Comparison of Mono-dopaminergic and Multi-target Pharmacotherapies in Primary Parkinson Syndrome and Assessment Tools to Evaluate Motor and Non-motor Symptoms

Author(s): Felix-Martin Werner*, Rafael Coveñas.

Journal Name: Current Drug Therapy

Volume 14 , Issue 2 , 2019

Become EABM
Become Reviewer

Graphical Abstract:


Abstract:

Background: Primary Parkinson syndrome is mostly treated by dopaminergic drugs, while the progression of the disease is not altered. Some non-dopaminergic are available, which are administered only after the Parkinsonian symptoms get worse.

Objective: The objective of this review is to give basic results in order to compare a dopaminergic and non-dopaminergic pharmacotherapy in Parkinson’s disease and to control whether the add-on pharmacotherapy with non-dopaminergic drugs can inhibit the progression of the disease.

Methods: In primary Parkinson syndrome, the altered activity of classical neurotransmitters and neuropeptides in the extrapyramidal system is summarized and up-dated. Anatomical studies on neural networks in the basal ganglia are mentioned. The direct, motor facilitatory pathway (D1 dopaminergic neurons) from the substantia nigra to the thalamus, via the internal globus pallidus, and the indirect, motor inhibitory pathway via D2 dopaminergic neurons have been considered. These established anatomical pathways have been brought in line with the neural interactions derived from neurotransmitter balances or imbalances. Besides, preclinical and clinical studies of effective non-dopaminergic anti-Parkinsonian drugs are reviewed.

Results: It can be hypothesized that glutamatergic neurons enhance dopamine deficiency in the substantia nigra and putamen through an increased presynaptic inhibition mediated by NMDA receptors. In the putamen, 5-HT2A serotonergic neurons counteract D2 dopaminergic neurons and A2A adenosine neurons antagonize D2 dopaminergic neurons by activating glutamatergic neurons, which presynaptically inhibit via subtype 5 of metabotropic glutamatergic receptors, D2 dopaminergic neurons. In the extrapyramidal system, an up-dated neural network, which harmonizes established anatomical pathways with derived neural interactions, is presented. In Parkinson’s disease, a question should be answered, whether a combination of dopaminergic and non-dopaminergic drugs can promote an increased motor and non-motor functioning.

Conclusion: A mono-target pharmacotherapy (using only dopaminergic drugs) and a multi-target pharmacotherapy (i.e. by combining dopaminergic and non-dopaminergic drugs) are compared. The alternate administration of dopaminergic and non-dopaminergic anti-Parkinsonian drugs, administered at different times during the day, must be tested in order to inhibit the progression of the disease. Assessment tools can be used to evaluate motor and cognitive functions. Moreover, imaging examination techniques can be also applied to control the course of the disease.

Keywords: A2A adenosine antagonist, basal ganglia, dopamine, mono-dopaminergic pharmacotherapy, multi-target pharmacotherapy, neural network, NMDA receptor antagonist.

[1]
Werner FM, Coveñas R. Classical neurotransmitters and neuropeptides involved in Parkinson’s disease: focus on anti-Parkinsonian drugs. Curr Drug Ther 2015; 10: 66-81.
[2]
Garzorz N. Extrapyramidales System.In: Neuroanatomie; Garzoz N. Elsevier: München 2009; pp. 120-1.
[3]
Chase TN, Oh JD, Blanchet PJ. Neostriatal mechanism in Parkinson’s disease. Neurology 1998; 39: 7-11.
[4]
Werner FM, Coveñas R. Classical neurotransmitters and neuropeptides involved in Parkinson’s disease: an enlarged neural network. Basal Ganglia 2011; 1: 17.
[5]
Ansah TA, Ferguson MD, Nayyar T. The 5-HT(2A) receptor antagonist M-100,907 produces antiparkinsonian effects and decreases striatal glutamate. Front Syst Neurosci 2011; 5: 48.
[6]
Liu QR, Canseco-Alba A, Zhang HY, et al. Cannabinoid type 2 receptors in dopamine neurons inhibit psychomotor behaviors, alters anxiety, depression and alcohol preference. Sci Rep 2017; 7: 17410.
[7]
Werner FM, Coveñas R. Vergleich einer monodopaminergen Pharmakotherapie miteiner multimodalen Pharmakotherapie des Morbus Parkinson. Neurol Rehabil 2017; (Suppl. 1)S47-8.
[8]
Berlanga ML, Simpson TK, Alcantara AA. Dopamine D5 receptor localization on cholinergic neurons of the rat forebrain and diencephalon: a potential neuroanatomical substrate involved in mediating dopaminergic influences on acetylcholine release. J Comp Neurol 2005; 492: 34-49.
[9]
Werner FM, Coveñas R. Assessments in primary Parkinson syndrome for comparison between mono-dopaminergic and multi-target anti-Parkinsonian pharmacotherapies. J Med Diagn Meth 2017; 6: 2.
[10]
Pérez LM, Farricis C, Puente V, Planas J, Ruiz J. The use of subcutaneous scopolamine as a palliative treatment in Parkinson’s disease. Palliat Med 2011; 25: 92-3.
[11]
Huang LZ, Grady SR, Quik M. Nicotine reduces L-DOPA-induced dyskinesia by acting at beta2* nicotinic receptors. J Pharmacol Exp Ther 2011; 338: 932-41.
[12]
Riahi G, Morissette M, Parent M, Di Paolo T. Brain 5-HT2A receptors in MPTP monkeys and levodopa-induced dyskinesia. Eur J Neurosci 2011; 33: 1823-31.
[13]
Markham A. Pimavanserin: a first global approval. Drugs 2016; 76: 1053-7.
[14]
Fergusson MC, Nayyar T, Ansah TA. Reverse microdialysis of a 5-HT2A receptor antagonist alters extracellular glutamate levels in the striatum of the MPTP mouse model of Parkinson’s disease. Neurochem Int 2014; 71: 36-46.
[15]
Rascol O, Lozano A, Stern M, Poewe W. Milestones in Parkinson’s disease therapeutics. Mov Disord 2011; 26: 1072-82.
[16]
Diguid IC, Smart TG. Presynaptic NMDA receptors. J Neurosci 2010; 30: 14440-5.
[17]
Huang YH, Ishikawa M, Lee BR, Nakanishi N, Schlüter OM, Dong Y. Searching for presynaptic NMDA receptors in the nucleus accumbens. J Neurosci 2011; 31: 8453-63.
[18]
Lindemann L, Jaeschke G, Michalon A, et al. CTEP: a novel, potent, long-acting and orally bioavialable mGlu5 inhibitor. J Pharmacol Exp Ther 2011; 339: 474-86.
[19]
Ammari R, Bioulac B, García DF, Hammond C. The subthalamic nucleus becomes a generator in the dopamine-depleted state. Its high frequency stimulation dramatically weakesn transmission to the globus pallidus. Front Syst Neurosci 2011; 4: 43.
[20]
Gajcy K, Lochynski S, Librowski T. A role of GABA analogues in the treatment of neurological diseases. Curr Med Chem 2010; 17: 2338-47.
[21]
Jenner P. A2A antagonists as novel non-dopaminergic therapy for motor dysfunction in PD. Neurology 2003; 61: S32-8.
[22]
Sako W, Murakami N, Motohama K, Izumi Y, Kaji R. The effect of istradefylline for Parkinson’s disease: a meta-analysis. Sci Rep 2017; 7: 18018.
[23]
Bogenpohl JW, Ritter SL, Hall RA, Smith Y. Adenosine A(2A) receptor in the monkey basal ganglia: ultrastructural localization and co-localization with the metabotropic glutamate receptor 5 in the striatum. J Comp Neurol 2012; 520: 570-89.
[24]
Lim K, See YM, Lee J. A Systematic review of the effectiveness of medical cannabis for psychiatric, movement and neurodegenerative disorders. Clin Psychopharmacol Neurosci 2017; 15: 301-12.
[25]
Shi J, Cai Q, Zhang J, He X, Liu Y, Zhu R, et al. AM-1,241 alleviates MPTP-induced Parkinson’s disease and promotes the regeneration of DA in PD mice. Oncotarget 2017; 8: 87837-50.
[26]
McGinty JF. Co-localization of GABA with other neuroactive substances in the basal ganglia. Prog Brain Res 2007; 160: 273-84.
[27]
Buxton D, Bracci E, Overton PG, Gurney K. Striatal neuropeptides enhance selection and rejection of sequential actions. Front Comput Neurosci 2017; 11: 62.
[28]
Ljundahl A, Hanrieder J, Fälth M, Bergquist J, Andersson M. Imaging mass spectrometry reveals elevated nigral levels of dynorphin neuropeptides in L-DOPA-induced dyskinesia in rat model of Parkinson’s disease. PLoS One 2011; 6e25653
[29]
Antonelli T, Tomasini MC, Finetti S, et al. Neurotensin enhances glutamate excitotoxicity in mesencephalic neurons in primary culture. J Neurosci Res 2002; 70: 766-73.
[30]
Thornton E, Tran TT, Vink R. A substance P mediated pathway contributes to 6-hydroxydopamine induced cell death. Neurosci Lett 2010; 481: 64-7.
[31]
Govindaiah G, Wang Y, Cox L. Substance selectively modulates GABA(A) receptor-mediated synaptic transmission in striatal cholinergic interneurons. Neuropharmacology 2010; 58: 413-22.
[32]
Herring WJ, Assaid C, Budd K, et al. A Phase Ib randomized controlled study to evaluate the effectiveness of a single-dose of the NR2B selective N-Methyl-D-Aspartate antagonist MK-657 on levodopa-induced dyskinesias and motor symptoms in patients with Parkinson disease. Clin Neuropharmacol 2017; 40: 255-60.
[33]
Michel A, Nicolas JM, Rose S, et al. Antiparkinsonian effects of the “Radiprodil and Tozadenant” combination in MPTP-treated marmosets. PLoS One 2017; 12e0182887
[34]
Fergusson MC, Nayyar T, Deutch AY, Ansah TA. 5-HT2A receptor antagonists improve motor impairments in MPTP mouse model of Parkinson’s disease. Neuropharmacology 2010; 59: 31-6.
[35]
Werner FM, Coveñas R. Classical neurotransmitter and neuropeptides involved in schizophrenia: how to choose the appropriate antipsychotic drug? Curr Drug Ther 2013; 8: 132-43.
[36]
Wang X, Han C, Xu Y, et al. Synthesis and evaluation of phenylxanthine derivates as potential dual A2AR antagonists/MAO-B inhibitors for Parkinson’s disease. Molecules 2017; 22: pii:E1010
[37]
Maranis S, Stamatis D, Tsironis C, Konitsiotis S. Investigation of the antidyskinetic site of action of metabotropic and ionotropic glutamte receptors antagonists. Intracerebral infusions in 6-hydroxydopamine-lesioned rats with levodopa-induced dyskinesia. Eur J Pharmacol 2012; 683: 71-7.
[38]
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: 166-79.
[39]
Kataoka H, Sawada Y, Namizaki T, Shimozato N, Yoshiji H, Ueno S. Intrajejunal infusion of levodopa-carbidopa gel can continuously reduce the severity of dropped head in Parkinson’s disease. Front Neurol 2017; 8: 547.
[40]
Millage B, Vesey E, Finkelstein M, Anheluk M. Effect on gait speed, balance, motor symptom rating, and quality of life in those with stage I Parkinson’s disease utilizing LSVT BIGR. Rehabil Res Pract 2017; 20179871070
[41]
FitzGerald JJ, Lu Z, Jarenosettasin P, Antoniades CA. Quantifying motor impairment in movement disorders. Front Neurosci 2018; 12: 202.
[42]
Wyman-Chick KA, Martin PK, Barrett MJ, Manning CA, Sperling SA. Diagnostic accuracy and confidence in the clinical detection of cognitive impairment in early-stage Parkinson disease. J Geriatr Psychiatry Neurol 2017; 30: 178-83.
[43]
Katunina E, Titova N. The epidemiology of non-motor symptoms in Parkinson’s disease (cohort and other studies). Int Rev Neurobiol 2017; 91-110.
[44]
Saeed U, Compagnone J, Aviv RJ, et al. Imaging biomarkers in Parkinson’s disease and Parkinsonian syndromes: current and emerging concepts. Transl Neurodener 2017; 28: 6-8.


Rights & PermissionsPrintExport Cite as

Article Details

VOLUME: 14
ISSUE: 2
Year: 2019
Page: [124 - 134]
Pages: 11
DOI: 10.2174/1574885513666181115104137
Price: $65

Article Metrics

PDF: 45
HTML: 2
EPUB: 1
PRC: 1

Special-new-year-discount