longev.,  2020, 2020, 1-15.
 [http://dx.doi.org/10.1155/2020/1941480] [PMID: 32273939]

[31]
Belaid, H.; Adrien, J.; Laffrat, E.; Tandé, D.; Karachi, C.; Grabli, D.; Arnulf, I.; Clark, S.D.; Drouot, X.; Hirsch, E.C.; François, C. Sleep disorders in Parkinsonian macaques: effects of L-dopa treatment and pedunculopontine nucleus lesion. J. Neurosci.,  2014, 34(27), 9124-9133.
 [http://dx.doi.org/10.1523/JNEUROSCI.0181-14.2014] [PMID: 24990932]

[32]
Madiha, S.; Haider, S. Curcumin restores rotenone induced depressive-like symptoms in animal model of neurotoxicity: assessment by social interaction test and sucrose preference test. Metab. Brain Dis.,  2019, 34(1), 297-308.
 [http://dx.doi.org/10.1007/s11011-018-0352-x] [PMID: 30506334]

[33]
Miyaue, N.; Yabe, H. Polysomnographic and clinical parameters before and after zonisamide therapy for Parkinson’s disease. Intern. Med.,  2022, 0037-22.
 [http://dx.doi.org/10.2169/internalmedicine.0037-22] [PMID: 35831101]

[34]
Kim, K.; Wi, S.; Seo, J.H.; Pyo, S.; Cho, S.R. Reduced interaction of aggregated α-synuclein and VAMP2 by environmental enrichment alleviates hyperactivity and anxiety in a model of Parkinson’s disease. Genes (Basel),  2021, 12(3), 392.
 [http://dx.doi.org/10.3390/genes12030392] [PMID: 33801790]

[35]
Crowley, E.K.; Nolan, Y.M.; Sullivan, A.M. Neuroprotective effects of voluntary running on cognitive dysfunction in an α-synuclein rat model of Parkinson’s disease. Neurobiol. Aging,  2018, 65, 60-68.
 [http://dx.doi.org/10.1016/j.neurobiolaging.2018.01.011] [PMID: 29407467]

[36]
Titova, N.; Schapira, A.H.V.; Chaudhuri, K.R.; Qamar, M.A.; Katunina, E.; Jenner, P. Nonmotor Symptoms in experimental models of Parkinson’s disease. Int. Rev. Neurobiol.,  2017, 133, 63-89.
 [http://dx.doi.org/10.1016/bs.irn.2017.05.018] [PMID: 28802936]

[37]
Duty, S.; Jenner, P. Animal models of Parkinson’s disease: a source of novel treatments and clues to the cause of the disease. Br. J. Pharmacol.,  2011, 164(4), 1357-1391.
 [http://dx.doi.org/10.1111/j.1476-5381.2011.01426.x] [PMID: 21486284]

[38]
McDowell, K.; Chesselet, M.F. Animal models of the non-motor features of Parkinson’s disease. Neurobiol. Dis.,  2012, 46(3), 597-606.
 [http://dx.doi.org/10.1016/j.nbd.2011.12.040] [PMID: 22236386]

[39]
Taguchi, T.; Ikuno, M.; Yamakado, H.; Takahashi, R. Animal model for prodromal Parkinson’s disease. Int. J. Mol. Sci.,  2020, 21(6), 1961.
 [http://dx.doi.org/10.3390/ijms21061961] [PMID: 32183024]

[40]
Hou, J.G.G.; Lai, E.C. Non-motor symptoms of Parkinson’s disease. Int. J. Gerontol.,  2007, 1(2), 53-64.
 [http://dx.doi.org/10.1016/S1873-9598(08)70024-3]

[41]
Weerasinghe-Mudiyanselage, P.D.E.; Ang, M.J.; Kang, S.; Kim, J.S.; Moon, C. Structural Plasticity of the Hippocampus in Neurodegenerative Diseases. Int. J. Mol. Sci.,  2022, 23(6), 3349.
 [http://dx.doi.org/10.3390/ijms23063349] [PMID: 35328770]

[42]
Ferreira, D.G. Temido-Ferreira, M.; Vicente Miranda, H.; Batalha, V.L.; Coelho, J.E.; Szegö, É.M.; Marques-Morgado, I.; Vaz, S.H.; Rhee, J.S.; Schmitz, M.; Zerr, I.; Lopes, L.V.; Outeiro, T.F. α-synuclein interacts with PrPC to induce cognitive impairment through mGluR5 and NMDAR2B. Nat. Neurosci.,  2017, 20(11), 1569-1579.
 [http://dx.doi.org/10.1038/nn.4648] [PMID: 28945221]

[43]
Tadaiesky, M.T.; Dombrowski, P.A.; Figueiredo, C.P.; Cargnin-Ferreira, E.; Da Cunha, C.; Takahashi, R.N. Emotional, cognitive and neurochemical alterations in a premotor stage model of Parkinson’s disease. Neuroscience,  2008, 156(4), 830-840.
 [http://dx.doi.org/10.1016/j.neuroscience.2008.08.035] [PMID: 18817851]

[44]
Masini, D.; Bonito-Oliva, A.; Bertho, M.; Fisone, G. Inhibition of mTORC1 signaling reverts cognitive and affective deficits in a mouse model of Parkinson’s disease. Front. Neurol.,  2018, 9, 208.
 [http://dx.doi.org/10.3389/fneur.2018.00208] [PMID: 29686643]

[45]
Taguchi, T. Ikuno, M.; Hondo, M.; Parajuli, L.K.; Taguchi, K.; Ueda, J.; Sawamura, M.; Okuda, S.; Nakanishi, E.; Hara, J.; Uemura, N.; Hatanaka, Y.; Ayaki, T.; Matsuzawa, S.; Tanaka, M.; El-Agnaf, O.M.A.; Koike, M.; Yanagisawa, M.; Uemura, M.T.; Yamakado, H.; Takahashi, R. α-Synuclein BAC transgenic mice exhibit RBD-like behaviour and hyposmia: a prodromal Parkinson’s disease model. Brain,  2020, 143(1), 249-265.
 [http://dx.doi.org/10.1093/brain/awz380] [PMID: 31816026]

[46]
Kudo, T.; Loh, D.H.; Truong, D.; Wu, Y.; Colwell, C.S. Circadian dysfunction in a mouse model of Parkinson’s disease. Exp. Neurol.,  2011, 232(1), 66-75.
 [http://dx.doi.org/10.1016/j.expneurol.2011.08.003] [PMID: 21864527]

[47]
Petrovic, J.; Radovanovic, L.; Saponjic, J. Prodromal local sleep disorders in a rat model of Parkinson’s disease cholinopathy, hemiparkinsonism and hemiparkinsonism with cholinopathy. Behav. Brain Res.,  2021, 397, 112957.
 [http://dx.doi.org/10.1016/j.bbr.2020.112957] [PMID: 33038348]

[48]
Hallett, P.J. McLean, J.R.; Kartunen, A.; Langston, J.W.; Isacson, O. α-synuclein overexpressing transgenic mice show internal organ pathology and autonomic deficits. Neurobiol. Dis.,  2012, 47(2), 258-267.
 [http://dx.doi.org/10.1016/j.nbd.2012.04.009] [PMID: 22549133]

[49]
Fleming, S.M.; Jordan, M.C.; Mulligan, C.K.; Masliah, E.; Holden, J.G.; Millard, R.W.; Chesselet, M.F.; Roos, K.P. Impaired baroreflex function in mice overexpressing alpha-synuclein. Front. Neurol.,  2013, 4, 103.
 [http://dx.doi.org/10.3389/fneur.2013.00103] [PMID: 23888153]

[50]
Nuckolls, A.L.; Worley, C.; Leto, C.; Zhang, H.; Morris, J.K.; Stanford, J.A. Tongue force and tongue motility are differently affected by unilateral vs. bilateral nigrostriatal dopamine depletion in rats. Behav. Brain Res.,  2012, 234(2), 343-348.
 [http://dx.doi.org/10.1016/j.bbr.2012.07.003] [PMID: 22796604]

[51]
Hansen, C.; Björklund, T.; Petit, G.H.; Lundblad, M.; Murmu, R.P.; Brundin, P.; Li, J.Y. A novel α-synuclein-GFP mouse model displays progressive motor impairment, olfactory dysfunction and accumulation of α-synuclein-GFP. Neurobiol. Dis.,  2013, 56, 145-155.
 [http://dx.doi.org/10.1016/j.nbd.2013.04.017] [PMID: 23643841]

[52]
Gu, P.S.; Moon, M.; Choi, J.G.; Oh, M.S. Mulberry fruit ameliorates Parkinson’s-disease-related pathology by reducing α-synuclein and ubiquitin levels in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/probenecid model. J. Nutr. Biochem.,  2017, 39, 15-21.
 [http://dx.doi.org/10.1016/j.jnutbio.2016.08.014] [PMID: 27741433]

[53]
Huang, J.; Cheng, Y.; Li, C.; Shang, H. Genetic heterogeneity on sleep disorders in Parkinson’s disease: a systematic review and meta-analysis. Transl. Neurodegener.,  2022, 11(1), 21.
 [http://dx.doi.org/10.1186/s40035-022-00294-1] [PMID: 35395825]

[54]
Tai, Y.C.; Lin, C.H. An overview of pain in Parkinson’s disease. Clin. Parkinsonism & Related Disord.,  2020, 2, 1-8.
 [http://dx.doi.org/10.1016/j.prdoa.2019.11.004] [PMID: 34316612]

[55]
Faivre, F.; Joshi, A.; Bezard, E.; Barrot, M. The hidden side of Parkinson’s disease: Studying pain, anxiety and depression in animal models. Neurosci. Biobehav. Rev.,  2019, 96, 335-352.
 [http://dx.doi.org/10.1016/j.neubiorev.2018.10.004] [PMID: 30365972]

[56]
Balleine, B.W. Animal models of action control and cognitive dysfunction in Parkinson’s disease. Prog. Brain Res.,  2022, 269(1), 227-255.
 [http://dx.doi.org/10.1016/bs.pbr.2022.01.006] [PMID: 35248196]

[57]
Agid, Y.; Arnulf, I.; Bejjani, P.; Bloch, F.; Bonnet, A.M.; Damier, P.; Dubois, B.; Francois, C.; Houeto, J.L.; Iacono, D.; Karachi, C.; Mesnage, V.; Messouak, O.; Vidailhet, M.; Welter, M.L.; Yelnik, J. Parkinson's disease is a neuropsychiatric disorder. In: Parkinson's Disease; , 2003; 91, pp. 365-370.

[58]
Hung, L.W.; Villemagne, V.L.; Cheng, L.; Sherratt, N.A.; Ayton, S.; White, A.R.; Crouch, P.J.; Lim, S.; Leong, S.L.; Wilkins, S.; George, J.; Roberts, B.R.; Pham, C.L.L.; Liu, X.; Chiu, F.C.K.; Shackleford, D.M.; Powell, A.K.; Masters, C.L.; Bush, A.I.; O’Keefe, G.; Culvenor, J.G.; Cappai, R.; Cherny, R.A.; Donnelly, P.S.; Hill, A.F.; Finkelstein, D.I.; Barnham, K.J. The hypoxia imaging agent CuII(atsm) is neuroprotective and improves motor and cognitive functions in multiple animal models of Parkinson’s disease. J. Exp. Med.,  2012, 209(4), 837-854.
 [http://dx.doi.org/10.1084/jem.20112285] [PMID: 22473957]

[59]
Zhang, L.; Yu, X.; Ji, M.; Liu, S.; Wu, X.; Wang, Y.; Liu, R. Resveratrol alleviates motor and cognitive deficits and neuropathology in the A53T α-synuclein mouse model of Parkinson’s disease. Food Funct.,  2018, 9(12), 6414-6426.
 [http://dx.doi.org/10.1039/C8FO00964C] [PMID: 30462117]

[60]
Hu, Q.; Ren, X.; Liu, Y.; Li, Z.; Zhang, L.; Chen, X.; He, C.; Chen, J.F. Aberrant adenosine A2A receptor signaling contributes to neurodegeneration and cognitive impairments in a mouse model of synucleinopathy. Exp Neurol.,  2016, 283(Pt A), 213-223.
 [http://dx.doi.org/10.1016/j.expneurol.2016.05.040] [PMID: 27342081]

[61]
Hsueh, S.C.; Chen, K.Y.; Lai, J.H.; Wu, C.C.; Yu, Y.W.; Luo, Y.; Hsieh, T.H.; Chiang, Y.H. Voluntary Physical Exercise Improves Subsequent Motor and Cognitive Impairments in a Rat Model of Parkinson’s Disease. Int. J. Mol. Sci.,  2018, 19(2), 508.
 [http://dx.doi.org/10.3390/ijms19020508] [PMID: 29419747]

[62]
Hsieh, M.H.; Ho, S.C.; Yeh, K.Y.; Pawlak, C.R.; Chang, H.M.; Ho, Y.J.; Lai, T.J.; Wu, F.Y. Blockade of metabotropic glutamate receptors inhibits cognition and neurodegeneration in an MPTP-induced Parkinson’s disease rat model. Pharmacol. Biochem. Behav.,  2012, 102(1), 64-71.
 [http://dx.doi.org/10.1016/j.pbb.2012.03.022] [PMID: 22487770]

[63]
Castro, A.A.; Wiemes, B.P.; Matheus, F.C.; Lapa, F.R.; Viola, G.G.; Santos, A.R.; Tasca, C.I.; Prediger, R.D. Atorvastatin improves cognitive, emotional and motor impairments induced by intranasal 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration in rats, an experimental model of Parkinson’s disease. Brain Res.,  2013, 1513, 103-116.
 [http://dx.doi.org/10.1016/j.brainres.2013.03.029] [PMID: 23548600]

[64]
Yabuki, Y.; Ohizumi, Y.; Yokosuka, A.; Mimaki, Y.; Fukunaga, K. Nobiletin treatment improves motor and cognitive deficits seen in MPTP-induced Parkinson model mice. Neuroscience,  2014, 259, 126-141.
 [http://dx.doi.org/10.1016/j.neuroscience.2013.11.051] [PMID: 24316474]

[65]
Haga, H.; Matsuo, K.; Yabuki, Y.; Zhang, C.; Han, F.; Fukunaga, K. Enhancement of ATP production ameliorates motor and cognitive impairments in a mouse model of MPTP−induced Parkinson’s disease. Neurochem. Int.,  2019, 129, 104492.
 [http://dx.doi.org/10.1016/j.neuint.2019.104492] [PMID: 31229554]

[66]
Aguiar, A.S., Jr; Lopes, S.C.; Tristão, F.S.M.; Rial, D.; de Oliveira, G.; da Cunha, C.; Raisman-Vozari, R.; Prediger, R.D. Exercise improves cognitive impairment and dopamine metabolism in MPTP-treated mice. Neurotox. Res.,  2016, 29(1), 118-125.
 [http://dx.doi.org/10.1007/s12640-015-9566-4] [PMID: 26464310]

[67]
Li, Z.; Chen, X.; Wang, T.; Gao, Y.; Li, F.; Chen, L.; Xue, J.; He, Y.; Li, Y.; Guo, W.; Zheng, W.; Zhang, L.; Ye, F.; Ren, X.; Feng, Y.; Chan, P.; Chen, J.F. The corticostriatal adenosine A2A receptor controls maintenance and retrieval of spatial working memory. Biol. Psychiatry,  2018, 83(6), 530-541.
 [http://dx.doi.org/10.1016/j.biopsych.2017.07.017] [PMID: 28941549]

[68]
Bichler, Z.; Lim, H.C.; Zeng, L.; Tan, E.K. Non-motor and motor features in LRRK2 transgenic mice. PLoS One,  2013, 8(7), e70249.
 [http://dx.doi.org/10.1371/journal.pone.0070249] [PMID: 23936174]

[69]
Schrag, A. Quality of life and depression in Parkinson’s disease. J. Neurol. Sci.,  2006, 248(1-2), 151-157.
 [http://dx.doi.org/10.1016/j.jns.2006.05.030] [PMID: 16797028]

[70]
Ravina, B.; Camicioli, R.; Como, P.G.; Marsh, L.; Jankovic, J.; Weintraub, D.; Elm, J. The impact of depressive symptoms in early Parkinson disease. Neurology,  2007, 69(4), 342-347.
 [http://dx.doi.org/10.1212/01.wnl.0000268695.63392.10] [PMID: 17581943]

[71]
Lim, J.; Bang, Y.; Choi, H.J. Abnormal hippocampal neurogenesis in Parkinson’s disease: relevance to a new therapeutic target for depression with Parkinson’s disease. Arch. Pharm. Res.,  2018, 41(10), 943-954.
 [http://dx.doi.org/10.1007/s12272-018-1063-x] [PMID: 30136247]

[72]
Li, Y.; Jiao, Q.; Du, X.; Jiang, H. Sirt1/FoxO1-associated MAO-A upregulation promotes depressive-like behavior in transgenic mice expressing human A53T α-synuclein. ACS Chem. Neurosci.,  2020, 11(22), 3838-3848.
 [http://dx.doi.org/10.1021/acschemneuro.0c00628] [PMID: 33155799]

[73]
Miquel-Rio, L.; Alarcón-Arís, D.; Torres-López, M.; Cóppola-Segovia, V.; Pavia-Collado, R.; Paz, V.; Ruiz-Bronchal, E.; Campa, L.; Casal, C.; Montefeltro, A.; Vila, M.; Artigas, F.; Revilla, R.; Bortolozzi, A. Human α-synuclein overexpression in mouse serotonin neurons triggers a depressive-like phenotype. Rescue by oligonucleotide therapy. Transl. Psychiatry,  2022, 12(1), 79.
 [http://dx.doi.org/10.1038/s41398-022-01842-z] [PMID: 35210396]

[74]
Chen, C.; Li, X.; Ge, G.; Liu, J.; Biju, K.C.; Laing, S.D.; Qian, Y.; Ballard, C.; He, Z.; Masliah, E.; Clark, R.A.; O’Connor, J.C.; Li, S. GDNF-expressing macrophages mitigate loss of dopamine neurons and improve Parkinsonian symptoms in MitoPark mice. Sci. Rep.,  2018, 8(1), 5460.
 [http://dx.doi.org/10.1038/s41598-018-23795-4] [PMID: 29615705]

[75]
Sinen, O.; Bülbül, M.; Derin, N.; Ozkan, A.; Akcay, G.; Aslan, M.A.; Agar, A. The effect of chronic neuropeptide-S treatment on non-motor parameters in experimental model of Parkinson’s disease. Int. J. Neurosci.,  2021, 131(8), 765-774.
 [http://dx.doi.org/10.1080/00207454.2020.1754213] [PMID: 32441169]

[76]
Chen, L.; Deltheil, T.; Turle-Lorenzo, N.; Liberge, M.; Rosier, C.; Watabe, I.; Sreng, L.; Amalric, M.; Mourre, C. SK channel blockade reverses cognitive and motor deficits induced by nigrostriatal dopamine lesions in rats. Int. J. Neuropsychopharmacol.,  2014, 17(8), 1295-1306.
 [http://dx.doi.org/10.1017/S1461145714000236] [PMID: 24661728]

[77]
Oh, S.J.; Ahn, H.; Jung, K.H.; Han, S.J.; Nam, K.R.; Kang, K.J.; Park, J.A.; Lee, K.C.; Lee, Y.J.; Choi, J.Y. Evaluation of the neuroprotective effect of microglial depletion by CSF-1R inhibition in a Parkinson’s animal model. Mol. Imaging Biol.,  2020, 22(4), 1031-1042.
 [http://dx.doi.org/10.1007/s11307-020-01485-w] [PMID: 32086763]

[78]
Vecchia, D.D.; Kanazawa, L.K.S.; Wendler, E.; de Almeida Soares Hocayen, P.; Bruginski, E.; Campos, F.R.; Stern, C.A.J.; Vital, M.A.B.F.; Miyoshi, E.; Wöhr, M.; Schwarting, R.K.W.; Andreatini, R. Effects of ketamine on vocal impairment, gait changes, and anhedonia induced by bilateral 6-OHDA infusion into the substantia nigra pars compacta in rats: Therapeutic implications for Parkinson’s disease. Behav. Brain Res.,  2018, 342, 1-10.
 [http://dx.doi.org/10.1016/j.bbr.2017.12.041] [PMID: 29307665]

[79]
Singh, S.; Mishra, A.; Srivastava, N.; Shukla, S. MK-801 (Dizocilpine) regulates multiple steps of adult hippocampal neurogenesis and alters psychological symptoms via Wnt/β-catenin signaling in Parkinsonian rats. ACS Chem. Neurosci.,  2017, 8(3), 592-605.
 [http://dx.doi.org/10.1021/acschemneuro.6b00354] [PMID: 27977132]

[80]
Souza, L.C.; Martynhak, B.J.; Bassani, T.B.; Turnes, J.M.; Machado, M.M.; Moura, E.; Andreatini, R.; Vital, M.A.B.F. Agomelatine’s effect on circadian locomotor rhythm alteration and depressive-like behavior in 6-OHDA lesioned rats. Physiol. Behav.,  2018, 188, 298-310.
 [http://dx.doi.org/10.1016/j.physbeh.2018.02.033] [PMID: 29458117]

[81]
Rampersaud, N.; Harkavyi, A.; Giordano, G.; Lever, R.; Whitton, J.; Whitton, P.S. Retracted: Exendin-4 reverts behavioural and neurochemical dysfunction in a pre-motor rodent model of Parkinson’s disease with noradrenergic deficit. Br. J. Pharmacol.,  2012, 167(7), 1467-1479.
 [http://dx.doi.org/10.1111/j.1476-5381.2012.02100.x] [PMID: 22774922]

[82]
Somensi, N.; Lopes, S.C.; Gasparotto, J.; Mayer Gonçalves, R.; Tiefensee-Ribeiro, C.; Oppermann Peixoto, D.; Ozorio Brum, P.; Pinho, C.M.; Agnes, J.P.; Santos, L.; de Oliveira, J.; Spiller, F.; Fonseca Moreira, J.C.; Zanotto-Filho, A.; Prediger, R.D.; Pens Gelain, D. Role of toll-like receptor 4 and sex in 6-hydroxydopamine-induced behavioral impairments and neurodegeneration in mice. Neurochem. Int.,  2021, 151, 105215.
 [http://dx.doi.org/10.1016/j.neuint.2021.105215] [PMID: 34710535]

[83]
Campolo, M.; Paterniti, I.; Siracusa, R.; Filippone, A.; Esposito, E.; Cuzzocrea, S. TLR4 absence reduces neuroinflammation and inflammasome activation in Parkinson’s diseases in vivo model. Brain Behav. Immun.,  2019, 76, 236-247.
 [http://dx.doi.org/10.1016/j.bbi.2018.12.003] [PMID: 30550933]

[84]
Chung, J.Y.; Lee, J.W.; Ryu, C.H.; Min, H.K.; Yoon, Y.J.; Lim, M.J.; Park, C.H. 1-[2-(4-Benzyloxyphenoxy)Ethyl]Imidazole inhibits monoamine oxidase B and protects against neuronal loss and behavioral impairment in rodent models of Parkinson’s disease. J. Neurosci. Res.,  2015, 93(8), 1267-1278.
 [http://dx.doi.org/10.1002/jnr.23577] [PMID: 25711470]

[85]
Ramkumar, M.; Rajasankar, S.; Swaminathan Johnson, W.M.; Prabu, K.; Venkatesh Gobi, V. Demethoxycurcumin ameliorates rotenone-induced toxicity in rats. Front. Biosci. (Elite Ed.),  2019, 11(1), 1-11.
 [PMID: 30468633]

[86]
Madiha, S.; Batool, Z.; Tabassum, S.; Liaquat, L.; Sadir, S.; Shahzad, S.; Naqvi, F.; Saleem, S.; Yousuf, S.; Nawaz, A.; Ahmad, S.; Sajid, I.; Afzal, A.; Haider, S. Quercetin exhibits potent antioxidant activity, restores motor and non-motor deficits induced by rotenone toxicity. PLoS One,  2021, 16(11), e0258928.
 [http://dx.doi.org/10.1371/journal.pone.0258928] [PMID: 34767546]

[87]
Zhao, X.; Kong, D.; Zhou, Q.; Wei, G.; Song, J.; Liang, Y.; Du, G. Baicalein alleviates depression-like behavior in rotenone- induced Parkinson’s disease model in mice through activating the BDNF/TrkB/CREB pathway. Biomed. Pharmacother.,  2021, 140, 111556.
 [http://dx.doi.org/10.1016/j.biopha.2021.111556] [PMID: 34087694]

[88]
Wada, M.; Ang, M.J.; Weerasinghe-Mudiyanselage, P.D.E.; Kim, S.H.; Kim, J.C.; Shin, T.; Moon, C. Behavioral characterization in MPTP/p mouse model of Parkinson’s disease. J. Integr. Neurosci.,  2021, 20(2), 307-320.
 [http://dx.doi.org/10.31083/j.jin2002030] [PMID: 34258929]

[89]
Ellgring, H.; Seiler, S.; Nagel, U.; Perleth, B.; Gasser, T.; Oertel, W.H. Psychosocial problems of Parkinson patients: approaches to assessment and treatment. Adv. Neurol.,  1990, 53, 349-353.
 [PMID: 2239476]

[90]
Prediger, R.D.S.; Matheus, F.C.; Schwarzbold, M.L.; Lima, M.M.S.; Vital, M.A.B.F. Anxiety in Parkinson’s disease: A critical review of experimental and clinical studies. Neuropharmacology,  2012, 62(1), 115-124.
 [http://dx.doi.org/10.1016/j.neuropharm.2011.08.039] [PMID: 21903105]

[91]
Chen, L.; Liu, J.; Ali, U.; Gui, Z.H.; Hou, C.; Fan, L.L.; Wang, Y.; Wang, T. Chronic, systemic treatment with a metabotropic glutamate receptor 5 antagonist produces anxiolytic-like effects and reverses abnormal firing activity of projection neurons in the basolateral nucleus of the amygdala in rats with bilateral 6-OHDA lesions. Brain Res. Bull.,  2011, 84(3), 215-223.
 [http://dx.doi.org/10.1016/j.brainresbull.2011.01.005] [PMID: 21255635]

[92]
Rothman, S.M.; Griffioen, K.J.; Vranis, N.; Ladenheim, B.; Cong, W.; Cadet, J.L.; Haran, J.; Martin, B.; Mattson, M.P. Neuronal expression of familial Parkinson’s disease A53T α-synuclein causes early motor impairment, reduced anxiety and potential sleep disturbances in mice. J. Parkinsons Dis.,  2013, 3(2), 215-229.
 [http://dx.doi.org/10.3233/JPD-120130] [PMID: 23938351]

[93]
Yamakado, H. Moriwaki, Y.; Yamasaki, N.; Miyakawa, T.; Kurisu, J.; Uemura, K.; Inoue, H.; Takahashi, M.; Takahashi, R. α-Synuclein BAC transgenic mice as a model for Parkinson’s disease manifested decreased anxiety-like behavior and hyperlocomotion. Neurosci. Res.,  2012, 73(2), 173-177.
 [http://dx.doi.org/10.1016/j.neures.2012.03.010] [PMID: 22475625]

[94]
Taylor, T.N.; Caudle, W.M.; Shepherd, K.R.; Noorian, A.; Jackson, C.R.; Iuvone, P.M.; Weinshenker, D.; Greene, J.G.; Miller, G.W. Nonmotor symptoms of Parkinson’s disease revealed in an animal model with reduced monoamine storage capacity. J. Neurosci.,  2009, 29(25), 8103-8113.
 [http://dx.doi.org/10.1523/JNEUROSCI.1495-09.2009] [PMID: 19553450]

[95]
Schrempf, W.; Brandt, M.D.; Storch, A.; Reichmann, H. Sleep disorders in Parkinson’s disease. J. Parkinsons Dis.,  2014, 4(2), 211-221.
 [http://dx.doi.org/10.3233/JPD-130301] [PMID: 24796235]

[96]
Shen, Y.; Yu, W.B.; Shen, B.; Dong, H.; Zhao, J.; Tang, Y.L.; Fan, Y.; Yang, Y.F.; Sun, Y.M.; Luo, S.S.; Chen, C.; Liu, F.T.; Wu, J.J.; Xiao, B.G.; Yu, H.; Koprich, J.B.; Huang, Z.L.; Wang, J. Propagated α-synucleinopathy recapitulates REM sleep behaviour disorder followed by parkinsonian phenotypes in mice. Brain,  2020, 143(11), 3374-3392.
 [http://dx.doi.org/10.1093/brain/awaa283] [PMID: 33170925]

[97]
Barraud, Q.; Lambrecq, V.; Forni, C.; McGuire, S.; Hill, M.; Bioulac, B.; Balzamo, E.; Bezard, E.; Tison, F.; Ghorayeb, I. Sleep disorders in Parkinson’s disease: The contribution of the MPTP non-human primate model. Exp. Neurol.,  2009, 219(2), 574-582.
 [http://dx.doi.org/10.1016/j.expneurol.2009.07.019] [PMID: 19635479]

[98]
Hyacinthe, C.; Barraud, Q.; Tison, F.; Bezard, E.; Ghorayeb, I. D1 receptor agonist improves sleep–wake parameters in experimental parkinsonism. Neurobiol. Dis.,  2014, 63, 20-24.
 [http://dx.doi.org/10.1016/j.nbd.2013.10.029] [PMID: 24211719]

[99]
Sun, X.; Ran, D.; Zhao, X.; Huang, Y.; Long, S.; Liang, F.; Guo, W.; Nucifora, F.C., Jr; Gu, H.; Lu, X.; Chen, L.; Zeng, J.; Ross, C.A.; Pei, Z. Melatonin attenuates hLRRK2-induced sleep disturbances and synaptic dysfunction in a Drosophila model of Parkinson’s disease. Mol. Med. Rep.,  2016, 13(5), 3936-3944.
 [http://dx.doi.org/10.3892/mmr.2016.4991] [PMID: 26985725]

[100]
Fifel, K.; Piggins, H.; Deboer, T. Modeling sleep alterations in Parkinson’s disease: How close are we to valid translational animal models? Sleep Med. Rev.,  2016, 25, 95-111.
 [http://dx.doi.org/10.1016/j.smrv.2015.02.005] [PMID: 26163055]

[101]
Ariza, D.; Lopes, F.N.C.; Crestani, C.C.; Martins-Pinge, M.C. Chemoreflex and baroreflex alterations in Parkinsonism induced by 6-OHDA in unanesthetized rats. Neurosci. Lett.,  2015, 607, 77-82.
 [http://dx.doi.org/10.1016/j.neulet.2015.09.024] [PMID: 26409036]

[102]
Jiang, Y.H.; Jiang, P.; Yang, J.; Ma, D.F.; Lin, H.Q.; Su, W.; Wang, Z.; Li, X. Cardiac dysregulation and myocardial injury in a 6-hydroxydopamine-induced rat model of sympathetic denervation. PLoS One,  2015, 10(7), e0133971.
 [http://dx.doi.org/10.1371/journal.pone.0133971] [PMID: 26230083]

[103]
Silva, A.S.; Ariza, D.; Dias, D.P.M.; Crestani, C.C.; Martins-Pinge, M.C. Cardiovascular and autonomic alterations in rats with Parkinsonism induced by 6-OHDA and treated with L-DOPA. Life Sci.,  2015, 127, 82-89.
 [http://dx.doi.org/10.1016/j.lfs.2015.01.032] [PMID: 25744393]

[104]
Falquetto, B.; Tuppy, M.; Potje, S.R.; Moreira, T.S.; Antoniali, C.; Takakura, A.C. Cardiovascular dysfunction associated with neurodegeneration in an experimental model of Parkinson’s disease. Brain Res.,  2017, 1657, 156-166.
 [http://dx.doi.org/10.1016/j.brainres.2016.12.008] [PMID: 27956121]

[105]
Joers, V.; Dilley, K.; Rahman, S.; Jones, C.; Shultz, J.; Simmons, H.; Emborg, M.E. Cardiac sympathetic denervation in 6-OHDA-treated nonhuman primates. PLoS One,  2014, 9(8), e104850.
 [http://dx.doi.org/10.1371/journal.pone.0104850] [PMID: 25133405]

[106]
Metzger, J.M.; Moore, C.F.; Boettcher, C.A.; Brunner, K.G.; Fleddermann, R.A.; Matsoff, H.N.; Resnikoff, H.A.; Bondarenko, V.; Kamp, T.J.; Hacker, T.A.; Barnhart, T.E.; Lao, P.J.; Christian, B.T.; Nickles, R.J.; Gallagher, C.L.; Holden, J.E.; Emborg, M.E. In vivo imaging of inflammation and oxidative stress in a nonhuman primate model of cardiac sympathetic neurodegeneration. NPJ Parkinsons Dis.,  2018, 4(1), 22.
 [http://dx.doi.org/10.1038/s41531-018-0057-1] [PMID: 30038956]

[107]
Zhang, Z.; Du, X.; Xu, H.; Xie, J.; Jiang, H. Lesion of medullary catecholaminergic neurons is associated with cardiovascular dysfunction in rotenone-induced Parkinson’s disease rats. Eur. J. Neurosci.,  2015, 42(6), 2346-2355.
 [http://dx.doi.org/10.1111/ejn.13012] [PMID: 26153521]

[108]
Billia, F.; Hauck, L.; Grothe, D.; Konecny, F.; Rao, V.; Kim, R.H.; Mak, T.W. Parkinson-susceptibility gene DJ-1/PARK7 protects the murine heart from oxidative damage in vivo. Proc. Natl. Acad. Sci. USA,  2013, 110(15), 6085-6090.
 [http://dx.doi.org/10.1073/pnas.1303444110] [PMID: 23530187]

[109]
Dorn, G.W., II Central Parkin: The evolving role of Parkin in the heart. Biochim. Biophys. Acta Bioenerg.,  2016, 1857(8), 1307-1312.
 [http://dx.doi.org/10.1016/j.bbabio.2016.03.014] [PMID: 26992930]

[110]
Billia, F.; Hauck, L.; Konecny, F.; Rao, V.; Shen, J.; Mak, T.W. PTEN-inducible kinase 1 (PINK1)/Park6 is indispensable for normal heart function. Proc. Natl. Acad. Sci. USA,  2011, 108(23), 9572-9577.
 [http://dx.doi.org/10.1073/pnas.1106291108] [PMID: 21606348]

[111]
Soler, R.; Füllhase, C.; Santos, C.; Andersson, K.E. Development of bladder dysfunction in a rat model of dopaminergic brain lesion. Neurourol. Urodyn.,  2011, 30(1), 188-193.
 [http://dx.doi.org/10.1002/nau.20917] [PMID: 20589898]

[112]
Kitta, T.; Chancellor, M.B.; de Groat, W.C.; Shinohara, N.; Yoshimura, N. Role of the anterior cingulate cortex in the control of micturition reflex in a rat model of Parkinson’s disease. J. Urol.,  2016, 195(5), 1613-1620.
 [http://dx.doi.org/10.1016/j.juro.2015.11.039] [PMID: 26626223]

[113]
Campeau, L.; Soler, R.; Sittadjody, S.; Pareta, R.; Nomiya, M.; Zarifpour, M.; Opara, E.C.; Yoo, J.J.; Andersson, K.E. Effects of allogeneic bone marrow derived mesenchymal stromal cell therapy on voiding function in a rat model of Parkinson disease. J. Urol.,  2014, 191(3), 850-859.
 [http://dx.doi.org/10.1016/j.juro.2013.08.026] [PMID: 23973520]

[114]
Mitra, R.; Aronsson, P.; Winder, M.; Tobin, G.; Bergquist, F.; Carlsson, T. Local change in urinary bladder contractility following CNS dopamine denervation in the 6-OHDA rat model of Parkinson’s disease. J. Parkinsons Dis.,  2015, 5(2), 301-311.
 [http://dx.doi.org/10.3233/JPD-140509] [PMID: 25697958]

[115]
Pritchard, S.; Jackson, M.J.; Hikima, A.; Lione, L.; Benham, C.D.; Chaudhuri, K.R.; Rose, S.; Jenner, P.; Iravani, M.M. Altered detrusor contractility in MPTP-treated common marmosets with bladder hyperreflexia. PLoS One,  2017, 12(5), e0175797.
 [http://dx.doi.org/10.1371/journal.pone.0175797] [PMID: 28520722]

[116]
Metzger, J.M.; Emborg, M.E. Autonomic dysfunction in Parkinson disease and animal models. Clin. Auton. Res.,  2019, 29(4), 397-414.
 [http://dx.doi.org/10.1007/s10286-018-00584-7] [PMID: 30604165]

[117]
Noorian, A.R.; Rha, J.; Annerino, D.M.; Bernhard, D.; Taylor, G.M.; Greene, J.G. Alpha-synuclein transgenic mice display age-related slowing of gastrointestinal motility associated with transgene expression in the vagal system. Neurobiol. Dis.,  2012, 48(1), 9-19.
 [http://dx.doi.org/10.1016/j.nbd.2012.06.005] [PMID: 22722052]

[118]
Cullen, K.P.; Grant, L.M.; Kelm-Nelson, C.A.; Brauer, A.F.L.; Bickelhaupt, L.B.; Russell, J.A.; Ciucci, M.R. Pink1−/− rats show early-onset swallowing deficits and correlative brainstem pathology. Dysphagia,  2018, 33(6), 749-758.
 [http://dx.doi.org/10.1007/s00455-018-9896-5] [PMID: 29713896]

[119]
Yang, K.M.; Blue, K.V.; Mulholland, H.M.; Kurup, M.P.; Kelm-Nelson, C.A.; Ciucci, M.R. Characterization of oromotor and limb motor dysfunction in the DJ1 -/- model of Parkinson disease. Behav. Brain Res.,  2018, 339, 47-56.
 [http://dx.doi.org/10.1016/j.bbr.2017.10.036] [PMID: 29109055]

[120]
Zheng, L.F.; Song, J.; Fan, R.F.; Chen, C.L.; Ren, Q.Z.; Zhang, X.L.; Feng, X.Y.; Zhang, Y.; Li, L.S.; Zhu, J.X. The role of the vagal pathway and gastric dopamine in the gastroparesis of rats after a 6-hydroxydopamine microinjection in the substantia nigra. Acta Physiol. (Oxf.),  2014, 211(2), 434-446.
 [http://dx.doi.org/10.1111/apha.12229] [PMID: 24410908]

[121]
Toti, L.; Travagli, R.A. Gastric dysregulation induced by microinjection of 6-OHDA in the substantia nigra pars compacta of rats is determined by alterations in the brain-gut axis. Am. J. Physiol. Gastrointest. Liver Physiol.,  2014, 307(10), G1013-G1023.
 [http://dx.doi.org/10.1152/ajpgi.00258.2014] [PMID: 25277799]

[122]
Fornai, M.; Pellegrini, C.; Antonioli, L.; Segnani, C.; Ippolito, C.; Barocelli, E.; Ballabeni, V.; Vegezzi, G.; Al Harraq, Z.; Blandini, F.; Levandis, G.; Cerri, S.; Blandizzi, C.; Bernardini, N.; Colucci, R. Enteric dysfunctions in experimental Parkinsons disease: Alterations of excitatory cholinergic neurotransmission regulating colonic motility in rats. J. Pharmacol. Exp. Ther.,  2016, 356(2), 233-243.
 [http://dx.doi.org/10.1124/jpet.115.228510] [PMID: 26582732]

[123]
Levandis, G.; Balestra, B.; Siani, F.; Rizzo, V.; Ghezzi, C.; Ambrosi, G.; Cerri, S.; Bonizzi, A.; Vicini, R.; Vairetti, M.; Ferrigno, A.; Pastoris, O.; Blandini, F. Response of colonic motility to dopaminergic stimulation is subverted in rats with nigrostriatal lesion: relevance to gastrointestinal dysfunctions in Parkinson’s disease. Neurogastroenterol. Motil.,  2015, 27(12), 1783-1795.
 [http://dx.doi.org/10.1111/nmo.12691] [PMID: 26433214]

[124]
M Shultz, J.; Resnikoff, H.; Bondarenko, V.; Joers, V.; Mejia, A.; Simmons, H.; Emborg, M.E. Neurotoxin-Induced catecholaminergic loss in the colonic myenteric plexus of rhesus monkeys. J. Alzheimers Dis. Parkinsonism,  2016, 6(6), 279.
 [http://dx.doi.org/10.4172/2161-0460.1000279] [PMID: 28090391]

[125]
Anselmi, L.; Toti, L.; Bove, C.; Hampton, J.; Travagli, R.A. A Nigro-Vagal pathway controls gastric motility and is affected in a rat model of Parkinsonism. Gastroenterology,  2017, 153(6), 1581-1593.
 [http://dx.doi.org/10.1053/j.gastro.2017.08.069] [PMID: 28912019]

[126]
Liu, Y.; Sun, J.D.; Song, L.K.; Li, J.; Chu, S.F.; Yuan, Y.H.; Chen, N.H. Environment-contact administration of rotenone: A new rodent model of Parkinson’s disease. Behav. Brain Res.,  2015, 294, 149-161.
 [http://dx.doi.org/10.1016/j.bbr.2015.07.058] [PMID: 26239001]

[127]
Arnhold, M.; Dening, Y.; Chopin, M.; Arévalo, E.; Schwarz, M.; Reichmann, H.; Gille, G.; Funk, R.H.W.; Pan-Montojo, F. Changes in the sympathetic innervation of the gut in rotenone treated mice as possible early biomarker for Parkinson’s disease. Clin. Auton. Res.,  2016, 26(3), 211-222.
 [http://dx.doi.org/10.1007/s10286-016-0358-6] [PMID: 27178445]

[128]
Dodiya, H.B.; Forsyth, C.B.; Voigt, R.M.; Engen, P.A.; Patel, J.; Shaikh, M.; Green, S.J.; Naqib, A.; Roy, A.; Kordower, J.H.; Pahan, K.; Shannon, K.M.; Keshavarzian, A. Chronic stress-induced gut dysfunction exacerbates Parkinson’s disease phenotype and pathology in a rotenone-induced mouse model of Parkinson’s disease. Neurobiol. Dis.,  2020, 135, 104352.
 [http://dx.doi.org/10.1016/j.nbd.2018.12.012] [PMID: 30579705]

[129]
Wang, L.; Magen, I.; Yuan, P.Q.; Subramaniam, S.R.; Richter, F.; Chesselet, M.F.; Taché, Y. Mice overexpressing wild-type human alpha-synuclein display alterations in colonic myenteric ganglia and defecation. Neurogastroenterol. Motil.,  2012, 24(9), e425-e436.
 [http://dx.doi.org/10.1111/j.1365-2982.2012.01974.x] [PMID: 22779732]

[130]
Tasselli, M.; Chaumette, T.; Paillusson, S.; Monnet, Y.; Lafoux, A.; Huchet-Cadiou, C.; Aubert, P.; Hunot, S.; Derkinderen, P.; Neunlist, M. Effects of oral administration of rotenone on gastrointestinal functions in mice. Neurogastroenterol. Motil.,  2013, 25(3), e183-e193.
 [http://dx.doi.org/10.1111/nmo.12070] [PMID: 23281940]

[131]
Jiao, Y.; Dou, Y.; Lockwood, G.; Pani, A.; Smeyne, R.J. Acute effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or paraquat on core temperature in C57BL/6J mice. J. Parkinsons Dis.,  2015, 5(2), 389-401.
 [http://dx.doi.org/10.3233/JPD-140424] [PMID: 25633843]

[132]
Griffioen, K.J.; Rothman, S.M.; Ladenheim, B.; Wan, R.; Vranis, N.; Hutchison, E.; Okun, E.; Cadet, J.L.; Mattson, M.P. Dietary energy intake modifies brainstem autonomic dysfunction caused by mutant α-synuclein. Neurobiol. Aging,  2013, 34(3), 928-935.
 [http://dx.doi.org/10.1016/j.neurobiolaging.2012.07.008] [PMID: 22883907]

[133]
Radad, K.; Hassanein, K.; Moldzio, R.; Rausch, W.D. Vascular damage mediates neuronal and non-neuronal pathology following short and long-term rotenone administration in Sprague-Dawley rats. Exp. Toxicol. Pathol.,  2013, 65(1-2), 41-47.
 [http://dx.doi.org/10.1016/j.etp.2011.05.008] [PMID: 21676605]

[134]
Schapira, A.H.V.; Chaudhuri, K.R.; Jenner, P. Non-motor features of Parkinson disease. Nat. Rev. Neurosci.,  2017, 18(7), 435-450.
 [http://dx.doi.org/10.1038/nrn.2017.62] [PMID: 28592904]

[135]
Pfeiffer, R.F. Non-motor symptoms in Parkinson’s disease. Parkinsonism Relat. Disord.,  2016, 22(Suppl. 1), S119-S122.
 [http://dx.doi.org/10.1016/j.parkreldis.2015.09.004] [PMID: 26372623]

[136]
Dranka, B.P.; Gifford, A.; McAllister, D.; Zielonka, J.; Joseph, J.; O’Hara, C.L.; Stucky, C.L.; Kanthasamy, A.G.; Kalyanaraman, B. A novel mitochondrially-targeted apocynin derivative prevents hyposmia and loss of motor function in the leucine-rich repeat kinase 2 (LRRK2R1441G) transgenic mouse model of Parkinson’s disease. Neurosci. Lett.,  2014, 583, 159-164.
 [http://dx.doi.org/10.1016/j.neulet.2014.09.042] [PMID: 25263790]

[137]
Kurtenbach, S.; Wewering, S.; Hatt, H.; Neuhaus, E.M.; Lübbert, H. Olfaction in three genetic and two MPTP-induced Parkinson’s disease mouse models. PLoS One,  2013, 8(10), e77509.
 [http://dx.doi.org/10.1371/journal.pone.0077509] [PMID: 24204848]

[138]
Rial, D.; Castro, A.A.; Machado, N.; Garção, P.; Gonçalves, F.Q.; Silva, H.B.; Tomé, Â.R.; Köfalvi, A.; Corti, O.; Raisman-Vozari, R.; Cunha, R.A.; Prediger, R.D. Behavioral phenotyping of Parkin-deficient mice: looking for early preclinical features of Parkinson’s disease. PLoS One,  2014, 9(12), e114216.
 [http://dx.doi.org/10.1371/journal.pone.0114216] [PMID: 25486126]

[139]
Santos-García, D.; de la Fuente-Fernández, R. Impact of non-motor symptoms on health-related and perceived quality of life in Parkinson’s disease. J. Neurol. Sci.,  2013, 332(1-2), 136-140.
 [http://dx.doi.org/10.1016/j.jns.2013.07.005] [PMID: 23890935]

[140]
Martinez-Martin, P.; Rodriguez-Blazquez, C.; Kurtis, M.M.; Chaudhuri, K.R.; Group, N.V. The impact of non-motor symptoms on health-related quality of life of patients with Parkinson’s disease. Mov. Disord.,  2011, 26(3), 399-406.
 [http://dx.doi.org/10.1002/mds.23462] [PMID: 21264941]

[141]
Liu, Q.R.; Canseco-Alba, A.; Zhang, H.Y.; Tagliaferro, P.; Chung, M.; Dennis, E.; Sanabria, B.; Schanz, N.; Escosteguy-Neto, J.C.; Ishiguro, H.; Lin, Z.; Sgro, S.; Leonard, C.M.; Santos-Junior, J.G.; Gardner, E.L.; Egan, J.M.; Lee, J.W.; Xi, Z.X.; Onaivi, E.S. Cannabinoid type 2 receptors in dopamine neurons inhibits psychomotor behaviors, alters anxiety, depression and alcohol preference. Sci. Rep.,  2017, 7(1), 17410.
 [http://dx.doi.org/10.1038/s41598-017-17796-y] [PMID: 29234141]

[142]
Wang, C.T.; Mao, C.J.; Zhang, X.Q.; Zhang, C.Y.; Lv, D.J.; Yang, Y.P.; Xia, K.L.; Liu, J.Y.; Wang, F.; Hu, L.F.; Xu, G.Y.; Liu, C.F. Attenuation of hyperalgesia responses via the modulation of 5-hydroxytryptamine signalings in the rostral ventromedial medulla and spinal cord in a 6-hydroxydopamine-induced rat model of Parkinson’s disease. Mol. Pain,  2017, 13.
 [http://dx.doi.org/10.1177/1744806917691525] [PMID: 28326933]

[143]
Domenici, R.A.; Campos, A.C.P.; Maciel, S.T.; Berzuino, M.B.; Hernandes, M.S.; Fonoff, E.T.; Pagano, R.L. Parkinson’s disease and pain: Modulation of nociceptive circuitry in a rat model of nigrostriatal lesion. Exp. Neurol.,  2019, 315, 72-81.
 [http://dx.doi.org/10.1016/j.expneurol.2019.02.007] [PMID: 30772369]

[144]
Kaszuba, B.C.; Walling, I.; Gee, L.E.; Shin, D.S.; Pilitsis, J.G. Effects of subthalamic deep brain stimulation with duloxetine on mechanical and thermal thresholds in 6OHDA lesioned rats. Brain Res.,  2017, 1655, 233-241.
 [http://dx.doi.org/10.1016/j.brainres.2016.10.025] [PMID: 27984022]

[145]
Gee, L.E.; Walling, I.; Ramirez-Zamora, A.; Shin, D.S.; Pilitsis, J.G. Subthalamic deep brain stimulation alters neuronal firing in canonical pain nuclei in a 6-hydroxydopamine lesioned rat model of Parkinson's disease. Exp Neurol.,  2016, 283(Pt A), 298-307.
 [http://dx.doi.org/10.1016/j.expneurol.2016.06.031] [PMID: 27373204]

[146]
Park, J.; Lim, C.S.; Seo, H.; Park, C.A.; Zhuo, M.; Kaang, B.K.; Lee, K. Pain perception in acute model mice of Parkinson’s disease induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Mol. Pain,  2015, 11, s12990-015-0026.
 [http://dx.doi.org/10.1186/s12990-015-0026-1] [PMID: 25981600]

[147]
Xiao, W.H.; Bennett, G.J. Effects of mitochondrial poisons on the neuropathic pain produced by the chemotherapeutic agents, paclitaxel and oxaliplatin. Pain,  2012, 153(3), 704-709.
 [http://dx.doi.org/10.1016/j.pain.2011.12.011] [PMID: 22244441]

[148]
Bonito-Oliva, A.; Masini, D.Ã.; Fisone, G. A mouse model of non-motor symptoms in Parkinson’s disease: focus on pharmacological interventions targeting affective dysfunctions. Front. Behav. Neurosci.,  2014, 8, 290.
 [http://dx.doi.org/10.3389/fnbeh.2014.00290] [PMID: 25221486]

[149]
Eskow, J.K.L.; George, J.A.; Bishop, C. L-DOPA-induced dysregulation of extrastriatal dopamine and serotonin and affective symptoms in a bilateral rat model of Parkinson’s disease. Neuroscience,  2012, 218, 243-256.
 [http://dx.doi.org/10.1016/j.neuroscience.2012.05.052] [PMID: 22659568]

[150]
Games, D.; Valera, E.; Spencer, B.; Rockenstein, E.; Mante, M.; Adame, A.; Patrick, C.; Ubhi, K.; Nuber, S.; Sacayon, P.; Zago, W.; Seubert, P.; Barbour, R.; Schenk, D.; Masliah, E. Reducing C-terminal-truncated alpha-synuclein by immunotherapy attenuates neurodegeneration and propagation in Parkinson’s disease-like models. J. Neurosci.,  2014, 34(28), 9441-9454.
 [http://dx.doi.org/10.1523/JNEUROSCI.5314-13.2014] [PMID: 25009275]

[151]
Masliah, E.; Rockenstein, E.; Mante, M.; Crews, L.; Spencer, B.; Adame, A.; Patrick, C.; Trejo, M.; Ubhi, K.; Rohn, T.T.; Mueller-Steiner, S.; Seubert, P.; Barbour, R.; McConlogue, L.; Buttini, M.; Games, D.; Schenk, D. Passive immunization reduces behavioral and neuropathological deficits in an alpha-synuclein transgenic model of Lewy body disease. PLoS One,  2011, 6(4), e19338.
 [http://dx.doi.org/10.1371/journal.pone.0019338] [PMID: 21559417]

[152]
Spencer, B.; Valera, E.; Rockenstein, E.; Overk, C.; Mante, M.; Adame, A.; Zago, W.; Seubert, P.; Barbour, R.; Schenk, D.; Games, D.; Rissman, R.A.; Masliah, E. Anti-α-synuclein immunotherapy reduces α-synuclein propagation in the axon and degeneration in a combined viral vector and transgenic model of synucleinopathy. Acta Neuropathol. Commun.,  2017, 5(1), 7.
 [http://dx.doi.org/10.1186/s40478-016-0410-8] [PMID: 28086964]

[153]
Kadowaki Horita, T.; Kobayashi, M.; Mori, A.; Jenner, P.; Kanda, T. Effects of the adenosine A2A antagonist istradefylline on cognitive performance in rats with a 6-OHDA lesion in prefrontal cortex. Psychopharmacology (Berl.),  2013, 230(3), 345-352.
 [http://dx.doi.org/10.1007/s00213-013-3158-x] [PMID: 23748382]

[154]
Zhang, X.; Bai, L.; Zhang, S.; Zhou, X.; Li, Y.; Bai, J. Trx-1 ameliorates learning and memory deficits in MPTP-induced Parkinson’s disease model in mice. Free Radic. Biol. Med.,  2018, 124, 380-387.
 [http://dx.doi.org/10.1016/j.freeradbiomed.2018.06.029] [PMID: 29960099]

[155]
Perez-Pardo, P.; Grobben, Y.; Willemsen-Seegers, N.; Hartog, M.; Tutone, M.; Muller, M.; Adolfs, Y.; Pasterkamp, R.J.; Vu-Pham, D.; Doornmalen, A.M.; Cauter, F.; Wit, J.; Gerard Sterrenburg, J.; Uitdehaag, J.C.M.; Man, J.; Buijsman, R.C.; Zaman, G.J.R.; Kraneveld, A.D. Pharmacological validation of TDO as a target for Parkinson’s disease. FEBS J.,  2021, 288(14), 4311-4331.
 [http://dx.doi.org/10.1111/febs.15721] [PMID: 33471408]

[156]
Berghauzen-Maciejewska, K.; Kuter, K.; Kolasiewicz, W.; Głowacka, U.; Dziubina, A.; Ossowska, K.; Wardas, J. Pramipexole but not imipramine or fluoxetine reverses the “depressive-like” behaviour in a rat model of preclinical stages of Parkinson’s disease. Behav. Brain Res.,  2014, 271, 343-353.
 [http://dx.doi.org/10.1016/j.bbr.2014.06.029] [PMID: 24956561]

[157]
Shi, L.; Huang, C.; Luo, Q.; Xia, Y.; Liu, W.; Zeng, W.; Cheng, A.; Shi, R.; Zhengli, C. Clioquinol improves motor and non-motor deficits in MPTP-induced monkey model of Parkinson’s disease through AKT/mTOR pathway. Aging (Albany NY),  2020, 12(10), 9515-9533.
 [http://dx.doi.org/10.18632/aging.103225] [PMID: 32424108]

[158]
Klein, C.; Rasińska, J.; Empl, L.; Sparenberg, M.; Poshtiban, A.; Hain, E.G.; Iggena, D.; Rivalan, M.; Winter, Y.; Steiner, B. Physical exercise counteracts MPTP-induced changes in neural precursor cell proliferation in the hippocampus and restores spatial learning but not memory performance in the water maze. Behav. Brain Res.,  2016, 307, 227-238.
 [http://dx.doi.org/10.1016/j.bbr.2016.02.040] [PMID: 27012392]

[159]
Gee, L.E.; Chen, N.; Ramirez-Zamora, A.; Shin, D.S.; Pilitsis, J.G. The effects of subthalamic deep brain stimulation on mechanical and thermal thresholds in 6OHDA-lesioned rats. Eur. J. Neurosci.,  2015, 42(4), 2061-2069.
 [http://dx.doi.org/10.1111/ejn.12992] [PMID: 26082992]

[160]
Kaszuba, B.C.; Maietta, T.; Walling, I.; Feustel, P.; Stapleton, A.; Shin, D.S.; Slyer, J.; Pilitsis, J.G. Effects of subthalamic deep brain stimulation with gabapentin and morphine on mechanical and thermal thresholds in 6-hydroxydopamine lesioned rats. Brain Res.,  2019, 1715, 66-72.
 [http://dx.doi.org/10.1016/j.brainres.2019.03.013] [PMID: 30898672]

[161]
Soler, R.; Füllhase, C.; Hanson, A.; Campeau, L.; Santos, C.; Andersson, K.E. Stem cell therapy ameliorates bladder dysfunction in an animal model of Parkinson disease. J. Urol.,  2012, 187(4), 1491-1497.
 [http://dx.doi.org/10.1016/j.juro.2011.11.079] [PMID: 22341818]

[162]
You, H.; Mariani, L.L.; Mangone, G.; Le Febvre de Nailly, D.; Charbonnier-Beaupel, F.; Corvol, J.C. Molecular basis of dopamine replacement therapy and its side effects in Parkinson’s disease. Cell Tissue Res.,  2018, 373(1), 111-135.
 [http://dx.doi.org/10.1007/s00441-018-2813-2] [PMID: 29516217]

[163]
Qamar, M.A.; Sauerbier, A.; Politis, M.; Carr, H.; Loehrer, P.; Chaudhuri, K.R. Presynaptic dopaminergic terminal imaging and non-motor symptoms assessment of Parkinson’s disease: evidence for dopaminergic basis? NPJ Parkinsons Dis.,  2017, 3(1), 5.
 [http://dx.doi.org/10.1038/s41531-016-0006-9] [PMID: 28649605]

[164]
Lane, E.L. L-DOPA for Parkinson’s disease-a bittersweet pill. Eur. J. Neurosci.,  2019, 49(3), 384-398.
 [http://dx.doi.org/10.1111/ejn.14119] [PMID: 30118169]

[165]
Ossipov, M.H.; Dussor, G.O.; Porreca, F. Central modulation of pain. J. Clin. Invest.,  2010, 120(11), 3779-3787.
 [http://dx.doi.org/10.1172/JCI43766] [PMID: 21041960]

[166]
Pertovaara, A. Noradrenergic pain modulation. Prog. Neurobiol.,  2006, 80(2), 53-83.
 [http://dx.doi.org/10.1016/j.pneurobio.2006.08.001] [PMID: 17030082]

[167]
Graves, S.M.; Xie, Z.; Stout, K.A.; Zampese, E.; Burbulla, L.F.; Shih, J.C.; Kondapalli, J.; Patriarchi, T.; Tian, L.; Brichta, L.; Greengard, P.; Krainc, D.; Schumacker, P.T.; Surmeier, D.J. Dopamine metabolism by a monoamine oxidase mitochondrial shuttle activates the electron transport chain. Nat. Neurosci.,  2020, 23(1), 15-20.
 [http://dx.doi.org/10.1038/s41593-019-0556-3] [PMID: 31844313]

[168]
Tsuboi, T.; Satake, Y.; Hiraga, K.; Yokoi, K.; Hattori, M.; Suzuki, M.; Hara, K.; Ramirez-Zamora, A.; Okun, M.S.; Katsuno, M. Effects of MAO-B inhibitors on non-motor symptoms and quality of life in Parkinson’s disease: A systematic review. NPJ Parkinsons Dis.,  2022, 8(1), 75.
 [http://dx.doi.org/10.1038/s41531-022-00339-2] [PMID: 35697709]

[169]
Dezsi, L.; Vecsei, L. Monoamine Oxidase B Inhibitors in Parkinson’s Disease. CNS Neurol. Disord. Drug Targets,  2017, 16(4), 425-439.
 [PMID: 28124620]

[170]
Fernandez, H.H.; Chen, J.J. Monoamine oxidase-B inhibition in the treatment of Parkinson’s disease. Pharmacotherapy,  2007, 27(12 Part 2), 174S-185S.
 [http://dx.doi.org/10.1592/phco.27.12part2.174S] [PMID: 18041937]

[171]
Tan, Y-Y.; Jenner, P.; Chen, S-D. Monoamine oxidase-B inhibitors for the treatment of Parkinson’s disease: past, present, and future. J. Parkinsons Dis.,  2022, 12(2), 477-493.
 [http://dx.doi.org/10.3233/JPD-212976] [PMID: 34957948]

[172]
Riederer, P.; Müller, T. Monoamine oxidase-B inhibitors in the treatment of Parkinson’s disease: clinical–pharmacological aspects. J. Neural Transm. (Vienna),  2018, 125(11), 1751-1757.
 [http://dx.doi.org/10.1007/s00702-018-1876-2] [PMID: 29569037]

[173]
Wu, Y.; Kazumura, K.; Maruyama, W.; Osawa, T.; Naoi, M. Rasagiline and selegiline suppress calcium efflux from mitochondria by PK11195-induced opening of mitochondrial permeability transition pore: a novel anti-apoptotic function for neuroprotection. J. Neural Transm. (Vienna),  2015, 122(10), 1399-1407.
 [http://dx.doi.org/10.1007/s00702-015-1398-0] [PMID: 25863936]

[174]
Braga, C.A.; Follmer, C.; Palhano, F.L.; Khattar, E.; Freitas, M.S.; Romão, L.; Di Giovanni, S.; Lashuel, H.A.; Silva, J.L.; Foguel, D. The anti-Parkinsonian drug selegiline delays the nucleation phase of α-synuclein aggregation leading to the formation of nontoxic species. J. Mol. Biol.,  2011, 405(1), 254-273.
 [http://dx.doi.org/10.1016/j.jmb.2010.10.027] [PMID: 21050861]

[175]
McKeith, I.G.; Burn, D. Spectrum of Parkinson’s disease, Parkinson’s dementia, and Lewy body dementia. Neurol. Clin.,  2000, 18(4), 865-883.
 [http://dx.doi.org/10.1016/S0733-8619(05)70230-9] [PMID: 11072265]

[176]
Kramer, M.L.; Schulz-Schaeffer, W.J. Presynaptic α-synuclein aggregates, not Lewy bodies, cause neurodegeneration in dementia with Lewy bodies. J. Neurosci.,  2007, 27(6), 1405-1410.
 [http://dx.doi.org/10.1523/JNEUROSCI.4564-06.2007] [PMID: 17287515]

[177]
Games, D.; Seubert, P.; Rockenstein, E.; Patrick, C.; Trejo, M.; Ubhi, K.; Ettle, B.; Ghassemiam, M.; Barbour, R.; Schenk, D.; Nuber, S.; Masliah, E. Axonopathy in an α-synuclein transgenic model of Lewy body disease is associated with extensive accumulation of C-terminal-truncated α-synuclein. Am. J. Pathol.,  2013, 182(3), 940-953.
 [http://dx.doi.org/10.1016/j.ajpath.2012.11.018] [PMID: 23313024]

[178]
Spillantini, M.G.; Schmidt, M.L.; Lee, V.M.Y.; Trojanowski, J.Q.; Jakes, R.; Goedert, M. α-Synuclein in Lewy bodies. Nature,  1997, 388(6645), 839-840.
 [http://dx.doi.org/10.1038/42166] [PMID: 9278044]

[179]
Prusiner, S.B.; Woerman, A.L.; Mordes, D.A.; Watts, J.C.; Rampersaud, R.; Berry, D.B.; Patel, S.; Oehler, A.; Lowe, J.K.; Kravitz, S.N.; Geschwind, D.H.; Glidden, D.V.; Halliday, G.M.; Middleton, L.T.; Gentleman, S.M.; Grinberg, L.T.; Giles, K. Evidence for α-synuclein prions causing multiple system atrophy in humans with parkinsonism. Proc. Natl. Acad. Sci. USA,  2015, 112(38), E5308-E5317.
 [http://dx.doi.org/10.1073/pnas.1514475112] [PMID: 26324905]

[180]
Bae, E.J.; Lee, H.J.; Rockenstein, E.; Ho, D.H.; Park, E.B.; Yang, N.Y.; Desplats, P.; Masliah, E.; Lee, S.J. Antibody-aided clearance of extracellular α-synuclein prevents cell-to-cell aggregate transmission. J. Neurosci.,  2012, 32(39), 13454-13469.
 [http://dx.doi.org/10.1523/JNEUROSCI.1292-12.2012] [PMID: 23015436]

[181]
Wang, Z.; Gao, G.; Duan, C.; Yang, H. Progress of immunotherapy of anti-α-synuclein in Parkinson’s disease. Biomed. Pharmacother.,  2019, 115, 108843.
 [http://dx.doi.org/10.1016/j.biopha.2019.108843] [PMID: 31055236]

[182]
Chatterjee, D.; Bhatt, M.; Butler, D.; De Genst, E.; Dobson, C.M.; Messer, A.; Kordower, J.H. Proteasome-targeted nanobodies alleviate pathology and functional decline in an α-synuclein-based Parkinson’s disease model. NPJ Parkinsons Dis.,  2018, 4(1), 25.
 [http://dx.doi.org/10.1038/s41531-018-0062-4] [PMID: 30155513]

[183]
Visanji, N.P.; Brotchie, J.M.; Kalia, L.V.; Koprich, J.B.; Tandon, A.; Watts, J.C.; Lang, A.E. α-Synuclein-based animal models of Parkinson’s disease: challenges and opportunities in a new era. Trends Neurosci.,  2016, 39(11), 750-762.
 [http://dx.doi.org/10.1016/j.tins.2016.09.003] [PMID: 27776749]

[184]
Borghammer, P. The α-Synuclein origin and connectome model (SOC model) of Parkinson’s disease: Explaining motor asymmetry, non-motor phenotypes, and cognitive decline. J. Parkinsons Dis.,  2021, 11(2), 455-474.
 [http://dx.doi.org/10.3233/JPD-202481] [PMID: 33682732]

[185]
Ferreira, D.G.; Batalha, V.L.; Vicente, M.H.; Coelho, J.E.; Gomes, R.; Gonçalves, F.Q.; Real, J.I.; Rino, J.; Albino-Teixeira, A.; Cunha, R.A.; Outeiro, T.F.; Lopes, L.V. Adenosine A2A Receptors modulate α-synuclein aggregation and toxicity. Cereb. Cortex,  2017, 27(1), 718-730.
 [PMID: 26534909]

[186]
Dungo, R.; Deeks, E.D. Istradefylline: first global approval. Drugs,  2013, 73(8), 875-882.
 [http://dx.doi.org/10.1007/s40265-013-0066-7] [PMID: 23700273]

[187]
Pinna, A. Adenosine A2A receptor antagonists in Parkinson’s disease: progress in clinical trials from the newly approved istradefylline to drugs in early development and those already discontinued. CNS Drugs,  2014, 28(5), 455-474.
 [http://dx.doi.org/10.1007/s40263-014-0161-7] [PMID: 24687255]

[188]
Mori, A.; Shindou, T. Modulation of GABAergic transmission in the striatopallidal system by adenosine A2A receptors: A potential mechanism for the antiparkinsonian effects of A2A antagonists. Neurology,  2003, 61(11, Supplement 6)(Suppl. 6), S44-S48.
 [http://dx.doi.org/10.1212/01.WNL.0000095211.71092.A0] [PMID: 14663009]

[189]
Mori, A.; Shindou, T.; Ichimura, M.; Nonaka, H.; Kase, H. The role of adenosine A2a receptors in regulating GABAergic synaptic transmission in striatal medium spiny neurons. J. Neurosci.,  1996, 16(2), 605-611.
 [http://dx.doi.org/10.1523/JNEUROSCI.16-02-00605.1996] [PMID: 8551344]

[190]
Gonzalez, B.; Paz, F.; Florán, L.; Aceves, J.; Erlij, D.; Florán, B. Adenosine A2A receptor stimulation decreases GAT-1-mediated GABA uptake in the globus pallidus of the rat. Neuropharmacology,  2006, 51(1), 154-159.
 [http://dx.doi.org/10.1016/j.neuropharm.2006.03.011] [PMID: 16730753]

[191]
Ochi, M.; Koga, K.; Kurokawa, M.; Kase, H.; Nakamura, J.; Kuwana, Y. Systemic administration of adenosine A2A receptor antagonist reverses increased GABA release in the globus pallidus of unilateral 6-hydroxydopamine-lesioned rats: a microdialysis study. Neuroscience,  2000, 100(1), 53-62.
 [http://dx.doi.org/10.1016/S0306-4522(00)00250-5] [PMID: 10996458]

[192]
Jenner, P.; Mori, A.; Hauser, R.; Morelli, M.; Fredholm, B.B.; Chen, J.F. Adenosine, adenosine A2A antagonists, and Parkinson’s disease. Parkinsonism Relat. Disord.,  2009, 15(6), 406-413.
 [http://dx.doi.org/10.1016/j.parkreldis.2008.12.006] [PMID: 19446490]

[193]
Ferré, S.; Karcz-Kubicha, M.; Hope, B.T.; Popoli, P.; Burgueño, J.; Gutiérrez, M.A.; Casadó, V.; Fuxe, K.; Goldberg, S.R.; Lluis, C.; Franco, R.; Ciruela, F. Synergistic interaction between adenosine A2A and glutamate mGlu5 receptors: Implications for striatal neuronal function. Proc. Natl. Acad. Sci. USA,  2002, 99(18), 11940-11945.
 [http://dx.doi.org/10.1073/pnas.172393799] [PMID: 12189203]

[194]
Ferré, S.; Lluís, C.; Justinova, Z.; Quiroz, C.; Orru, M.; Navarro, G.; Canela, E.I.; Franco, R.; Goldberg, S.R. Adenosine-cannabinoid receptor interactions. Implications for striatal function. Br. J. Pharmacol.,  2010, 160(3), 443-453.
 [http://dx.doi.org/10.1111/j.1476-5381.2010.00723.x] [PMID: 20590556]

[195]
Łukasiewicz, S.; Błasiak, E.; Faron-Górecka, A.; Polit, A.; Tworzydło, M.; Górecki, A.; Wasylewski, Z.; Dziedzicka- Wasylewska, M. Fluorescence studies of homooligomerization of adenosine A2A and serotonin 5-HT1A receptors reveal the specificity of receptor interactions in the plasma membrane. Pharmacol. Rep.,  2007, 59(4), 379-392.
 [PMID: 17901566]

[196]
Carriba, P.; Ortiz, O.; Patkar, K.; Justinova, Z.; Stroik, J.; Themann, A.; Müller, C.; Woods, A.S.; Hope, B.T.; Ciruela, F.; Casadó, V.; Canela, E.I.; Lluis, C.; Goldberg, S.R.; Moratalla, R.; Franco, R.; Ferré, S. Striatal adenosine A2A and cannabinoid CB1 receptors form functional heteromeric complexes that mediate the motor effects of cannabinoids. Neuropsychopharmacology,  2007, 32(11), 2249-2259.
 [http://dx.doi.org/10.1038/sj.npp.1301375] [PMID: 17356572]

[197]
Pagonabarraga, J.; Tinazzi, M.; Caccia, C.; Jost, W.H. The role of glutamatergic neurotransmission in the motor and non-motor symptoms in Parkinson’s disease: Clinical cases and a review of the literature. J. Clin. Neurosci.,  2021, 90, 178-183.
 [http://dx.doi.org/10.1016/j.jocn.2021.05.056] [PMID: 34275546]

[198]
Albin, R.L.; Greenamyre, J.T. Alternative excitotoxic hypotheses. Neurology,  1992, 42(4), 733-738.
 [http://dx.doi.org/10.1212/WNL.42.4.733] [PMID: 1314341]

[199]
Rouse, S.T.; Marino, M.J.; Bradley, S.R.; Awad, H.; Wittmann, M.; Conn, P.J. Distribution and roles of metabotropic glutamate receptors in the basal ganglia motor circuit: implications for treatment of Parkinson’s Disease and related disorders. Pharmacol. Ther.,  2000, 88(3), 427-435.
 [http://dx.doi.org/10.1016/S0163-7258(00)00098-X] [PMID: 11337032]

[200]
Sebastianutto, I.; Cenci, M.A. mGlu receptors in the treatment of Parkinson’s disease and L-DOPA-induced dyskinesia. Curr. Opin. Pharmacol.,  2018, 38, 81-89.
 [http://dx.doi.org/10.1016/j.coph.2018.03.003] [PMID: 29625424]

[201]
Litim, N.; Morissette, M.; Di Paolo, T. Metabotropic glutamate receptors as therapeutic targets in Parkinson’s disease: An update from the last 5 years of research. Neuropharmacology,  2017, 115, 166-179.
 [http://dx.doi.org/10.1016/j.neuropharm.2016.03.036] [PMID: 27055772]

[202]
Rodrigues, R.J.; Alfaro, T.M.; Rebola, N.; Oliveira, C.R.; Cunha, R.A. Co-localization and functional interaction between adenosine A2A and metabotropic group 5 receptors in glutamatergic nerve terminals of the rat striatum. J. Neurochem.,  2005, 92(3), 433-441.
 [http://dx.doi.org/10.1111/j.1471-4159.2004.02887.x] [PMID: 15659214]

[203]
O’Leary, D.M.; Movsesyan, V.; Vicini, S.; Faden, A.I. Selective mGluR5 antagonists MPEP and SIB-1893 decrease NMDA or glutamate-mediated neuronal toxicity through actions that reflect NMDA receptor antagonism. Br. J. Pharmacol.,  2000, 131(7), 1429-1437.
 [http://dx.doi.org/10.1038/sj.bjp.0703715] [PMID: 11090117]

[204]
Barkus, C.; McHugh, S.B.; Sprengel, R.; Seeburg, P.H.; Rawlins, J.N.P.; Bannerman, D.M. Hippocampal NMDA receptors and anxiety: At the interface between cognition and emotion. Eur. J. Pharmacol.,  2010, 626(1), 49-56.
 [http://dx.doi.org/10.1016/j.ejphar.2009.10.014] [PMID: 19836379]

[205]
Pałucha, A.; Brański, P.; Szewczyk, B.; Wierońska, J.M.; Kłak, K.; Pilc, A. Potential antidepressant-like effect of MTEP, a potent and highly selective mGluR5 antagonist. Pharmacol. Biochem. Behav.,  2005, 81(4), 901-906.
 [http://dx.doi.org/10.1016/j.pbb.2005.06.015] [PMID: 16040106]

[206]
Guo, J.D.; Zhao, X.; Li, Y.; Li, G.R.; Liu, X.L. Damage to dopaminergic neurons by oxidative stress in Parkinson’s disease. (Review). Int. J. Mol. Med.,  2018, 41(4), 1817-1825.
 [http://dx.doi.org/10.3892/ijmm.2018.3406] [PMID: 29393357]

[207]
Chang, K.H.; Chen, C.M. The role of oxidative stress in Parkinson’s disease. Antioxidants,  2020, 9(7), 597.
 [http://dx.doi.org/10.3390/antiox9070597] [PMID: 32650609]

[208]
Fabbri, M.; Rosa, M.M.; Abreu, D.; Ferreira, J.J. Clinical pharmacology review of safinamide for the treatment of Parkinson’s disease. Neurodegener. Dis. Manag.,  2015, 5(6), 481-496.
 [http://dx.doi.org/10.2217/nmt.15.46] [PMID: 26587996]

[209]
Trist, B.G.; Hare, D.J.; Double, K.L. Oxidative stress in the aging substantia nigra and the etiology of Parkinson’s disease. Aging Cell,  2019, 18(6), e13031.
 [http://dx.doi.org/10.1111/acel.13031] [PMID: 31432604]

[210]
Vallée, A.; Lecarpentier, Y.; Guillevin, R.; Vallée, J.N. Circadian rhythms, neuroinflammation and oxidative stress in the story of Parkinson’s disease. Cells,  2020, 9(2), 314.
 [http://dx.doi.org/10.3390/cells9020314] [PMID: 32012898]

[211]
Allen Reish, H.E.; Standaert, D.G. Role of α-synuclein in inducing innate and adaptive immunity in Parkinson disease. J. Parkinsons Dis.,  2015, 5(1), 1-19.
 [http://dx.doi.org/10.3233/JPD-140491] [PMID: 25588354]

[212]
Kannarkat, G.T.; Boss, J.M.; Tansey, M.G. The role of innate and adaptive immunity in Parkinson’s disease. J. Parkinsons Dis.,  2013, 3(4), 493-514.
 [http://dx.doi.org/10.3233/JPD-130250] [PMID: 24275605]

[213]
Niranjan, R. The role of inflammatory and oxidative stress mechanisms in the pathogenesis of Parkinson’s disease: focus on astrocytes. Mol. Neurobiol.,  2014, 49(1), 28-38.
 [http://dx.doi.org/10.1007/s12035-013-8483-x] [PMID: 23783559]

[214]
Percário, S.; da Silva Barbosa, A.; Varela, E.L.P.; Gomes, A.R.Q.; Ferreira, M.E.S.; de Nazaré Araújo Moreira, T.; Dolabela, M.F. Oxidative stress in Parkinson’s disease: Potential benefits of antioxidant supplementation. Oxid. Med. Cell. Longev.,  2020, 2020, 1-23.
 [http://dx.doi.org/10.1155/2020/2360872] [PMID: 33101584]

[215]
Lin, L.F.H.; Doherty, D.H.; Lile, J.D.; Bektesh, S.; Collins, F. GDNF: a glial cell line-derived neurotrophic factor for midbrain dopaminergic neurons. Science,  1993, 260(5111), 1130-1132.
 [http://dx.doi.org/10.1126/science.8493557] [PMID: 8493557]

[216]
Tomac, A.; Lindqvist, E.; Lin, L.F.H.; Ögren, S.O.; Young, D.; Hoffer, B.J.; Olson, L. Protection and repair of the nigrostriatal dopaminergic system by GDNF in vivo. Nature,  1995, 373(6512), 335-339.
 [http://dx.doi.org/10.1038/373335a0] [PMID: 7830766]

[217]
Si, W.; Aluisio, L.; Okamura, N.; Clark, S.D.; Fraser, I.; Sutton, S.W.; Bonaventure, P.; Reinscheid, R.K. Neuropeptide S stimulates dopaminergic neurotransmission in the medial prefrontal cortex. J. Neurochem.,  2010, 115(2), 475-482.
 [http://dx.doi.org/10.1111/j.1471-4159.2010.06947.x] [PMID: 20722970]

[218]
Ramos, S.F.; Mendonça, B.P.; Leffa, D.D.; Pacheco, R.; Damiani, A.P.; Hainzenreder, G.; Petronilho, F.; Dal-Pizzol, F.; Guerrini, R.; Calo’, G.; Gavioli, E.C.; Boeck, C.R.; de Andrade, V.M. Effects of neuropeptide S on seizures and oxidative damage induced by pentylenetetrazole in mice. Pharmacol. Biochem. Behav.,  2012, 103(2), 197-203.
 [http://dx.doi.org/10.1016/j.pbb.2012.09.001] [PMID: 22960046]

[219]
Pupíková, M.; Rektorová, I. Non-pharmacological management of cognitive impairment in Parkinson’s disease. J. Neural Transm. (Vienna),  2020, 127(5), 799-820.
 [http://dx.doi.org/10.1007/s00702-019-02113-w] [PMID: 31823066]

[220]
Qureshi, A.R.; Jamal, M.K.; Rahman, E.; Paul, D.A.; Oghli, Y.S.; Mulaffer, M.T.; Qureshi, D.; Danish, M.A.; Rana, A.Q. Nonpharmacological therapies for pain management in Parkinson’s disease: A systematic review. Acta Neurol. Scand.,  2021, 144(2), 115-131.
 [http://dx.doi.org/10.1111/ane.13435] [PMID: 33982803]

[221]
Cammisuli, D.; Ceravolo, R.; Bonuccelli, U. Non-pharmacological interventions for Parkinson’s disease mild cognitive impairment: future directions for research. Neural Regen. Res.,  2020, 15(9), 1650-1651.
 [http://dx.doi.org/10.4103/1673-5374.276329] [PMID: 32209764]

[222]
Taximaimaiti, R.; Luo, X.; Wang, X.P. Pharmacological and non-pharmacological treatments of sleep disorders in Parkinson’s disease. Curr. Neuropharmacol.,  2021, 19(12), 2233-2249.
 [http://dx.doi.org/10.2174/1570159X19666210517115706] [PMID: 33998990]

[223]
Lee, M.Y.; Yu, J.H.; Kim, J.Y.; Seo, J.H.; Park, E.S.; Kim, C.H.; Kim, H.; Cho, S.R. Alteration of synaptic activity-regulating genes underlying functional improvement by long-term exposure to an enriched environment in the adult brain. Neurorehabil. Neural Repair,  2013, 27(6), 561-574.
 [http://dx.doi.org/10.1177/1545968313481277] [PMID: 23558143]

[224]
Drake, D.F.; Harkins, S.; Qutubuddin, A. Pain in Parkinson’s disease: Pathology to treatment, medication to deep brain stimulation. NeuroRehabilitation,  2005, 20(4), 335-341.
 [http://dx.doi.org/10.3233/NRE-2005-20408] [PMID: 16403999]

[225]
Borsook, D.; Upadhyay, J.; Chudler, E.H.; Becerra, L. A key role of the basal ganglia in pain and analgesia--insights gained through human functional imaging. Mol. Pain,  2010, 6, 1744-8069-6-27.
 [http://dx.doi.org/10.1186/1744-8069-6-27] [PMID: 20465845]

[226]
Hamani, C.; Saint-Cyr, J.A.; Fraser, J.; Kaplitt, M.; Lozano, A.M. The subthalamic nucleus in the context of movement disorders. Brain,  2004, 127(1), 4-20.
 [http://dx.doi.org/10.1093/brain/awh029] [PMID: 14607789]

[227]
Anderson, C.; Sheppard, D.; Dorval, A.D. Parkinsonism and subthalamic deep brain stimulation dysregulate behavioral motivation in a rodent model. Brain Res.,  2020, 1736, 146776.
 [http://dx.doi.org/10.1016/j.brainres.2020.146776] [PMID: 32171706]

[228]
Mosley, P.E.; Smith, D.; Coyne, T.; Silburn, P.; Breakspear, M.; Perry, A. The site of stimulation moderates neuropsychiatric symptoms after subthalamic deep brain stimulation for Parkinson’s disease. Neuroimage Clin.,  2018, 18, 996-1006.
 [http://dx.doi.org/10.1016/j.nicl.2018.03.009] [PMID: 29876284]

[229]
Church, F.C. Treatment options for motor and non-motor symptoms of Parkinson’s disease. Biomolecules,  2021, 11(4), 612.
 [http://dx.doi.org/10.3390/biom11040612] [PMID: 33924103]

[230]
Hayes, M.W.; Fung, V.S.C.; Kimber, T.E.; O’Sullivan, J.D. Updates and advances in the treatment of Parkinson disease. Med. J. Aust.,  2019, 211(6), 277-283.
 [http://dx.doi.org/10.5694/mja2.50224] [PMID: 31203580]
Cite As
Current Neuropharmacology

Therapeutic Approaches to Non-Motor Symptoms of Parkinson's Disease: A Current Update on Preclinical Evidence

Abstract

Graphical Abstract
