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
[http://dx.doi.org/10.1016/S1474-4422(06)70471-9] [PMID: 16713924]
[http://dx.doi.org/10.14802/jmd.15003] [PMID: 26090081]
[http://dx.doi.org/10.1038/nrdp.2017.13] [PMID: 28332488]
[http://dx.doi.org/10.7326/AITC201809040] [PMID: 30178019]
[http://dx.doi.org/10.1001/jama.2019.22360] [PMID: 32044947]
[http://dx.doi.org/10.5694/mja17.00993] [PMID: 29764353]
[http://dx.doi.org/10.1212/WNL.0000000000001684] [PMID: 25995056]
[http://dx.doi.org/10.1038/nrneurol.2017.27] [PMID: 28257128]
[http://dx.doi.org/10.1016/j.parkreldis.2019.04.020] [PMID: 31109727]
[http://dx.doi.org/10.1002/gps.4261] [PMID: 25676160]
[http://dx.doi.org/10.3389/fnagi.2019.00021] [PMID: 30800065]
[http://dx.doi.org/10.1002/mds.22868] [PMID: 20437539]
[http://dx.doi.org/10.1016/S1353-8020(98)00022-4] [PMID: 18591098]
[http://dx.doi.org/10.1586/14737175.2015.1091727] [PMID: 26394528]
[http://dx.doi.org/10.1016/S1474-4422(09)70068-7] [PMID: 19375664]
[http://dx.doi.org/10.1002/mds.22596] [PMID: 19425079]
[http://dx.doi.org/10.1016/S1474-4422(08)70214-X] [PMID: 18848312]
[http://dx.doi.org/10.1093/brain/awh445] [PMID: 15716302]
[http://dx.doi.org/10.1007/s12031-019-01444-3] [PMID: 31927768]
[http://dx.doi.org/10.1016/j.parkreldis.2015.03.021] [PMID: 25921825]
[http://dx.doi.org/10.1371/journal.pone.0108982] [PMID: 25330404]
[http://dx.doi.org/10.1016/j.jns.2016.08.059] [PMID: 27772789]
[http://dx.doi.org/10.1002/mds.26587] [PMID: 27041545]
[http://dx.doi.org/10.3389/fpsyt.2021.635494] [PMID: 33633615]
[http://dx.doi.org/10.1002/mds.26125] [PMID: 25488260]
[http://dx.doi.org/10.1007/s40265-016-0566-3] [PMID: 27091215]
[http://dx.doi.org/10.1136/jnnp-2019-322338] [PMID: 32576618]
[http://dx.doi.org/10.1016/j.neuropharm.2016.07.012] [PMID: 27424102]
[http://dx.doi.org/10.3389/fnbeh.2017.00075] [PMID: 28515684]
[http://dx.doi.org/10.1155/2020/1941480] [PMID: 32273939]
[http://dx.doi.org/10.1523/JNEUROSCI.0181-14.2014] [PMID: 24990932]
[http://dx.doi.org/10.1007/s11011-018-0352-x] [PMID: 30506334]
[http://dx.doi.org/10.2169/internalmedicine.0037-22] [PMID: 35831101]
[http://dx.doi.org/10.3390/genes12030392] [PMID: 33801790]
[http://dx.doi.org/10.1016/j.neurobiolaging.2018.01.011] [PMID: 29407467]
[http://dx.doi.org/10.1016/bs.irn.2017.05.018] [PMID: 28802936]
[http://dx.doi.org/10.1111/j.1476-5381.2011.01426.x] [PMID: 21486284]
[http://dx.doi.org/10.1016/j.nbd.2011.12.040] [PMID: 22236386]
[http://dx.doi.org/10.3390/ijms21061961] [PMID: 32183024]
[http://dx.doi.org/10.1016/S1873-9598(08)70024-3]
[http://dx.doi.org/10.3390/ijms23063349] [PMID: 35328770]
[http://dx.doi.org/10.1038/nn.4648] [PMID: 28945221]
[http://dx.doi.org/10.1016/j.neuroscience.2008.08.035] [PMID: 18817851]
[http://dx.doi.org/10.3389/fneur.2018.00208] [PMID: 29686643]
[http://dx.doi.org/10.1093/brain/awz380] [PMID: 31816026]
[http://dx.doi.org/10.1016/j.expneurol.2011.08.003] [PMID: 21864527]
[http://dx.doi.org/10.1016/j.bbr.2020.112957] [PMID: 33038348]
[http://dx.doi.org/10.1016/j.nbd.2012.04.009] [PMID: 22549133]
[http://dx.doi.org/10.3389/fneur.2013.00103] [PMID: 23888153]
[http://dx.doi.org/10.1016/j.bbr.2012.07.003] [PMID: 22796604]
[http://dx.doi.org/10.1016/j.nbd.2013.04.017] [PMID: 23643841]
[http://dx.doi.org/10.1016/j.jnutbio.2016.08.014] [PMID: 27741433]
[http://dx.doi.org/10.1186/s40035-022-00294-1] [PMID: 35395825]
[http://dx.doi.org/10.1016/j.prdoa.2019.11.004] [PMID: 34316612]
[http://dx.doi.org/10.1016/j.neubiorev.2018.10.004] [PMID: 30365972]
[http://dx.doi.org/10.1016/bs.pbr.2022.01.006] [PMID: 35248196]
[http://dx.doi.org/10.1084/jem.20112285] [PMID: 22473957]
[http://dx.doi.org/10.1039/C8FO00964C] [PMID: 30462117]
[http://dx.doi.org/10.1016/j.expneurol.2016.05.040] [PMID: 27342081]
[http://dx.doi.org/10.3390/ijms19020508] [PMID: 29419747]
[http://dx.doi.org/10.1016/j.pbb.2012.03.022] [PMID: 22487770]
[http://dx.doi.org/10.1016/j.brainres.2013.03.029] [PMID: 23548600]
[http://dx.doi.org/10.1016/j.neuroscience.2013.11.051] [PMID: 24316474]
[http://dx.doi.org/10.1016/j.neuint.2019.104492] [PMID: 31229554]
[http://dx.doi.org/10.1007/s12640-015-9566-4] [PMID: 26464310]
[http://dx.doi.org/10.1016/j.biopsych.2017.07.017] [PMID: 28941549]
[http://dx.doi.org/10.1371/journal.pone.0070249] [PMID: 23936174]
[http://dx.doi.org/10.1016/j.jns.2006.05.030] [PMID: 16797028]
[http://dx.doi.org/10.1212/01.wnl.0000268695.63392.10] [PMID: 17581943]
[http://dx.doi.org/10.1007/s12272-018-1063-x] [PMID: 30136247]
[http://dx.doi.org/10.1021/acschemneuro.0c00628] [PMID: 33155799]
[http://dx.doi.org/10.1038/s41398-022-01842-z] [PMID: 35210396]
[http://dx.doi.org/10.1038/s41598-018-23795-4] [PMID: 29615705]
[http://dx.doi.org/10.1080/00207454.2020.1754213] [PMID: 32441169]
[http://dx.doi.org/10.1017/S1461145714000236] [PMID: 24661728]
[http://dx.doi.org/10.1007/s11307-020-01485-w] [PMID: 32086763]
[http://dx.doi.org/10.1016/j.bbr.2017.12.041] [PMID: 29307665]
[http://dx.doi.org/10.1021/acschemneuro.6b00354] [PMID: 27977132]
[http://dx.doi.org/10.1016/j.physbeh.2018.02.033] [PMID: 29458117]
[http://dx.doi.org/10.1111/j.1476-5381.2012.02100.x] [PMID: 22774922]
[http://dx.doi.org/10.1016/j.neuint.2021.105215] [PMID: 34710535]
[http://dx.doi.org/10.1016/j.bbi.2018.12.003] [PMID: 30550933]
[http://dx.doi.org/10.1002/jnr.23577] [PMID: 25711470]
[PMID: 30468633]
[http://dx.doi.org/10.1371/journal.pone.0258928] [PMID: 34767546]
[http://dx.doi.org/10.1016/j.biopha.2021.111556] [PMID: 34087694]
[http://dx.doi.org/10.31083/j.jin2002030] [PMID: 34258929]
[PMID: 2239476]
[http://dx.doi.org/10.1016/j.neuropharm.2011.08.039] [PMID: 21903105]
[http://dx.doi.org/10.1016/j.brainresbull.2011.01.005] [PMID: 21255635]
[http://dx.doi.org/10.3233/JPD-120130] [PMID: 23938351]
[http://dx.doi.org/10.1016/j.neures.2012.03.010] [PMID: 22475625]
[http://dx.doi.org/10.1523/JNEUROSCI.1495-09.2009] [PMID: 19553450]
[http://dx.doi.org/10.3233/JPD-130301] [PMID: 24796235]
[http://dx.doi.org/10.1093/brain/awaa283] [PMID: 33170925]
[http://dx.doi.org/10.1016/j.expneurol.2009.07.019] [PMID: 19635479]
[http://dx.doi.org/10.1016/j.nbd.2013.10.029] [PMID: 24211719]
[http://dx.doi.org/10.3892/mmr.2016.4991] [PMID: 26985725]
[http://dx.doi.org/10.1016/j.smrv.2015.02.005] [PMID: 26163055]
[http://dx.doi.org/10.1016/j.neulet.2015.09.024] [PMID: 26409036]
[http://dx.doi.org/10.1371/journal.pone.0133971] [PMID: 26230083]
[http://dx.doi.org/10.1016/j.lfs.2015.01.032] [PMID: 25744393]
[http://dx.doi.org/10.1016/j.brainres.2016.12.008] [PMID: 27956121]
[http://dx.doi.org/10.1371/journal.pone.0104850] [PMID: 25133405]
[http://dx.doi.org/10.1038/s41531-018-0057-1] [PMID: 30038956]
[http://dx.doi.org/10.1111/ejn.13012] [PMID: 26153521]
[http://dx.doi.org/10.1073/pnas.1303444110] [PMID: 23530187]
[http://dx.doi.org/10.1016/j.bbabio.2016.03.014] [PMID: 26992930]
[http://dx.doi.org/10.1073/pnas.1106291108] [PMID: 21606348]
[http://dx.doi.org/10.1002/nau.20917] [PMID: 20589898]
[http://dx.doi.org/10.1016/j.juro.2015.11.039] [PMID: 26626223]
[http://dx.doi.org/10.1016/j.juro.2013.08.026] [PMID: 23973520]
[http://dx.doi.org/10.3233/JPD-140509] [PMID: 25697958]
[http://dx.doi.org/10.1371/journal.pone.0175797] [PMID: 28520722]
[http://dx.doi.org/10.1007/s10286-018-00584-7] [PMID: 30604165]
[http://dx.doi.org/10.1016/j.nbd.2012.06.005] [PMID: 22722052]
[http://dx.doi.org/10.1007/s00455-018-9896-5] [PMID: 29713896]
[http://dx.doi.org/10.1016/j.bbr.2017.10.036] [PMID: 29109055]
[http://dx.doi.org/10.1111/apha.12229] [PMID: 24410908]
[http://dx.doi.org/10.1152/ajpgi.00258.2014] [PMID: 25277799]
[http://dx.doi.org/10.1124/jpet.115.228510] [PMID: 26582732]
[http://dx.doi.org/10.1111/nmo.12691] [PMID: 26433214]
[http://dx.doi.org/10.4172/2161-0460.1000279] [PMID: 28090391]
[http://dx.doi.org/10.1053/j.gastro.2017.08.069] [PMID: 28912019]
[http://dx.doi.org/10.1016/j.bbr.2015.07.058] [PMID: 26239001]
[http://dx.doi.org/10.1007/s10286-016-0358-6] [PMID: 27178445]
[http://dx.doi.org/10.1016/j.nbd.2018.12.012] [PMID: 30579705]
[http://dx.doi.org/10.1111/j.1365-2982.2012.01974.x] [PMID: 22779732]
[http://dx.doi.org/10.1111/nmo.12070] [PMID: 23281940]
[http://dx.doi.org/10.3233/JPD-140424] [PMID: 25633843]
[http://dx.doi.org/10.1016/j.neurobiolaging.2012.07.008] [PMID: 22883907]
[http://dx.doi.org/10.1016/j.etp.2011.05.008] [PMID: 21676605]
[http://dx.doi.org/10.1038/nrn.2017.62] [PMID: 28592904]
[http://dx.doi.org/10.1016/j.parkreldis.2015.09.004] [PMID: 26372623]
[http://dx.doi.org/10.1016/j.neulet.2014.09.042] [PMID: 25263790]
[http://dx.doi.org/10.1371/journal.pone.0077509] [PMID: 24204848]
[http://dx.doi.org/10.1371/journal.pone.0114216] [PMID: 25486126]
[http://dx.doi.org/10.1016/j.jns.2013.07.005] [PMID: 23890935]
[http://dx.doi.org/10.1002/mds.23462] [PMID: 21264941]
[http://dx.doi.org/10.1038/s41598-017-17796-y] [PMID: 29234141]
[http://dx.doi.org/10.1177/1744806917691525] [PMID: 28326933]
[http://dx.doi.org/10.1016/j.expneurol.2019.02.007] [PMID: 30772369]
[http://dx.doi.org/10.1016/j.brainres.2016.10.025] [PMID: 27984022]
[http://dx.doi.org/10.1016/j.expneurol.2016.06.031] [PMID: 27373204]
[http://dx.doi.org/10.1186/s12990-015-0026-1] [PMID: 25981600]
[http://dx.doi.org/10.1016/j.pain.2011.12.011] [PMID: 22244441]
[http://dx.doi.org/10.3389/fnbeh.2014.00290] [PMID: 25221486]
[http://dx.doi.org/10.1016/j.neuroscience.2012.05.052] [PMID: 22659568]
[http://dx.doi.org/10.1523/JNEUROSCI.5314-13.2014] [PMID: 25009275]
[http://dx.doi.org/10.1371/journal.pone.0019338] [PMID: 21559417]
[http://dx.doi.org/10.1186/s40478-016-0410-8] [PMID: 28086964]
[http://dx.doi.org/10.1007/s00213-013-3158-x] [PMID: 23748382]
[http://dx.doi.org/10.1016/j.freeradbiomed.2018.06.029] [PMID: 29960099]
[http://dx.doi.org/10.1111/febs.15721] [PMID: 33471408]
[http://dx.doi.org/10.1016/j.bbr.2014.06.029] [PMID: 24956561]
[http://dx.doi.org/10.18632/aging.103225] [PMID: 32424108]
[http://dx.doi.org/10.1016/j.bbr.2016.02.040] [PMID: 27012392]
[http://dx.doi.org/10.1111/ejn.12992] [PMID: 26082992]
[http://dx.doi.org/10.1016/j.brainres.2019.03.013] [PMID: 30898672]
[http://dx.doi.org/10.1016/j.juro.2011.11.079] [PMID: 22341818]
[http://dx.doi.org/10.1007/s00441-018-2813-2] [PMID: 29516217]
[http://dx.doi.org/10.1038/s41531-016-0006-9] [PMID: 28649605]
[http://dx.doi.org/10.1111/ejn.14119] [PMID: 30118169]
[http://dx.doi.org/10.1172/JCI43766] [PMID: 21041960]
[http://dx.doi.org/10.1016/j.pneurobio.2006.08.001] [PMID: 17030082]
[http://dx.doi.org/10.1038/s41593-019-0556-3] [PMID: 31844313]
[http://dx.doi.org/10.1038/s41531-022-00339-2] [PMID: 35697709]
[PMID: 28124620]
[http://dx.doi.org/10.1592/phco.27.12part2.174S] [PMID: 18041937]
[http://dx.doi.org/10.3233/JPD-212976] [PMID: 34957948]
[http://dx.doi.org/10.1007/s00702-018-1876-2] [PMID: 29569037]
[http://dx.doi.org/10.1007/s00702-015-1398-0] [PMID: 25863936]
[http://dx.doi.org/10.1016/j.jmb.2010.10.027] [PMID: 21050861]
[http://dx.doi.org/10.1016/S0733-8619(05)70230-9] [PMID: 11072265]
[http://dx.doi.org/10.1523/JNEUROSCI.4564-06.2007] [PMID: 17287515]
[http://dx.doi.org/10.1016/j.ajpath.2012.11.018] [PMID: 23313024]
[http://dx.doi.org/10.1038/42166] [PMID: 9278044]
[http://dx.doi.org/10.1073/pnas.1514475112] [PMID: 26324905]
[http://dx.doi.org/10.1523/JNEUROSCI.1292-12.2012] [PMID: 23015436]
[http://dx.doi.org/10.1016/j.biopha.2019.108843] [PMID: 31055236]
[http://dx.doi.org/10.1038/s41531-018-0062-4] [PMID: 30155513]
[http://dx.doi.org/10.1016/j.tins.2016.09.003] [PMID: 27776749]
[http://dx.doi.org/10.3233/JPD-202481] [PMID: 33682732]
[PMID: 26534909]
[http://dx.doi.org/10.1007/s40265-013-0066-7] [PMID: 23700273]
[http://dx.doi.org/10.1007/s40263-014-0161-7] [PMID: 24687255]
[http://dx.doi.org/10.1212/01.WNL.0000095211.71092.A0] [PMID: 14663009]
[http://dx.doi.org/10.1523/JNEUROSCI.16-02-00605.1996] [PMID: 8551344]
[http://dx.doi.org/10.1016/j.neuropharm.2006.03.011] [PMID: 16730753]
[http://dx.doi.org/10.1016/S0306-4522(00)00250-5] [PMID: 10996458]
[http://dx.doi.org/10.1016/j.parkreldis.2008.12.006] [PMID: 19446490]
[http://dx.doi.org/10.1073/pnas.172393799] [PMID: 12189203]
[http://dx.doi.org/10.1111/j.1476-5381.2010.00723.x] [PMID: 20590556]
[PMID: 17901566]
[http://dx.doi.org/10.1038/sj.npp.1301375] [PMID: 17356572]
[http://dx.doi.org/10.1016/j.jocn.2021.05.056] [PMID: 34275546]
[http://dx.doi.org/10.1212/WNL.42.4.733] [PMID: 1314341]
[http://dx.doi.org/10.1016/S0163-7258(00)00098-X] [PMID: 11337032]
[http://dx.doi.org/10.1016/j.coph.2018.03.003] [PMID: 29625424]
[http://dx.doi.org/10.1016/j.neuropharm.2016.03.036] [PMID: 27055772]
[http://dx.doi.org/10.1111/j.1471-4159.2004.02887.x] [PMID: 15659214]
[http://dx.doi.org/10.1038/sj.bjp.0703715] [PMID: 11090117]
[http://dx.doi.org/10.1016/j.ejphar.2009.10.014] [PMID: 19836379]
[http://dx.doi.org/10.1016/j.pbb.2005.06.015] [PMID: 16040106]
[http://dx.doi.org/10.3892/ijmm.2018.3406] [PMID: 29393357]
[http://dx.doi.org/10.3390/antiox9070597] [PMID: 32650609]
[http://dx.doi.org/10.2217/nmt.15.46] [PMID: 26587996]
[http://dx.doi.org/10.1111/acel.13031] [PMID: 31432604]
[http://dx.doi.org/10.3390/cells9020314] [PMID: 32012898]
[http://dx.doi.org/10.3233/JPD-140491] [PMID: 25588354]
[http://dx.doi.org/10.3233/JPD-130250] [PMID: 24275605]
[http://dx.doi.org/10.1007/s12035-013-8483-x] [PMID: 23783559]
[http://dx.doi.org/10.1155/2020/2360872] [PMID: 33101584]
[http://dx.doi.org/10.1126/science.8493557] [PMID: 8493557]
[http://dx.doi.org/10.1038/373335a0] [PMID: 7830766]
[http://dx.doi.org/10.1111/j.1471-4159.2010.06947.x] [PMID: 20722970]
[http://dx.doi.org/10.1016/j.pbb.2012.09.001] [PMID: 22960046]
[http://dx.doi.org/10.1007/s00702-019-02113-w] [PMID: 31823066]
[http://dx.doi.org/10.1111/ane.13435] [PMID: 33982803]
[http://dx.doi.org/10.4103/1673-5374.276329] [PMID: 32209764]
[http://dx.doi.org/10.2174/1570159X19666210517115706] [PMID: 33998990]
[http://dx.doi.org/10.1177/1545968313481277] [PMID: 23558143]
[http://dx.doi.org/10.3233/NRE-2005-20408] [PMID: 16403999]
[http://dx.doi.org/10.1186/1744-8069-6-27] [PMID: 20465845]
[http://dx.doi.org/10.1093/brain/awh029] [PMID: 14607789]
[http://dx.doi.org/10.1016/j.brainres.2020.146776] [PMID: 32171706]
[http://dx.doi.org/10.1016/j.nicl.2018.03.009] [PMID: 29876284]
[http://dx.doi.org/10.3390/biom11040612] [PMID: 33924103]
[http://dx.doi.org/10.5694/mja2.50224] [PMID: 31203580]