Parkinson's disease: Mechanisms and models

The cause of Parkinson's disease (PD) is unknown, but epidemiological studies suggest an association with pesticides and other environmental toxins, and biochemical studies implicate a systemic defect in mitochondrial complex I. We report that chronic, systemic inhibition of complex I by the lipophilic pesticide, rotenone, causes highly selective nigrostriatal dopaminergic degeneration that is associated behaviorally with hypokinesia and rigidity. Nigral neurons in rotenone-treated rats accumulate fibrillar cytoplasmic inclusions that contain ubiquitin and alpha-synuclein. These results indicate that chronic exposure to a common pesticide can reproduce the anatomical, neurochemical, behavioral and neuropathological features of PD.

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Chronic systemic pesticide exposure reproduces features of Parkinson's disease

Interpretation of clinical trials comparing different drug regimens for Parkinson's disease (PD) is complicated by the different dose intensities used: higher doses of levodopa and, possibly, other drugs produce better symptomatic control but more late complications. To address this problem, conversion factors have been calculated for antiparkinsonian drugs that yield a total daily levodopa equivalent dose (LED). LED estimates vary, so we undertook a systematic review of studies reporting LEDs to provide standardized formulae. Electronic database and hand searching of references identified 56 primary reports of LED estimates. Data were extracted and the mean and modal LEDs calculated. This yielded a standardized LED for each drug, providing a useful tool to express dose intensity of different antiparkinsonian drug regimens on a single scale. Using these conversion formulae to report LEDs would improve the consistency of reporting and assist the interpretation of clinical trials comparing different PD medications.

Systematic review of levodopa dose equivalency reporting in Parkinson's disease

Lewy bodies and Lewy neurites are the defining neuropathological characteristics of Parkinson’s disease and dementia with Lewy bodies. They are made of abnormal filamentous assemblies of unknown composition. We show here that Lewy bodies and Lewy neurites from Parkinson’s disease and dementia with Lewy bodies are stained strongly by antibodies directed against amino-terminal and carboxyl-terminal sequences of α-synuclein, showing the presence of full-length or close to full-length α-synuclein. The number of α-synuclein-stained structures exceeded that immunoreactive for ubiquitin, which is currently the most sensitive marker of Lewy bodies and Lewy neurites. Staining for α-synuclein thus will replace staining for ubiquitin as the preferred method for detecting Lewy bodies and Lewy neurites. We have isolated Lewy body filaments by a method used for the extraction of paired helical filaments from Alzheimer’s disease brain. By immunoelectron microscopy, extracted filaments were labeled strongly by anti-α-synuclein antibodies. The morphologies of the 5- to 10-nm filaments and their staining characteristics suggest that extended α-synuclein molecules run parallel to the filament axis and that the filaments are polar structures. These findings indicate that α-synuclein forms the major filamentous component of Lewy bodies and Lewy neurites.

https://www.pnas.org/content/pnas/95/11/6469.full.pdf

α-Synuclein in filamentous inclusions of Lewy bodies from Parkinson’s disease and dementia with Lewy bodies

Polyphenols are the most abundant antioxidants in the diet and are widespread constituents of fruits, vegetables, cereals, dry legumes, chocolate, and beverages, such as tea, coffee, or wine. Experimental studies on animals or cultured human cell lines support a role of polyphenols in the prevention of cardiovascular diseases, cancers, neurodegenerative diseases, diabetes, or osteoporosis. However, it is very difficult to predict from these results the effects of polyphenol intake on disease prevention in humans. One of the reasons is that these studies have often been conducted at doses or concentrations far beyond those documented in humans. The few clinical studies on biomarkers of oxidative stress, cardiovascular disease risk factors, and tumor or bone resorption biomarkers have often led to contradictory results. Epidemiological studies have repeatedly shown an inverse association between the risk of myocardial infarction and the consumption of tea and wine or the intake level of some particular flavonoids, but no clear associations have been found between cancer risk and polyphenol consumption. More human studies are needed to provide clear evidence of their health protective effects and to better evaluate the risks possibly resulting from too high a polyphenol consumption.

Dietary polyphenols and the prevention of diseases

Several lines of evidence suggest that endogenous and exogenous toxins may play a major role in the pathogenesis of Parkinson's disease (PD). In vivo aromatic beta-carbolines, like harman or norharman, may easily be formed by cyclization of indoleamines with e.g. aldehydes. Because of the structural similarity to MPTP, beta-carbolines have been proposed as endogenous toxins. For further elucidation of the role of beta-carbolines in neurodegenerative disorders, harman and norharman plasma levels were measured in 36 patients with PD and compared to an age- and sex-matched control group. Plasma levels of norharman in PD were significantly higher compared to the control group. Harman in the plasma of Parkinsonian patients was also elevated compared to controls, but this difference was not significant. Correlation of beta-carbolines with plasma levels of L-dopa, oral doses of bromocriptine and selegiline in treated Parkinsonian patients showed no significant results. On the one hand these results may suggest a possible role of beta-carbolines in the pathophysiological processes initiating PD, by, e.g., inducing mitochondrial respiratory inhibition like MPP+. One may speculate, however, that elevated levels of norharman and harman are due to an endogenous upregulation caused by unknown metabolic processes.

Plasma levels of the β‐carbolines harman and norharman in Parkinson's disease

No significant increase of the maximum concentration (Cmax) of levodopa after addition of catechol-O-methyltransferase inhibitor tolcapone occurred in previous pharmacokinetic studies predominantly on healthy volunteers. We compared pharmacokinetics of levodopa in plasma before and after addition of tolcapone in 13 treated parkinsonian subjects under standardized conditions. We found a significant increase of Cmax of levodopa after the addition of tolcapone. This may represent one cause for the occurrence of dyskinesia previously early in the course of treatment with tolcapone.

Tolcapone increases maximum concentration of levodopa.

Homocysteine, cysteine, and cysteinyl-glycine are all metabolically interrelated. Levodopa/decarboxylase inhibitor (LD/DCI) administration increases total homocysteine (tHcy) plasma levels. Objectives were to investigate associations between LD/DCI intake, concentrations of tHcy, cysteine, and cysteinyl-glycine in PD patients and healthy controls. Cysteine levels were significant lower in controls and PD patients with tHcy below the treshold of 15 [μmol/L] when compared with PD patients with tHcy above 15. Cysteinyl-glycine did not significantly differ between the three cohorts. Significant associations appeared between tHcys and cysteine in PD patients. tHcy and cysteine concentrations correlated to LD/DCI intake and severity of PD. The cysteine increase may be due to the significant higher dosing of daily LD/DCI and the significant higher morning LD/DCI dose 1 hour before blood sampling in PD patients with tHcy above 15 when compared with the remaining PD patients and the controls. The correlation outcomes support the view that LD/DCI intake may also increase cysteine. © 2009 Movement Disorder Society

Cysteine elevation in levodopa-treated patients with Parkinson's disease.

Significantly increased plasma total homocysteine levels (t-Hcys) appeared in treated Huntington disease (HD) patients compared to controls and untreated HD subjects. Because the protein Huntingtin interacts with the homocysteine metabolism modulating enzyme cystathionine beta-synthase, we hypothesize that homocysteine promotes neurodegeneration in HD.

Hyperhomocysteinaemia in treated patients with Huntington's disease homocysteine in HD.

Objective Several case reports with dystonia and homocysteinuria suggest a putative pathogenetic importance of homocysteine for the development of dystonia. We investigated relations between plasma homocysteine, age, severity and duration of primary idiopathic torsion dystonia. Subjects and methods We measured homocysteine levels in blood samples drawn from 24 subjects with dystonia and controls. Results Patients with dystonia (19.3 +/- 8.5, range 8.4-37 micromol/l) showed significantly (P= 0.008, t-test) increased levels of total homocysteine compared with age- and sex-matched controls (13.9 +/- 4.2, range 5.8-24.5 micromol/l). No significant influence of age and duration of dystonia appeared, but we found a significant trend for an association between severity of dystonia and homocysteine (P = 0.046, R = 0.41). Conclusions Our study supports previous reports on subjects with dystonia with homocysteinuria. Neurotoxic effects and N-methyl-D-aspartate agonistic properties of homocysteine may hypothetically contribute to onset and severity of dystonia.

Wilfried Kuhn

Papers

Plasma levels of the β‐carbolines harman and norharman in Parkinson's disease

Tolcapone increases maximum concentration of levodopa.

Cysteine elevation in levodopa-treated patients with Parkinson's disease.

Hyperhomocysteinaemia in treated patients with Huntington's disease homocysteine in HD.

Elevated plasma levels of homocysteine in dystonia.