Health  Vol.4 No.11 A , November 2012
Pharmacological strategies for Parkinson’s disease
Abstract: Parkinson’s disease (PD) or Paralysis Agitans was first formally described in “An essay on the shaking palsy”, published in 1817 by a British physician named James Parkinson. In the late 1950’s, dopamine was related with the function of the corpus striatum, thus with the control of motor function. But it was not until 1967, when the landmark study of George C. Cotzias, demonstrated that oral L-DOPA, the precursor of dopamine metabolism, was shown to induce remission of PD symptoms, that the definitive association between the two was firmly established. However, later on L-DOPA treatment began to show a loss of effectiveness and demonstrated to induce a variety of undesirable effects, the most prominent being diskinesia. As a result of this, a variety of alternative or complementary pharmacological strategies have been developed. In this chapter we review the wide variety of strategies that have been used through time, which are geared toward reducing the most disabling symptoms of PD. We additionally make some suggestions as to which are the most promising ones.
Cite this paper: García-Montes, J. , Boronat-García, A. and Drucker-Colín, R. (2012) Pharmacological strategies for Parkinson’s disease. Health, 4, 1153-1166. doi: 10.4236/health.2012.431174.

[1]   Zhang, Z.X., Dong, Z.H. and Roman, G.C. (2006) Early descriptions of Parkinson disease in ancient China. Archives of Neurology, 5, 782-784. doi:10.1001/archneur.63.5.782

[2]   Manyam, B.V. (1990) Paralysis agitans and levodopa in “Ayurveda”: Ancient Indian medical treatise. Movement Disorders, 1, 47-48. doi:10.1002/mds.870050112

[3]   Dorsey, E.R., Constantinescu, R., Thompson, J.P., Biglan, K.M., Holloway, R.G., Kieburtz, K., Marshall, F.J., Ravina, B.M., Schifitto, G., Siderowf, A. and Tanner, C.M. (2007) Projected number of people with Parkinson disease in the most populous nations, 2005 through 2030. Neurology, 5, 384-386. doi:10.1212/01.wnl.0000247740.47667.03

[4]   Vollmer, H. (1942) Comparative value of solanaceus alka- loids in treatment of Parkinson’s syndrome. Archives of Neurology and Psychiatry, 48, 72-84.

[5]   Meter, J.R.V. (1950) Therapy of Parkinson’s disease. California Medicine, 4, 322-324.

[6]   Sano, I., Gamo, T. and Kakimoto, Y. (1959) Distribution of cathecol compounds in human brain. Biochemica et Biophysica Acta, 32, 586-587. doi:10.1016/0006-3002(59)90652-3

[7]   Bertler, A. (1959) Ocurrence and distribution of dopamine in brain and other issues. Experientia, 15, 10-11. doi:10.1007/BF02157069

[8]   Hornykiewicz, O. and Ehringer, J. (1960) Verteilung von noradrenalin and dopamin im gehirn des menschen und ihr verhalten bei erkrankungen des extrapyramidalen systems. Klinische Wochenschrift, 38, 1126-1239.

[9]   Birkmayer, W. and Hornykiewicz, O. (1961) The L-3,4- dioxyphenylalanine (DOPA)-effect in Parkinson-akinesia. Wiener Klinische Wochenschrift, 73, 787-788.

[10]   Cotzias, G.C., Van Woert, M.H. and Schiffer, L.M. (1967) Aromatic amino acids and modification of parkinsonism. The New England Journal of Medicine, 7, 374-379. doi:10.1056/NEJM196702162760703

[11]   Ansari, K.A. and Johnson, A. (1975) Olfactory function in patients with Parkin-son's disease. Journal of Chronic Diseases, 9, 493-497. doi:10.1016/0021-9681(75)90058-2

[12]   Doty, R.L., Golbe, L.I., McKeown, D.A., Stern, M.B., Lehrach, C.M. and Craw-ford, D. (1993) Olfactory testing differentiates between progressive supranuclear palsy and idiopathic Parkinson’s disease. Neurology, 5, 962-965. doi:10.1212/WNL.43.5.962

[13]   Doty, R.L. (2012) Olfactory dysfunction in Parkinson disease. Nature Reviews Neurology, 6, 329-339.

[14]   Del Tredici, K., Rub, U., De Vos, R.A., Bohl, J.R. and Braak, H. (2002) Where does parkinson disease pathology begin in the brain? Journal of Neuropathology & Experimental Neurology, 5, 413-426.

[15]   Postuma, R.B. and Montplaisir, J. (2009) Predicting Parkinson's disease—why, when, and how? Parkinsonism & Related Disorders, 15, S105-S109. doi:10.1016/S1353-8020(09)70793-X

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

[17]   Schapira, A.H. (2010) Future strategies for neuroprotec- tion in Parkinson's disease. Neurodegenerative Disease, 1-3, 210-212. doi:10.1159/000295666

[18]   Postuma, R.B., Gagnon, J.F., Vendette, M. and Montplaisir, J.Y. (2009) Markers of neurodegeneration in idiopathic rapid eye movement sleep behaviour disorder and Parkinson’s disease. Brain, Pt 12, 3298-3307. doi:10.1093/brain/awp244

[19]   Forno, L.S. (1996) Neuropa-thology of Parkinson’s disease. Journal of Neuropathology & Experimental Neurology, 3, 259-272. doi:10.1097/00005072-199603000-00001

[20]   Jellinger, K.A. (2003) Alpha-synuclein pathology in Parkinson’s and Alz-heimer’s disease brain: Incidence and topographic distribu-tion—A pilot study. Acta Neuropa- thologica, 3, 191-201. doi:10.1007/s00401-003-0725-y

[21]   Ohama, E. and Ikuta, F. (1976) Parkinson’s disease: Distribution of Lewy bodies and monoamine neuron system. Acta Neuropathologica, 4, 311-319. doi:10.1007/BF00696560

[22]   Braak, H., Del Tredici, K., Bratzke, H., Hamm-Clement, J., Sandmann-Keil, D. and Rub, U. (2002) Staging of the intracerebral inclusion body pathology associated with idiopathic Parkinson’s disease (preclinical and clinical stages). Journal of Neurology, 3, 1-5. doi:10.1007/s00415-002-1301-4

[23]   Dickson, D.W., Braak, H., Duda, J.E., Duyckaerts, C., Gasser, T., Halliday, G.M., Hardy, J., Leverenz, J.B., Del Tredici, K., Wszolek, Z.K. and Litvan, I. (2009) Neuropathological assessment of Parkinson’s disease: Refining the diagnostic criteria. The Lancet Neurology, 12, 1150- 1157. doi:10.1016/S1474-4422(09)70238-8

[24]   Lewy (1919) Pa-ralysis agitans. I. pathologische anatomie. In: Lewandowsky, M., Ed., Hundbuch der Neurologie, 920-933.

[25]   Tretiakoff (1919) Contribution a L’étude de L’anatomie Pathologique de Locus Niger de Soemmerling. Université de Paris, Paris.

[26]   Xia, Q., Liao, L., Cheng, D., Duong, D.M., Gearing, M., Lah, J.J., Levey, A.I. and Peng, J. (2008) Proteomic identification of novel proteins associated with Lewy bodies. Frontiers in Bioscience, 13, 3850-3856. doi:10.2741/2973

[27]   Wakabayashi, K., Takahashi, H., Obata, K. and Ikuta, F. (1992) Immunocytochemical localization of synaptic vesicle-specific protein in Lewy body-containing neurons in Parkinson's disease. Neuroscience Letters, 2, 237-240. doi:10.1016/0304-3940(92)90923-U

[28]   Spillantini, M.G., Schmidt, M.L., Lee, V. M., Trojanowski, J.Q., Jakes, R. and Goedert, M. (1997) Alpha-synuclein in Lewy bodies. Nature, 6645, 839-840. doi:10.1038/42166

[29]   Iwai, A., Masliah, E., Yoshimoto, M., Ge, N., Flanagan, L., de Silva, H.A., Kittel, A. and Saitoh, T. (1995) The precursor protein of non—A beta component of Alzheimer’s disease amyloid is a presynaptic protein of the central nervous system. Neuron, 2, 467-475. doi:10.1016/0896-6273(95)90302-X

[30]   Baba, M., Nakajo, S., Tu, P.H., Tomita, T., Nakaya, K., Lee, V.M., Trojanowski, J.Q. and Iwatsubo, T. (1998) Aggregation of alpha-synuclein in Lewy bodies of sporadic Parkinson’s disease and dementia with Lewy bodies. American Journal of Pathology, 4, 879-884.

[31]   Hashimoto, M., Hsu, L.J., Xia, Y., Takeda, A., Sisk, A., Sundsmo, M. and Masliah, E. (1999) Oxidative stress induces amyloid-like aggregate formation of NACP/alpha- synuclein in vitro. Neuroreport, 4, 717-721. doi:10.1097/00001756-199903170-00011

[32]   Fujiwara, H., Hasegawa, M., Dohmae, N., Kawashima, A., Masliah, E., Goldberg, M.S., Shen, J., Takio, K. and Iwatsubo, T. (2002) alpha-Synuclein is phosphorylated in synucleinopathy lesions. Nature Cell Biology, 2, 160-164.

[33]   Sevcsik, E., Trexler, A.J., Dunn, J.M. and Rhoades, E. (2011) Allostery in a disordered protein: Oxidative modifications to alpha-synuclein act distally to regulate membrane binding. Journal of the American Chemical Society, 18, 7152-7158. doi:10.1021/ja2009554

[34]   Somogyi, A., Rosta, K., Pusztai, P., Tulassay, Z. and Nagy, G. (2007) Antioxidant measurements. Physiological Measurement, 4, R41-55. doi:10.1088/0967-3334/28/4/R01

[35]   Segura-Aguilar, J. and Lind, C. (1989) On the mechanism of the Mn3(+)-induced neurotoxicity of dopamine: Pre- vention of quinone-derived oxygen toxicity by DT diaphorase and superoxide dismutase. Chemico-Biological Interactions, 3, 309-324. doi:10.1016/0009-2797(89)90006-9

[36]   Napolitano, A., Manini, P. and d’Ischia, M. (2011) Oxidation chemistry of catecholamines and neuronal degeneration: An update. Current Medicinal Chemistry, 12, 1832- 1845. doi:10.2174/092986711795496863

[37]   Gerlach, M., Double, K.L., Ben-Shachar, D., Zecca, L., Youdim, M.B. and Riederer, P. (2003) Neuromelanin and its interaction with iron as a potential risk factor for dopaminergic neurodegeneration underlying Parkinson’s disease. Neurotoxicity Research, 1-2, 35-44. doi:10.1007/BF03033371

[38]   Fasano, M., Bergamasco, B. and Lopiano, L. (2006) Modi- fications of the iron-neuromelanin system in Parkinson’s disease. Journal of Neurochemistry, 4, 909-916. doi:10.1111/j.1471-4159.2005.03638.x

[39]   Wolozin, B. and Golts, N. (2002) Iron and Parkinson’s disease. Neuroscientist, 1, 22-32. doi:10.1177/107385840200800107

[40]   Zecca, L., Tampellini, D., Gerlach, M., Riederer, P., Fariello, R.G. and Sulzer, D. (2001) Substantia nigra neuromelanin: structure, synthesis, and molecular behaviour. Molecular Pathology, 6, 414-418.

[41]   Ostrerova-Golts, N., Petrucelli, L., Hardy, J., Lee, J.M., Farer, M. and Wolozin, B. (2000) The A53T alpha-synu- clein mutation increases iron-dependent aggregation and toxicity. The Journal of Neuroscience, 16, 6048-6054.

[42]   Turnbull, S., Tabner, B.J., El-Agnaf, O.M., Moore, S., Davies, Y. and Allsop, D. (2001) alpha-Synuclein implicated in Parkinson’s disease catalyses the formation of hydrogen peroxide in vitro. Free Radical Biology & Medicine, 10, 1163-1170. doi:10.1016/S0891-5849(01)00513-5

[43]   Shamoto-Nagai, M., Maruyama, W., Yi, H., Akao, Y., Tribl, F., Gerlach, M., Osawa, T., Riederer, P. and Naoi, M. (2006) Neuromelanin induces oxidative stress in mi- tochondria through release of iron: Mechanism behind the inhibition of 26S proteasome. Journal of Neural Transmission, 5, 633-644. doi:10.1007/s00702-005-0410-5

[44]   Braak, H., Ghebremedhin, E., Rub, U., Bratzke, H. and Del Tredici, K. (2004) Stages in the development of Parkinson’s disease-related pathology. Cell and Tissue Research, 1, 121-134. doi:10.1007/s00441-004-0956-9

[45]   Uchiyama, M., Isse, K., Tanaka, K., Yokota, N., Hamamoto, M., Aida, S., Ito, Y., Yoshimura, M. and Okawa, M. (1995) Incidental Lewy body disease in a patient with REM sleep behavior disorder. Neurology, 4, 709-712. doi:10.1212/WNL.45.4.709

[46]   Turner, R.S., D’Amato, C.J., Chervin, R.D. and Blaivas, M. (2000) The pathology of REM sleep behavior disorder with comorbid Lewy body dementia. Neurology, 11, 1730- 1732. doi:10.1212/WNL.55.11.1730

[47]   Boeve, B.F., Silber, M.H., Saper, C.B., Ferman, T.J., Dickson, D.W., Parisi, J.E., Benarroch, E.E., Ahlskog, J.E., Smith, G.E., Caselli, R.C., Tippman-Peikert, M., Olson, E.J., Lin, S.C., Young, T., Wszolek, Z., Schenck, C. H., Mahowald, M.W., Castillo, P.R., Del Tredici, K. and Braak, H. (2007) Pathophysiology of REM sleep behaviiour disorder and relevance to neurodegenerative disease. Brain, Pt 11, 2770-2788. doi:10.1093/brain/awm056

[48]   Alexander, G.E., DeLong, M.R. and Strick, P.L. (1986) Parallel organization of functionally segregated circuits linking basal ganglia and cortex. Annual Review of Neuroscience, 9, 357-381. doi:10.1146/

[49]   Albin, R.L., Young, A.B. and Penney, J.B. (1989) The functional anatomy of basal ganglia disorders. Trends in Neurosciences, 10, 366-375. doi:10.1016/0166-2236(89)90074-X

[50]   DeLong, M.R. (1990) Primate models of movement dis- orders of basal ganglia origin. Trends in Neurosciences, 7, 281-285. doi:10.1016/0166-2236(90)90110-V

[51]   Bamford, N.S., Robinson, S., Palmiter, R.D., Joyce, J.A., Moore, C. and Meshul, C.K. (2004) Dopamine modulates release from corticostriatal terminals. The Journal of Neuroscience, 43, 9541-9552. doi:10.1523/JNEUROSCI.2891-04.2004

[52]   Gerfen, C.R., Engber, T.M., Mahan, L.C., Susel, Z., Chase, T.N., Monsma, F.J., Jr. and Sibley, D.R. (1990) D1 and D2 dopamine receptor-regulated gene expression of striatonigral and striatopallidal neurons. Science, 4986, 1429-1432. doi:10.1126/science.2147780

[53]   Kravitz, A.V., Freeze, B.S., Parker, P.R., Kay, K., Thwin, M.T., Deisseroth, K. and Kreitzer, A.C. (2010) Regulation of parkinsonian motor behaviours by optogenetic control of basal ganglia circuitry. Nature, 7306, 622-626. doi:10.1038/nature09159

[54]   Kempster, P.A., O’Sullivan, S.S., Holton, J.L., Revesz, T. and Lees, A.J. (2010) Relationships between age and late progression of Parkinson’s disease: A clinico-pathological study. Brain, Pt 6, 1755-1762. doi:10.1093/brain/awq059

[55]   Scarpa, M., Rigo, A., Maiorino, M., Ursini, F. and Grego- lin, C. (1984) Formation of al-pha-tocopherol radical and recycling of alpha-tocopherol by ascorbate during peroxidation of phosphatidylcholine lipo-somes. An electron paramagnetic resonance study. Biochimica et Biophysica Acta, 2, 215-219. doi:10.1016/0304-4165(84)90070-9

[56]   Lew, M.F. (2011) The evidence for disease modification in Parkinson’s disease. International Journal of Neuroscience, 121, 18-26. doi:10.3109/00207454.2011.620194

[57]   Fahn, S. (1991) An open trial of high-dosage antioxidants in early Parkinson’s disease. The American Journal of Clinical Nutrition, 1, 380S-382S.

[58]   Burne, T.H., McGrath, J.J., Eyles, D.W. and Mackay-Sim, A. (2005) Behavioural characterization of vitamin D receptor knockout mice. Behavioural Brain Research, 2, 299-308. doi:10.1016/j.bbr.2004.07.008

[59]   Baluchnejadmojarad, T., Roghani, M., Nadoushan, M.R. and Bagheri, M. (2009) Neuroprotective effect of genistein in 6-hydroxydopamine hemi-parkinsonian rat model. Phytotherapy Research, 1, 132-135. doi:10.1002/ptr.2564

[60]   Bousquet, M., Calon, F. and Cicchetti, F. (2011) Impact of omega-3 fatty acids in Park-inson's disease. Ageing Research Reviews, 4, 453-463. doi:10.1016/j.arr.2011.03.001

[61]   Chang, Y.L., Chen, S.J., Kao, C.L., Hung, S.C., Ding, D.C., Yu, C.C., Chen, Y.J., Ku, H.H., Lin, C.P., Lee, K.H. Y., Chen, C., Wang, J.J., Hsu, C.C., Chen, L.K., Li, H.Y. and Chiou, S.H. (2012) Docosahexaenoic acid promotes dopaminergic differentiation in induced pluripo-tent stem cells and inhibits teratoma formation in rats with Parkinson-like pathology. Cell Transplantation, 1, 313-332.

[62]   Sakayori, N., Maekawa, M., Numayama-Tsuruta, K., Katura, T., Moriya, T. and Osumi, N. (2011) Distinctive effects of arachidonic acid and docosahexaenoic acid on neural stem /progenitor cells. Genes Cells, 7, 778-790. doi:10.1111/j.1365-2443.2011.01527.x

[63]   Li, S.C., Schoen-berg, B.S., Wang, C.C., Cheng, X.M., Rui, D.Y., Bolis, C.L. and Schoenberg, D.G. (1985) A prevalence survey of Parkinson’s disease and other movement disorders in the People’s Republic of China. Archives of Neurology, 7, 655-657. doi:10.1001/archneur.1985.04060070045013

[64]   Zhang, Z.X. and Roman, G.C. (1993) Worldwide occur- rence of Parkinson’s disease: An updated review. Neuroepidemiology, 4, 195-208. doi:10.1159/000110318

[65]   Barranco Quintana, J.L., Allam, M.F., Del Castillo, A.S. and Navajas, R.F. (2009) Parkinson’s disease and tea: A quantitative review. Journal of the American College of Nutrition, 1, 1-6.

[66]   Zhang, X., Xie, W., Qu, S., Pan, T., Wang, X. and Le, W. (2005) Neuroprotection by iron chelator against proteasome inhibitor-induced nigral degeneration. Biochemical and Biophysical Research Communication, 2, 544-549. doi:10.1016/j.bbrc.2005.05.150

[67]   Gal, M., Hromadova, M., Pospisil, L., Hives, J., Sokolova, R., Kolivoska, V. and Bulickova, J. (2010) Voltammetry of hypoxic cells radiosensitizer etanidazole radical anion in water. Bioelectrochemistry, 2, 118-123. doi:10.1016/j.bioelechem.2009.08.008

[68]   Ghosh, B., Antonio, T., Reith, M.E. and Dutta, A.K. (2010) Discovery of 4-(4-(2-((5-Hydroxy-1,2,3,4-tetra-hydronaphtha-len-2-yl)(propyl)amino)ethyl)piperazin-1-yl) quinolin-8-ol and its analogues as highly potent dopamine D2/D3 agonists and as iron chelator: In vivo activity indicates potential application in symptomatic and neuro- protective therapy for Parkinson’s disease. Journal of the Medicinal Chemistry, 5, 2114-2125. doi:10.1021/jm901618d

[69]   Ascherio, A., Weisskopf, M.G., O’Reilly, E.J., McCullough, M.L., Calle, E.E., Rodriguez, C. and Thun, M.J. (2004) Coffee consumption, gender, and Parkinson’s dis- ease mortality in the cancer prevention study II cohort: The modifying effects of estrogen. American Journal of Epidemiology, 10, 977-984. doi:10.1093/aje/kwh312

[70]   Fredholm, B.B., Battig, K., Holmen, J., Nehlig, A. and Zvartau, E.E. (1999) Actions of caffeine in the brain with special reference to factors that contribute to its widespread use. Pharmacological Reviews, 1, 83-133.

[71]   Trinh, K., Andrews, L., Krause, J., Hanak, T., Lee, D., Gelb, M. and Pallanck, L. (2010) Decaffeinated coffee and nicotine-free tobacco provide neuroprotection in Drosophila models of Parkinson’s disease through an NRF2-dependent mechanism. The Journal of Neuroscience, 16, 5525-5532. doi:10.1523/JNEUROSCI.4777-09.2010

[72]   Simoes, A.P., Duarte, J.A., Agasse, F., Canas, P.M., Tome, A.R., Agostinho, P. and Cunha, R.A. (2012) Blockade of adenosine A2A receptors prevents interleukin-1beta-induced exacerbation of neuronal toxicity through a p38 mitogen-activated protein kinase pathway. Journal of Neuroinflammation, 204. doi:10.1186/1742-2094-9-204

[73]   Alfinito, P.D., Wang, S.P., Manzino, L., Rijhsinghani, S., Zeevalk, G.D. and Sonsalla, P.K. (2003) Adenosinergic protection of dopaminergic and GABAergic neurons against mitochondrial inhibition through receptors located in the substantia nigra and striatum, respectively. The Journal of Neuroscience, 34, 10982-10987.

[74]   Birkmayer, W., Riederer, P., Youdim, M.B. and Linauer, W. (1975) The potentiation of the anti akinetic effect after L-dopa treatment by an inhibitor of MAO-B, Deprenil. Journal of Neural Transmission, 3-4, 303-326. doi:10.1007/BF01253131

[75]   Riederer, P. and Laux, G. (2011) MAO-inhibitors in Parkinson’s disease. Experimental Neurobiology, 1, 1-17.

[76]   Jenner, P. and Langston, J.W. (2011) Explaining ADAGIO: A critical review of the biological basis for the clinical effects of rasagiline. Movement Disorders, 13, 2316-2323. doi:10.1002/mds.23926

[77]   Nyholm, D., Johansson, A., Lennernas, H. and Askmark, H. (2012) Levodopa infusion combined with entacapone or tolcapone in Parkinson disease: A pilot trial. European Journal of Neurology, 6, 820-826. doi:10.1111/j.1468-1331.2011.03614.x

[78]   Hauser, R.A., Schapira, A.H., Rascol, O., Barone, P., Mizuno, Y., Salin, L., Haaksma, M., Juhel, N. and Poewe, W. (2010) Randomized, double-blind, multicenter evalua- tion of pramipexole extended release once daily in early Parkinson's disease. Movement Disorders, 15, 2542-2549. doi:10.1002/mds.23317

[79]   Whone, A.L., Watts, R.L., Stoessl, A.J., Davis, M., Reske, S., Nahmias, C., Lang, A.E., Rascol, O., Ribeiro, M.J., Remy, P., Poewe, W.H., Hauser, R.A. and Brooks, D.J. (2003) Slower progression of Parkinson’s disease with ropinirole versus levodopa: The REAL-PET study. Annals of Neurology, 1, 93-101. doi:10.1002/ana.10609

[80]   (2003) A controlled trial of rotigotine monotherapy in early Parkinson’s disease. Archives of Neurology, 12, 1721- 1728.

[81]   Jones, C.A., Johnston, L.C., Jackson, M.J., Smith, L.A., van Scharrenburg, G., Rose, S., Jenner, P.G. and McCreary, A.C. (2010) An in vivo pharmacological evaluation of pardoprunox (SLV308)—a novel combined dopamine D(2)/D(3) receptor partial agonist and 5-HT(1A) receptor agonist with efficacy in experimental models of Parkinson's disease. European Neuropsychopharmacology, 8, 582-593. doi:10.1016/j.euroneuro.2010.03.001

[82]   Rascol, O., Bronzova, J., Hauser, R.A., Lang, A.E., Sampaio, C., Theeuwes A. and van de Witte, S.V. (2012) Pardoprunox as adjunct therapy to levodopa in patients with Parkinson’s disease experiencing motor fluctuations: Results of a double-blind, randomized, placebo-controlled, trial. Parkinsonism & Related Disorders, 4, 370-376. doi:10.1016/j.parkreldis.2011.12.006

[83]   Bonuccelli, U., Piccini, P. and Rabey, J.M. (2009) Old and new dopamine agonists in Parkinson’s disease: A reappraisal. Introduction. Parkinsonism & Related Disor- ders, 15, S1. doi:10.1016/S1353-8020(09)00312-5

[84]   Yoshioka, M., Tanaka, K., Miyazaki, I., Fujita, N., Higashi, Y., Asanuma, M. and Ogawa, N. (2002) The dopa-mine agonist cabergoline provides neuroprotection by activation of the glutathione system and scavenging free radicals. Neuroscience Research, 3, 259-267. doi:10.1016/S0168-0102(02)00040-8

[85]   Katayama, S. (2001) Actigraph analysis of diurnal motor fluctuations during dopamine agonist therapy. European Neurology, 46, 11-17. doi:10.1159/000058048

[86]   Bracco, F., Battaglia, A., Chouza, C., Dupont, E., Gershanik, O., Marti Masso, J.F. and Montastruc, J.L. (2004) The long-acting dopamine receptor agonist cabergoline in early Parkinson’s disease: Final results of a 5-year, double-blind, levodopa-controlled study. CNS Drugs, 11, 733- 746. doi:10.2165/00023210-200418110-00003

[87]   Calabresi, P., Centonze, D., Gubellini, P., Pisani, A. and Bernardi, G. (2000) Acetylcholine-mediated modulation of striatal function. Trends Neuroscience, 3, 120-126. doi:10.1016/S0166-2236(99)01501-5

[88]   Luginger, E., Wenning, G.K., Bosch, S. and Poewe, W. (2000) Beneficial effects of amantadine on L-dopa-induced dyskinesias in Parkinson’s disease. Movement Disorders, 5, 873-878. doi:10.1002/1531-8257(200009)15:5<873::AID-MDS1017>3.0.CO;2-I

[89]   Crosby, N.J., Deane, K.H. and Clarke, C.E. (2003) Amantadine for dyskinesia in Parkinson’s disease. The Cochrane Database of Systematic Reviews, 2, CD003467.

[90]   Gorell, J.M., Rybicki, B.A., Johnson, C.C. and Peterson, E.L. (1999) Smoking and Parkinson’s disease: A dose-response relationship. Neurology, 1, 115-119. doi:10.1212/WNL.52.1.115

[91]   Baron, J.A. (1986) Cigarette smoking and Parkinson’s disease. Neurology, 11, 1490-1496. doi:10.1212/WNL.36.11.1490

[92]   Grandinetti, A., Morens, D.M., Reed, D. and MacEachern, D. (1994) Prospective study of cigarette smoking and the risk of developing idiopathic Parkinson’s disease. Ameri- can Journal of Epidemiology, 12, 1129-1138.

[93]   Morens, D.M., Grandinetti, A., Davis, J.W., Ross, G.W., White, L.R. and Reed, D. (1996) Evidence against the operation of selective mortality in explaining the associa- tion between cigarette smoking and reduced occurrence of idiopathic Parkinson disease. American Journal of Epidemiology, 4, 400-404. doi:10.1093/oxfordjournals.aje.a008941

[94]   Thacker, E.L., O’Reilly, E.J., Weisskopf, M.G., Chen, H., Schwarzschild, M.A., McCullough, M.L., Calle, E.E., Thun, M.J. and Ascherio, A. (2007) Temporal relationship between cigarette smoking and risk of Parkinson disease. Neurology, 10, 764-768. doi:10.1212/01.wnl.0000256374.50227.4b

[95]   Quik, M. (2004) Smoking, nicotine and Parkinson’s disease. Trends in Neuroscience, 9, 561-568. doi:10.1016/j.tins.2004.06.008

[96]   Jeyarasasingam, G., Tompkins, L. and Quik, M. (2002) Stimulation of non-alpha7 nicotinic receptors partially protects dopaminergic neurons from 1-methyl-4-phenyl- pyridinium-induced toxicity in culture. Neuroscience, 2, 275-285. doi:10.1016/S0306-4522(01)00488-2

[97]   Ryan, R.E., Ross, S.A., Drago, J. and Loiacono, R.E. (2001) Dose-related neuroprotective effects of chronic nicotine in 6-hydroxydopamine treated rats, and loss of neuroprotection in alpha4 nicotinic receptor subunit knock-out mice. British Journal of Pharmacology, 8, 1650- 1656. doi:10.1038/sj.bjp.0703989

[98]   Soto-Otero, R., Mendez-Alvarez, E., Hermida-Ameijeiras, A., Lopez-Real, A.M. and Labandeira-Garcia, J.L. (2002) Effects of (-)-nicotine and (-)-cotinine on 6-hydroxy-do- pamine-induced oxidative stress and neurotoxicity: Relevance for Parkinson’s disease. Biochemical Pharmacol- ogy, 1, 125-135. doi:10.1016/S0006-2952(02)01070-5

[99]   Visanji, N.P., O’Neill, M.J. and Duty, S. (2006) Nicotine, but neither the alpha4beta2 ligand RJR2403 nor an alpha7 nAChR subtype selective agonist, protects against a partial 6-hydroxydopamine lesion of the rat median forebrain bundle. Neuropharmacology, 3, 506-516. doi:10.1016/j.neuropharm.2006.04.015

[100]   Quik, M., Parameswaran, N., McCallum, S.E., Bordia, T., Bao, S., McCormack, A., Kim, A., Tyndale, R.F., Langston, J.W. and Di Monte, D.A. (2006) Chronic oral nicotine treatment protects against striatal degeneration in MPTP- treated primates. Journal of Neurochemistry, 6, 1866- 1875. doi:10.1111/j.1471-4159.2006.04078.x

[101]   Bordia, T., Parameswaran, N., Fan, H., Langston, J.W., McIntosh, J.M. and Quik, M. (2006) Partial recovery of striatal nicotinic receptors in 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP)-lesioned monkeys with chronic oral nicotine. Journal of Pharmacology and Experimental Therapeutics, 1, 285-292. doi:10.1124/jpet.106.106997

[102]   Costa, G., Abin-Carriquiry, J.A. and Dajas, F. (2001) Nicotine prevents striatal dopamine loss produced by 6-hydroxydopamine lesion in the substantia nigra. Brain Research, 2, 336-342. doi:10.1016/S0006-8993(00)03087-0

[103]   Behmand, R.A. and Harik, S.I. (1992) Nicotine enhances 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine neurotoxicity. Journal of Neurochemistry, 2, 776-779. doi:10.1111/j.1471-4159.1992.tb09786.x

[104]   Moll, H. (1926) The treatment of post-encephalitig park- insonism by nicotine. British Medical Journal, 3416, 1079-1081. doi:10.1136/bmj.1.3416.1079

[105]   Villafane, G., Cesaro, P., Rialland, A., Baloul, S., Azimi, S., Bourdet, C., Le Houezec, J., Macquin-Mavier, I. and Maison, P. (2007) Chronic high dose transdermal nicotine in Parkinson’s disease: An open trial. European Journal of Neurology, 12, 1313-1316. doi:10.1111/j.1468-1331.2007.01949.x

[106]   Fagerstrom, K.O., Pomerleau, O., Giordani, B. and Stel- son, F. (1994) Nicotine may relieve symptoms of Parkin- son’s disease. Psychophar-macology (Berl), 1, 117-119. doi:10.1007/BF02244882

[107]   Bordia, T., Campos, C., Huang, L. and Quik, M. (2008) Continuous and intermittent nicotine treatment reduces L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyski- nesias in a rat model of Parkinson’s disease. Journal of Pharmacology and Experimental Therapeutics, 1, 239- 247. doi:10.1124/jpet.108.140897

[108]   Picciotto, M.R. and Zoli, M. (2008) Neuroprotection via nAChRs: The role of nAChRs in neurodegenerative dis- orders such as Alzheimer’s and Parkinson’s disease. Frontiers in Bioscience, 13, 492-504. doi:10.2741/2695

[109]   Lindvall, O., Bjorklund, A. and Skagerberg, G. (1984) Selective histochemical demonstration of dopamine terminal systems in rat di- and telencephalon: new evidence for dopaminergic innervation of hypothalamic neuros cretory nuclei. Brain Research, 1-2, 19-30. doi:10.1016/0006-8993(84)90352-4

[110]   Dehorter, N., Guigoni, C., Lopez, C., Hirsch, J., Eusebio, A., Ben-Ari, Y. and Hammond, C. (2009) Dopamine-deprived striatal GABAergic interneurons burst and gener- ate repetitive gigantic IPSCs in medium spiny neurons. The Journal of Neuroscience, 24, 7776-7787. doi:10.1523/JNEUROSCI.1527-09.2009

[111]   Xiao, C., Nashmi, R., McKinney, S., Cai, H., McIntosh, J. M. and Lester, H.A. (2009) Chronic nicotine selectively enhances alpha4beta2* nicotinic acetylcholine receptors in the nigrostriatal dopamine pathway. The Journal of Neuroscience, 40, 12428-12439. doi:10.1523/JNEUROSCI.2939-09.2009

[112]   Gittis, A.H., Leventhal, D.K., Fensterheim, B.A., Pettibone, J.R., Berke, J.D. and Kreitzer, A.C. (2011) Selective inhibition of striatal fast-spiking interneurons causes dyskinesias. The Journal of Neuroscience, 44, 15727- 15731. doi:10.1523/JNEUROSCI.3875-11.2011

[113]   Gregorio, M.L., Wietzikoski, E.C., Ferro, M.M., Silveira, J.L., Vital, M.A. and Da Cunha, C. (2009) Nicotine induces sensitization of turning behavior in 6-hydroxy-dopamine lesioned rats. Neurotoxicity Research, 4, 359-366. doi:10.1007/s12640-009-9041-1

[114]   Zhao-Shea, R., Cohen, B.N., Just, H., McClure-Begley, T., Whiteaker, P., Grady, S.R., Salminen, O., Gardner, P.D., Lester, H.A. and Tapper, A.R. (2010) Dopamine D2-receptor activation elicits akinesia, rigidity, catalepsy, and tremor in mice expressing hypersensitive {alpha}4 nicotinic receptors via a cholinergic-dependent mechanism. The FASEB Journal, 1, 49-57. doi:10.1096/fj.09-137034

[115]   Kalivas, P.W., Churchill, L. and Klitenick, M.A. (1993) GABA and enkephalin projection from the nucleus ac- cumbens and ventral pallidum to the ventral tegmental area. Neuroscience, 4, 1047-1060. doi:10.1016/0306-4522(93)90048-K

[116]   McGehee, D.S., Heath, M.J., Gelber, S., Devay, P. and Role, L.W. (1995) Nicotine enhancement of fast excitatory synaptic transmission in CNS by presynaptic recep- tors. Science, 5231, 1692-1696. doi:10.1126/science.7569895

[117]   Ribeiro, E.B., Bettiker, R.L., Bogdanov, M. and Wurtman, R.J. (1993) Effects of systemic nicotine on serotonin re- lease in rat brain. Brain Research, 2, 311-318. doi:10.1016/0006-8993(93)90121-3

[118]   Boyadjieva, N.I. and Sarkar, D.K. (1997) The secretory response of hypothalamic beta-endorphin neurons to acute and chronic nicotine treatments and following nicotine withdrawal. Life Science, 6, PL59-66.

[119]   Pierzchala, K., Houdi, A.A. and Van Loon, G.R. (1987) Nicotine-induced alterations in brain regional concentrations of native and cryptic Met- and Leu-enkephalin. Pep- tides, 6, 1035-1043. doi:10.1016/0196-9781(87)90133-1

[120]   de Rover, M., Lodder, J.C., Kits, K.S., Schoffelmeer, A.N. and Brussaard, A.B. (2002) Cholinergic modulation of nucleus accumbens medium spiny neurons. European Journal of Neuroscience, 12, 2279-2290. doi:10.1046/j.1460-9568.2002.02289.x

[121]   Gittis, A.H., Nelson, A.B., Thwin, M.T., Palop, J.J. and Kreitzer, A.C. (2010) Distinct roles of GABAergic in- terneurons in the regulation of striatal output pathways. The Journal of Neuroscience, 6, 2223-2234. doi:10.1523/JNEUROSCI.4870-09.2010

[122]   García-Montes, J.R., Boronat-García, A., López-Colomé, A.M., Bargas, J., Guerra-Crespo, M. and Drucker-Colín, R. (2012) Is nicotine protective against Parkinson’s disease? An experimental analysis. CNS & Neurological Disorders-Drug Targets, in press.