Clinical Studies and Therapies in Parkinson's Disease: Translations from Preclinical Models

By Juan Segura-Aguilar

More than 50 years have passed since the use of L-dopa in the palliative treatment of Parkinson’s disease, but it remains the most common treatment despite inducing severe side effects such as dyskinesia after 4–6 years of use. Numerous preclinical investigations based on endogenous neurotoxin models have promised various therapies for Parkinson’s disease, but these efforts have failed when attempting to transfer these successful results to preclinical studies. Although several publications have warned of these failures, the scientific community remains mostly unaware, and there is a need to focus their efforts on potential therapeutics that can slow or halt development of the disease.

Clinical Studies and Therapies in Parkinson’s Disease: Translations from Preclinical Models analyzes preclinical models based on exogenous neurotoxins and why they have failed. Neuroscientists, neurologists, and neuropharmacologists will benefit greatly from the book’s discussion of these newer models, their benefits, and the need for their implementation. This book also provides the basic concepts of dopamine metabolism for students taking courses in neurochemistry, neuroscience, neuropharmacology, biochemistry, and medicine.

• Reviews Parkinson's disease classification, pharmacological therapies, and nonmotor and motor symptoms
• Analyzes preclinical models of Parkinson’s disease therapies based on exogenous neurotoxins and why they have failed
• Reviews genetic preclinical models based on genetic mutations and endogenous neurotoxins
• Proposes a more physiological model directly related to the metabolism of dopaminergic neurons
• Provides the basic concepts and mechanisms of dopamine metabolism

• Language: English
• Publisher: Academic Press
• Release date: Jun 12, 2021
• ISBN: 9780128221587

Juan Segura-Aguilar

Dr. Juan Segura-Aguilar, PhD, is a professor of molecular and clinical pharmacology at the University of Chile, Santiago, Chile. He obtained his PhD in biochemistry from Stockholm University, Stockholm, Sweden in 1989. He was previously an associate professor at Uppsala University, Uppsala, Sweden. In 1998, he began as an associate professor at University of Chile, and since 2001 has been a full professor. His research has been focused on mechanisms involved in dopaminergic neuron degeneration in Parkinson´s disease. He has more than 140 publications of his research work on neurodegenerative disorders.

Book preview

Clinical Studies and Therapies in Parkinson's Disease

Translations from Preclinical Models

Juan Segura-Aguilar

University of Chile, Santiago, Chile

Table of Contents

Cover image

Title page

Copyright

Dedication

Chapter 1. Parkinson's disease

A. Epidemiology

B. Parkinson's disease classification

C. Parkinsonism

C.2. Paraquat-induced parkinsonism

C.3. Copper-induced parkinsonism

C.4. Manganese-induced parkinsonism

C.5. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine–induced parkinsonism

D. Idiopathic Parkinson’s disease

D.1. Nonmotor symptoms

D.1.1. Olfactory dysfunction

D.1.2. Rapid eye movement sleep behavior disorder

D.1.3. Depression

D.1.4. Constipation

D.1.5. Excessive daytime somnolence

D.1.6. Insomnia

D.1.7. Anxiety

D.1.8. Cognitive decline

D.1.9. Parkinson's disease dementia and dementia with Lewy bodies

D.1.10. Orthostatic hypotension

D.1.11. Visual disturbances

D.2. Motor symptoms

(ii) Alpha-synuclein aggregation to neurotoxic oligomers

D.2.2. Mitochondrial dysfunction

D.2.3. Protein degradation dysfunction role in degeneration of nigrostriatal neurons

D.2.4. Role of oxidative stress in degeneration of nigrostriatal neurons

D.2.5. Neuroinflammation's role in degeneration of nigrostriatal neurons

D.2.6. Role of endoplasmic reticulum stress in degeneration of nigrostriatal neurons

D.3. Diagnosis of idiopathic Parkinson's disease

E. Genetic Parkinson's disease

Chapter 2. Parkinson's pharmacological therapy

Dopaminergic drugs

Anticholinergic drugs

Other pharmacological treatments

New targets and disease-modifying drugs for Parkinson's disease treatment in phase 3

Drugs in clinical trials

Chapter 3. Dopamine synthesis

Tyrosine hydroxylase

Aromatic amino acid decarboxylase

Chapter 4. Dopamine storage and release

Chapter 5. Dopamine oxidative deamination

Monoamine oxidases

Monoamine oxidase-B

Chapter 6. Dopamine methylation

Catechol ortho-methyltransferase

Chapter 7. Dopamine oxidation to neuromelanin and neurotoxic metabolites

Dopamine ortho-quinone

Aminochrome

5,6-Indolequinone

Dopaminochrome

Neuromelanin

Chapter 8. Neuroprotective mechanisms against dopamine oxidation-dependent neurotoxicity

Vesicular monoamine transporter-2

DT-diaphorase

Glutathione transferase-M2-2

Astrocytes neuroprotection against aminochrome neurotoxicity

Chapter 9. Exogenous neurotoxins as a preclinical model for Parkinson's disease

6-Hydroxydopamine

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine

Rotenone

Exogenous neurotoxin preclinical models for Parkinson's disease

Chapter 10. Preclinical models based on genetic mutations associated with the familial form of Parkinson's disease

Chapter 11. Preclinical models based on endogenous neurotoxins

Alpha-synuclein

3,4-Dihydroxyphenylacetaldehyde

Aminochrome

Chapter 12. Conclusions

Index

Copyright

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Dedication

I would like to dedicate this book to Maria Ester Munoz Herrera, my wife and life partner during the difficult times I have lived, including my clandestine fight against the Pinochet dictatorship in Chile, kidnapping and torture by Pinochet's covert intelligence service (DINA), disappearance to the Villa Grimaldi torture center for 3   months, detention in the Tres Alamos concentration camp for 9   months, and eventual exile in Sweden. Maria Ester was a fundamental support who enabled me to study and pursue a doctorate at the University of Stockholm; she cared for my three children so that I could dedicate myself to study. She accompanied me on my return to Chile, where I joined the Faculty of Medicine of the University of Chile. I want to thank Maria Ester—I have been so fortunate to have received all her love and support for nearly 50   years.

Chapter 1: Parkinson's disease

Abstract

Parkinson’s disease is the second-most prevalent neurodegenerative disease after Alzheimer disease. The prevalence in developed countries is 1% in populations over 60 years old, but prevalence increases with age to 4% for those over 80 years of age, suggesting that age is a risk factor in Parkinson’s disease. This chapter review and discuss Parkinsonism induced by drugs such as antipsychotic agents, antidepressants, cholinomimetics, antiemetics, antiepileptic drugs, anti-vertigo medications, calcium channel antagonists and antiarrhythmics; metals such as manganese, iron, and cooper; herbicides such as paraquat and contaminant of illegal such as methyl-4-phenyl-1,2,5,6-tetrahydropyridine. The discovery of genes associated with familial forms of Parkinson’s disease has been an enormous input in Parkinson’s disease field. The idiopathic form of the disease is responsible for 70% Parkinson’s disease patients and role of mitochondrial dysfunction, alpha synuclein aggregation to neurotoxic oligomers, protein degradation dysfunction, oxidative stress, neuroinflammation and endoplasmic reticulum stress in motor symptoms are discussed. The role of olfactory dysfunction, depression, constipation, excessive daytime somnolence, anxiety, rapid-eye-movement sleep behavior disorder, insomnia, cognitive decline, orthostatic hypotension, visual disturbances, and Lewy bodies in non-motor symptoms are review and discussed.

Keywords

1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Alpha-synuclein aggregation; Alpha-synuclein; Antidepressive; Anxiety; Autophagy dysfunction; Autosomal-dominant mutations; Autosomal-recessive mutations; Basal ganglia; Calcium channel antagonists; Cognitive decline; Constipation; Cooper; Corticotropin-releasing hormone; Dementia with Lewy bodies; Depression; Dopamine; Dopamine transporter; Drug-induced parkinsonism; Epidemiology; Excessive daytime somnolence; Genetic Parkinson's disease; Idiopathic Parkinson's disease; Insomnia; L-dopa; Leucine-rich repeat kinase-2; Lewy bodies; Maneb; Manganese; Mild cognitive impairment; Mitochondrial dysfunction; Motor symptoms; NADPH oxidase; Neurodegeneration; Neuroinflammation and endoplasmic reticulum stress; Neuroleptics; Neuromelanin; Nigrostriatal neurons; Nonmotor symptoms; Norepinephrine; Olfactory dysfunction; Oligomers; Orthostatic hypotension; Oxidative stress; Paraquat; Parkin; Parkinson's disease dementia; Parkinsonism; Prevalence; Proteasomal dysfunction; Protein degradation dysfunction; PTEN-induced kinase-1; Rapid eye movement sleep behavior disorder; Serotonin; Vacuolar protein sorting-35; Visual disturbances; Wilson's disease

A. Epidemiology

Parkinson's disease is the second-most prevalent neurodegenerative disease after Alzheimer disease. The prevalence in developed countries is 1% in populations over 60   years old [1,2], but prevalence increases with age to 4% for those over 80   years of age, suggesting that age is a risk factor in Parkinson's disease. A prevalence of 3.5% has been estimated for Parkinson's disease at 85–89   years of age in Europe [3].

The incidence of Parkinson's disease in developed countries is 8 to 18 persons per 100,000 [1]. A meta-analysis of 13 publications showed that the prevalence of Parkinson's disease in China was lower than in developed countries, but the incidence of Parkinson's disease was higher. The prevalence of Parkinson's disease also increases with age in China, and a higher prevalence of Parkinson’s disease was found in men than in women in China [4].

Sex differences in Parkinson's disease prevalence in developed countries is controversial due to some reports suggest a higher prevalence of Parkinson's disease in men than in women, whereas other reports did not find significant differences in Parkinson's disease prevalence between gender [1]. The prevalence of Parkinson's disease in South Africa was 2.8 times higher in white compared with black patients [5].

A global epidemiological study revealed a marked increase in the prevalence of Parkinson's disease by comparing data from 1990 to 2016. In 1990, 2.5 million individuals had Parkinson’s disease globally compared with 6.1 million in 2016. This study also revealed that Parkinson’s disease caused 211,000 deaths in 2016 [6]. These results can be explained by the fact that age is a risk factor for the disease and the increase in life expectancy implies an increase in the number of elderly people who are living longer. However, in this study the increase in prevalence is also observed in most regions when the results are compared by age. This global study also pointed to higher Parkinson's disease prevalence in men than in women and also that industrialized countries experienced the highest increases in mortality and prevalence associated with Parkinson's disease [6].

References

1. de Lau L.M, Breteler M.M. Epidemiology of Parkinson's disease.  Lancet Neurol . 2006;5:525–535.

2. Tysnes O.B, Storstein A. Epidemiology of Parkinson's disease.  J Neural Transm . 2017;124:901–905.

3. Clarke C.E, Moore A.P. Parkinson's disease.  Am Fam Physician . 2007;75:1045–1048.

4. Ma C.L, Su L, Xie J.J, Long J.X, Wu P, Gu L. The prevalence and incidence of Parkinson's disease in China: a systematic review and meta-analysis.  J Neural Transm . 2014;121:123–134.

5. Amod F.H, Bhigjee A.I. Clinical series of Parkinson's disease in KwaZulu-Natal, South Africa: retrospective chart review.  J Neurol Sci . 2019;401:62–65.

6. GBD 2016 Parkinson's Disease Collaborators. Global, regional, and national burden of Parkinson's disease, 1990–2016: a systematic analysis for the global burden of disease study 2016.  Lancet Neurol . 2018;17:939–953.

B. Parkinson's disease classification

The concept of Parkinson’s disease is used indiscriminately without considering the origin of symptoms. Idiopathic Parkinson’s disease is the largest of the parkinsonian groups (70%), and the cause of this disease is still unknown. The second-most important parkinsonian group is those who have a defined reason for motor symptoms, and this group represents about 20% of parkinsonian cases. The third-most important group by number of cases is the familial form of Parkinson's disease, in which the disease is associated with a specific mutation that is responsible for 5% to 10% of total parkinsonian Fig. 1.1.

C. Parkinsonism

C.1. Drug-induced parkinsonism

The second cause of parkinsonism is drug-induced parkinsonism in which parkinsonism is induced by a known agent [1]. The existence of drug-induced parkinsonism is an important factor in erroneous diagnoses in Parkinson's disease. Clinical insecurity in Parkinson’s disease diagnosis is usual when patients are prescribed dopamine-blocking medications; it has been suggested that DAT-SPECT imaging can improve diagnostic certainty [2]. DAT-SPECT imaging is a useful tool in the early diagnosis of Parkinson's disease and allow for other nondegenerative parkinsonian disorders such drug-induced parkinsonism, dystonic tremor, psychogenic parkinsonism and essential tremor to be disregarded because this technique can truthfully detect dopaminergic presynaptic deficit [3,4].

Figure 1.1 Parkinson's disease classification.The largest parkinsonian group is classified as idiopathic Parkinson's disease. The second-largest parkinsonian syndrome group is classified as patients with parkinsonism. Finally, the smallest parkinsonian syndrome group is composed of genetic Parkinson's disease.

Transcranial sonography of the substantia nigra has been extensively used to diagnose Parkinson's disease, and it can also be used to diagnose drug-induced parkinsonism. Transcranial sonographic substantia nigra echogenicity of drug-induced parkinsonism patients and control are the same, contrasting with a significant increase in echogenicity in Parkinson's disease patients [5].

It has been suggested that nonmotor symptoms, principally excessive daytime, urinary symptoms, restless leg syndrome, sleepiness, hyposmia and attention deficit may be useful to discriminate between Parkinson's disease and drug-induced parkinsonism in the early stages [6]. Drugs used as antipsychotic agents, antidepressants, cholinomimetics, antiemetics, antiepileptic drugs, antivertigo medications, calcium channel antagonists, and antiarrhythmics have been associated with drug-induced parkinsonism [7].

The symptoms of drug-induced parkinsonism induced by drug side effects will disappear when the offending drug is withdrawn. However, in some patients, symptoms persist or may worsen over time when neuroleptics have been withdrawn, suggesting that a degenerative process has probably been initiated in the patient before the use of neuroleptics that hastened this process. We must remember that motor symptoms appear after the loss of 60% to 70% of dopaminergic neurons that contain neuromelanin. A causal relationship has been suggested between neuroleptic exposure and Parkinson's disease based on the unexpectedly high prevalence of Parkinson’s disease following neuroleptic exposure [8].

Trimetazidine, an antianginal drug used in European countries and Asia, was associated with parkinsonism in trimetazidine users [9]. Tacrolimus treatment prescribed for immunosuppression after orthotopic liver transplant induced severe, symmetric parkinsonism, which included resting tremor, rigidity, bradykinesia, and postural instability [10]. Lenalidomide has been reported to induce reversible parkinsonism [11]. This parkinsonism is induced by a blockade of postsynaptic receptors for dopamine that is generally reversible and is directly related to the dose. Drug-induced parkinsonism symptoms in general disappear within 6 months of withdrawal of drug treatment. In a study done in Olmsted County, Minnesota, with 364 incident cases of parkinsonism, 20% of the cases were drug-induced parkinsonism [12].

A 3-decade-long study on drug-induced parkinsonism was performed in a geographically demarcated American population (Olmsted County, Minnesota, from 1976 through 2005). Of 906 cases of parkinsonism from 1976 to 2005, 11.5% of the total, or 108 individuals, presented drug-induced parkinsonism [13]. A recent publication estimates the prevalence of drug-induced parkinsonism in users of antipsychotics at 20 to 35% [14]. A study done in France with stabilized schizophrenia patients revealed that the prevalence of group-induced parkinsonism was 13% [15].

It was reported that 12% of a population aged 75   years or more exhibited drug-induced parkinsonism in Brazil [16]. In Korea, the annual prevalence of drug-induced parkinsonism was reported to have increases from 0.000041% to 0.00007% from 2009 to 2015, and the common drug that induced drug-induced parkinsonism comprised derivatives of benzamide [17]. It is generally believed that drug-induced parkinsonism is described by symmetry of symptoms. A study of 11 patients with a diagnosis of drug-induced parkinsonism and asymmetric symptoms with SPECT-DaTSCAN did not confirm asymmetry of drug-induced parkinsonism [18]. A study of 21 cases of drug-induced parkinsonism revealed that the age at onset was between 40 and 87   years with a Hoehn and Yahr Scale score of 4%, and 70% of the cases were induced by sulpiride. Interestingly, the drugs responsible for drug-induced parkinsonism were not prescribed by neurological or psychiatric departments [19] Fig. 1.2.

Figure 1.2 Drugs used for therapeutic treatment that induce parkinsonism.Typical antipsychotic drugs that induce parkinsonism include haloperidol, amisulpride, sulpiride, levomepromazine, and promazine, calcium channel antagonists (L-channel) such as diltiazem, antidepressants such as fluoxetine and sertraline, antiarrhythmics such as amiodarone, and antiemetic and gastric mobility agents such as itopride [17].

References

1. Brigo F, Erro R, Marangi A, Bhatia K, Tinazzi M. Differentiating drug-induced parkinsonism from Parkinson's disease: an update on non-motor symptoms and investigations.  Park Relat Disord . 2014;20:808–814.

2. Yomtoob J, Koloms K. Bega D DAT-SPECT imaging in cases of drug-induced parkinsonism in a specialty movement disorders practice.  Park Relat Disord . 2018;53:37–41.

3. Ba F, Martin W.R. Dopamine transporter imaging as a diagnostic tool for parkinsonism and related disorders in clinical practice.  Park Relat Disord . 2015;21:87–94.

4. Rodriguez-Porcel F, Jamali S, Duker A.P, Espay A.J. Dopamine transporter scanning in the evaluation of patients with suspected Parkinsonism: a case-based user's guide.  Expert Rev Neurother . 2016;16:23–29.

5. Oh Y.S, Kwon D.Y, Kim J.S, Park M.H, Berg D. Transcranial sonographic findings may predict prognosis of gastroprokinetic drug-induced parkinsonism.  Park Relat Disord . 2018;46:36–40.

6. Kim J.S, Youn J, Shin H, Cho J.W. Nonmotor symptoms in drug-induced parkinsonism and drug-naïve Parkinson disease.  Can J Neurol Sci . 2013;40:36–41.

7. Mena M.A, de Yebenes J.G. Drug-induced parkinsonism.  Expet Opin Drug Saf . 2006;5:759e71.

8. Erro R, Bhatia K.P, Tinazzi M. Parkinsonism following neuroleptic exposure: a double-hit hypothesis?  Mov Disord . 2015;30:780–785.

9. Kwon J, Yu Y.M, Kim S, Jeong K.H, Lee E. Association between trimetazidine and parkinsonism: a population-based study.  Neuroepidemiology . 2019;52:220–226.

10. Gmitterová K, Minár M, Žigrai M, Košutzká Z, Kušnírová A, Valkovič P. Tacrolimus-induced parkinsonism in a patient after liver transplantation - case report.  BMC Neurol . 2018;18:44.

11. Argente-Escrig H, Martinez J.C, Gómez E, Balaguer A, Sevilla T, Bataller L.Lenalidomide induced reversible parkinsonism, dystonia, and dementia in subclinical Creutzfeldt-Jakob disease.  J Neurol Sci . 2018;393:140–141.

12. Bower J.H, Maraganore D.M, McDonnell S.K, Rocca W.A. Incidence and distribution of parkinsonism in Olmsted County, Minnesota, 1976–1990.  Neurology . 1999;52:1214–1220.

13. Savica R, Grossardt B.R, Bower J.H, Ahlskog J.E, Mielke M.M, Rocca W.A. Incidence and time trends of drug-induced parkinsonism: a 30-year population-based study.  Mov Disord . 2017;32:227–234.

14. Ward K.M, Citrome L. Antipsychotic-related movement disorders: drug-induced parkinsonism vs. Tardive dyskinesia-key differences in pathophysiology and clinical management.  Neurol Ther . 2018;7:233–248.

15. Misdrahi D, Tessier A, Daubigney A, et al. Prevalence of and risk factors for extrapyramidal side effects of antipsychotics: results from the national FACE-SZ cohort.  J Clin Psychiatr . 2019;80 pii: 18m12246.

16. Vale T.C, Barbosa M.T, Resende E.P.F, et al. Parkinsonism in a population-based study of individuals aged 75+ years: the Pietà study.  Park Relat Disord . 2018;56:76–81.

17. Byun J.H, Cho H, Kim Y.J, Kim J.S, Baik J.S, Jang S, Ma H.I. Trends in the prevalence of drug-induced parkinsonism in Korea.  Yonsei Med J . 2019;60:760–767.

18. Gajos A, Dąbrowski J, Bieńkiewicz M, Płachcińska A, Kuśmierek J, Bogucki A.The symptoms asymmetry of drug-induced parkinsonism is not related to nigrostriatal cell degeneration: a SPECT-DaTSCAN study.  Neurol Neurochir Pol . 2019;53:311–314.

19. Shiraiwa N, Tamaoka A, Ohkoshi N. Clinical features of drug-induced Parkinsonism.  Neurol Int . 2018;10:7877.

C.2. Paraquat-induced parkinsonism

Drug-induced parkinsonism is not only related to the use of drugs prescribed in disease treatment in which the drugs block postsynaptic receptors for dopamine. However, human beings are exposed to a large number of chemicals used in agriculture, domestic activities, and drug abuse. Exposure to glyphosate in the absence of protective equipment for over 3   h daily over a week induced parkinsonism symptoms such as bradykinesia, rigidity, reduced arm swing, mask face, and rest tremors [1].

Paraquat (1,1′-dimethyl-4–4′-bipyridinium dichloride) is a nonselective quaternary ammonium herbicide used in agriculture that is forbidden in many countries. The herbicide paraquat is used in agriculture and is sold in 90 countries, including the USA, Canada, Australia, Japan, New Zealand, Chile, China, and others [2]. Paraquat exposure has been associated with parkinsonism [3–8 ].

Paraquat can cross the blood–brain barrier because systemic administration of paraquat results in regional distribution of the herbicide within the brain, mostly in the hypothalamus and prefrontal cortex [9]. Paraquat transport into dopaminergic neurons is mediated by dopamine transporter, but the divalent cation paraquat²+ must be converted to its monovalent cation paraquat+ to be the substrate for dopamine transporters. Microglial NADPH oxidase has been proposed to catalyze paraquat²+ reduction to paraquat+. The organic cation transporter-3 also transports paraquat and is amply expressed in nondopaminergic neurons in the nigrostriatal region [10].

Mitochondrial quality control and dynamics play an essential role in the maintenance of mitochondrial function and homeostasis. Paraquat induces mitochondrial dysfunction by disturbing mitochondrial dynamics both in vitro and in vivo [11]. Paraquat induces mitochondrial damage by (1) decreasing mitochondrial cristae; (2) increasing autophagy vesicles and vacuole area; and (3) impairment of mitochondrial membrane potential and decrease ATP level [12]. Paraquat induces oxidative stress, and superoxide dismutase has been demonstrated to reduce motor slowing and mitochondrial damage [13]. Paraquat induces glutamate efflux-starting excitotoxicity mediated by reactive nitrogen species [14].

Paraquat induces an increase in glucose uptake y that increases the levels of Na+-glucose transporters isoform-1 proteins and glucose transporter type-4. Overexpression of alpha-synuclein triggers glucose accumulation and paraquat toxicity, which is reduced by inhibiting the pentose phosphate pathway and glucose metabolism/transport [15]. Maneb, a fungicide, has been reported to be associated with parkinsonism [16]. It has been reported that paraquat and maneb together exert a synergistic effect [17,18]. Paraquat and maneb induce activation of NADPH oxidase and ferroptosis in SH-SY5Y dopaminergic cells. NFE2L2 and PPARGC1α genes encode transcription factor participation in the regulation of antioxidant enzyme expression. NFE2L2 and PPARGC1α are involved in paraquat/maneb-induced parkinsonism [19].

Paraquat/maneb exposure induces toxicity in the hippocampus in the early life of rats that may impair memory, learning, and cognition [20]. In vivo, NADPH oxidase involvement in ferroptosis resulted in neuroinflammation, lipid peroxidation, reduced iron content, and neurodegeneration of dopaminergic neurons [21]. In vivo, paraquat induces memory impairment, motor deficit, oxidative stress, and neuroinflammation [22,23]. Paraquat induces severe lung damage resulting in pulmonary fibrosis, but the mechanism is unknown.

Paraquat induces endoplasmic reticulum stress-dependent cell death in human lung epithelial A549 cells by disrupting the expression levels of unfolded protein response-related molecules [24]. Paraquat induces activation of autophagy in response to early endoplasmic reticulum stress, which is speeded in cells that overexpress wild-type apoptosis signal-regulating kinase 1 [25].

Paraquat also induces dysfunction of protein both proteasomal and lysosomal degradation systems. Paraquat impairs proteasomal activity, which is a late event in cell death progression and autophagy flux [26]. Paraquat induces cardiac contractile dysfunction, and ablation of the innate proinflammatory mediator toll-like receptor-4 improved paraquat-dependent myocardial contractile dysfunction, probably through a reduction in inflammation, endoplasmic reticulum stress, and apoptosis [27]. Paraquat induces changes in miRNA expression such as downregulation of miR-17-5p expression, which suggests that miRNA involvement in the progression of neurodegeneration in paraquat-induced parkinsonism [18].

References

1. Zheng Q, Yin J, Zhu L, Jiao L, Xu Z. Reversible Parkinsonism induced by acute exposure glyphosate.  Park Relat Disord . 2018;50:121.

2. Bastías-Candia S, Zolezzi J.M, Inestrosa N.C. Revisiting the paraquat-induced sporadic Parkinson's disease-like model.  Mol Neurobiol . 2019;56:1044–1055.

3. Tanner C.M, Kamel F, Ross G.W, et al. Rotenone, paraquat, and Parkinson's disease.  Environ Health Perspect . 2011;119:866–872.

4. León-Verastegui A.G. Parkinson's disease due to laboral exposition to paraquat.  Rev Med Inst Mex Seguro Soc . 2012;50:665–672.

5. Costello S, Cockburn M, Bronstein J, Zhang X, Ritz B. Parkinson's disease and residential exposure to maneb and paraquat from agricultural applications in the central valley of California.  Am J Epidemiol . 2009;169:919–926.

6. Kamel F, Tanner C, Umbach D, Hoppin J, Alavanja M, Blair A, Comyns K, Goldman S, Korell M, Langston J.Pesticide exposure and self-reported Parkinson's disease in the agricultural health study.  Am J Epidemiol.  2007;165:364–374.

7. Le Couteur D.G, Mc Lean A.J, Taylor M.C, Woodham B.L, Board P.G. Pesticides and Parkinson's disease.  Biomed Pharmacother . 1999;53:122–130.

8. Dick F.D, De Palma G, Ahmadi A, Scott N.W, Prescott G.J, Bennett J, et al. Environmental risk factors for Parkinson's disease and parkinsonism: the Geoparkinson study.  Occup Environ Med . 2007;64:666–672.

9. Corasaniti M.T, Strongoli M.C, Pisanelli A, Bruno P, Rotiroti D, Nappi G, Nisticò G.Distribution of paraquat into the brain after its systemic injection in rats.  Funct Neurol . 1992;7:51–56.

10. Rappold P.M, Cui M, Chesser A.S, Tibbett J, Grima J.C, Duan L, Sen N, Javitch J.A, Tieu K.Paraquat neurotoxicity is mediated by the dopamine transporter and organic cation transporter-3.  Proc Natl Acad Sci U S A . 2011;108:20766–20771.

11. Zhao F, Wang W, Wang C, Siedlak S.L, Fujioka H, Tang B, Zhu X. Mfn2 protects dopaminergic neurons exposed to paraquat both in vitro and in vivo: implications for idiopathic Parkinson's disease.  Biochim Biophys Acta Mol Basis Dis . 2017;1863:1359–1370.

12. Wu S, Lei L, Song Y, Liu M, Lu S, Lou D, Shi Y, Wang Z, He D. Mutation of hop-1 and pink-1 attenuates vulnerability of neurotoxicity in C. elegans: the role of mitochondria-associated membrane proteins in Parkinsonism.  Exp Neurol . 2018;309:67–78.

13. Filograna R, Godena V.K, Sanchez-Martinez A, Ferrari E, Casella L, Beltramini M, Bubacco L, Whitworth A.J, Bisaglia M.Superoxide dismutase (SOD)-mimetic M40403 is protective in cell and fly models of paraquat toxicity.  J. Biol. Chem.  2016;291:9257–9267.

14. Shimuzu K, Matsubara K, Ohtaki K, Fujimaru S, Saito O, Shiono H. Paraquat induces long-lasting dopamine overflow through the excitotoxic pathway in the striatum of freely moving rats.  Brain Res . 2003;976:243–252.

15. Anandhan A, Lei S, Levytskyy R, et al. Glucose metabolism and AMPK signaling regulate dopaminergic cell death induced by gene (α-Synuclein)-environment (paraquat) interactions.  Mol Neurobiol . 2017;54:3825–3842.

16. Ferraz H.B, Bertolucci P.H, Pereira J.S, Lima J.G, Andrade L.A. Chronic exposure to the fungicide maneb may produce symptoms and signs of CNS manganese intoxication.  Neurology . 1988;38:550–553.

17. Thiruchelvam M, Richfield E.K, Baggs R.B, Tank A.W, Cory-Slechta D.A. The nigrostriatal dopaminergic system as a preferential target of repeated exposures to combined paraquat and maneb: implications for Parkinson's disease.  J. Neurosci.  2000;20:9207–9214.

18. Wang Q, Zhan Y, Ren N, Wang Z, Zhang Q, Wu S, Li H. Paraquat and MPTP alter microRNA expression profiles, and downregulated expression of miR-17-5p contributes to PQ-induced dopaminergic neurodegeneration.  J Appl Toxicol . 2018;38:665–677.

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C.3. Copper-induced parkinsonism

Young workers exposed to high concentrations of copper in mineral-processing refineries in Chile developed parkinsonism [1]. One of these workers reported that due to the high temperatures at which the copper melts, protective masks are removed, and therefore, workers inhale high concentrations of copper. He also mentioned that even the lunchroom was highly contaminated with copper. Wilson's disease is an autosomal-recessive disease caused by mutations in a transmembrane copper-transporter ATPase (ATP7B gene) that transports copper excess from the liver to the bile for excretion from the body [2–4 ].

This inability to remove excess copper results in copper accumulation in multiple organs in the body including the brain. The typical symptoms of Wilson’s disease include cirrhosis, the ocular finding of Kayser-Fleischer rings, and neurological manifestations [4]. A study of 281 Wilson’s disease patients evaluated over 3   decades revealed that the major symptoms of Wilson’s disease were neurological (69%). Interestingly, 62% of neurologic symptoms were caused by parkinsonism. This means that 43% of all patients in this study presented parkinsonism, and only 15% of total symptoms were hepatic [5]. Wilson’s disease is treated with copper chelators and zinc salts. Early genetic diagnosis of the disease is important, and new therapies are under development to circumvent ATP7B-deficiency [3]. In difficult cases, liver transplantation has been used, and tetrathiomolybdate salts are under clinical trial [6].

The ATP7B gene encodes an ATPase located in the liver transmembrane whose function is to transport excess copper from the liver to the bile for excretion. A mutation of the ATP7B gene implies an increase in the concentration of copper in the liver, which goes into the bloodstream and accumulates in different tissues. The brain is one of the tissues where copper accumulates (Cu²+). Under normal conditions, dopamine is released from dopaminergic neurons under neurotransmission and binds to postsynaptic dopaminergic receptors. Subsequently, reuptake of free dopamine from the interneuronal space is mediated by dopamine transporter localized in the membranes of presynaptic neurons.

Figure 1.3 Possible mechanism for copper-induced parkinsonism.Possible mechanism for copper-induced parkinsonism. The positive charges of copper (II) bind to the negative charges of hydroxyl groups when they are dissociated. This copper–dopamine complex has affinity for the dopamine transporter that transports the complex into the cytosol of dopaminergic neurons. The copper (II) in the complex is reduced by oxidizing dopamine to aminochrome, releasing free copper (I). Aminochrome has been shown to be able to induce alpha-synuclein aggregation to neurotoxic oligomers, mitochondrial dysfunction, oxidative stress, autophagy dysfunction, endoplasmic reticulum stress, proteosomal dysfunction, and neuroinflammation.

Under high levels of brain copper (Cu²+), free dopamine in the intersynaptic space can form a complex with Cu²+ composed of a copper (Cu²+) molecule and a dopamine molecule [7]. This dopamine-Cu²+ complex has affinity for the dopamine transporter that transports this complex into cytosolic dopaminergic neurons. In the cytosol of dopaminergic neurons, the dopamine-Cu²+ complex Cu²+ is reduced to Cu+ by oxidation of dopamine to aminochrome. In this oxidoreduction reaction, Cu+ and aminochrome are released from the complex. Aminochrome can be neurotoxic in dopaminergic neurons, but the enzyme DT-diaphorase prevents aminochrome neurotoxicity by catalyzing its two-electron reduction. However, when the aminochrome concentration is too high, the protective capacity of the DT-diaphorase enzyme is suppressed. Experiments with high concentrations of copper suppressed DT-diaphorase protective capacity inducing neurotoxicity and loss of tyrosine hydroxylase-positive neurons [8]. The ability of copper (Cu²+) to complex with dopamine, its specific transport by neurons that express dopamine transporter, and the catalysis of dopamine oxidation to aminochrome in the copper–dopamine complex explains the high incidence of parkinsonism in Wilson's disease. Aminochrome is neurotoxic by inducing the aggregation of alpha-synuclein to neurotoxic oligomers, mitochondrial dysfunction, oxidative stress, autophagy dysfunction, endoplasmic reticulum stress, proteasomal system dysfunction, and neuroinflammation (Fig. 1.3).

References

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2. Bandmann O, Weiss K.H, Kaler S.G. Wilson's disease and other neurological copper disorders.  Lancet Neurol . 2015;14:103–113.

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4. Capone K, Azzam R.K. Wilson's disease: a review for the general pediatrician.  Pediatr Ann . 2018;47:e440–e444.

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6. Członkowska A, Litwin T, Dusek P, Ferenci P, Lutsenko S, Medici V, Rybakowski J.K, Weiss K.H, Schilsky M.L.Wilson disease.  Nat Rev Dis Primers . 2018;4:21.

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C.4. Manganese-induced parkinsonism

Prolonged and excessive manganese inhalation in occupational activities, such as mining, welding, and other industries, induces manganese accumulation in certain brain regions that causes extrapyramidal motor disorder and central nervous system dysfunctions [1–3 ]. High exposure to manganese results in an accumulation in the brain related to the control of motor and nonmotor functions, and exposure also induces progressive neuronal degeneration, specifically in the striatum, substantia nigra, subthalamic nucleus, and globus pallidus [4–8 ].

A welder exposed for 30   years presented rigidity, bradykinesia, writing clumsiness, masked face, and postural instability. Magnetic resonance imaging of the brain showed hyperintensity lesions in the bilateral globus pallidus, pontine tegmentum, dentate nucleus, midbrain, and cerebral white matter. The patient had high manganese levels of urine and serum [9]. A man occupationally exposed to manganese presented symptoms that included resting tremor, bradykinesia, and masked face. The patient was not responsive to levodopa treatment, and his fluorodopa PET scan was normal [10]. A man who received parenteral nutrition for intestinal failure presented a significantly increased manganese concentration and had developed resting tremor and extrapyramidal dyskinesia. This man did not have a history of parkinsonism, essential tremor, or other neurological symptoms [11].

Magnetic resonance imaging brain