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

New approaches in Parkinsonian pharmacotherapy may be (1) inhibition of catechol-O-methyl-transferase influencing the metabolism of dopamine, (2) the use of budipine, which is assumed to be neuroprotective, with an effect especially on tremor, (3) the application of NADH with the postulated stimulation of the endogenous dopamine synthesis and (4) the revival of stereotaxic surgery with the lesion or the stimulation of certain brain areas, enabled by the development of new and more sensitive methods. Neuroprotective, and/or neuroregenerative therapeutic approaches, like e.g. application or stimulation of growth factors and/or transplantation of neuronal dopaminergic cells, may redirect Parkinsonian therapy from present palliative, symptomatic therapeutic principles to acurative therapy in the future.

Therapie des Morbus Parkinson Teil 2: Neue Therapiekonzepte für die Behandlung motorischer Symptome

CorrespondenceAntipyretic therapy in acute stroke

Aktuelle therapie der idiopathischen parkinson-erkrankung: teil 2: neuere und alternative therapieverfahren

Early diagnosis is important for satisfactory pharmacotherapy of idiopathic Parkinson's disease (PD). L-Dopa therapy is still the gold standard in the treatment of PD, but due to complications of long term L-Dopa application, a combination therapy of levodopa with various dopamine agonists and putative neuroprotective drugs, like e.g. selegiline, is becoming increasingly important and attracts more and more attention, especially in the early phases of PD. Moreover, disturbances of the autonomic nervous system and the mind have to be considered and treated besides pharmacotherapy of motor symptoms in idiopathic Parkinson's disease (PD). Hypersalivation, seborrhoea, dysregulation of the cardiovascular system and disturbances of gastrointestinal and bladder motility and sleep are common mainly in the context of autonomic failure in PD. Moreover, Parkinsonian patients often complain of psychopathological features like depression, dementia and psychosis, which may also be due to dopaminergic Parkinsonian therapy. This review surveys possible therapeutic approaches of these disturbances of the psyche and the autonomic nervous system in PD.

Wilfried Kuhn

Papers

Therapie des Morbus Parkinson Teil 2: Neue Therapiekonzepte für die Behandlung motorischer Symptome

CorrespondenceAntipyretic therapy in acute stroke

Aktuelle therapie der idiopathischen parkinson-erkrankung: teil 2: neuere und alternative therapieverfahren

[Therapy of Parkinson disease. 1: Standard therapy of motor and non-motor symptoms].

Aktuelle therapie der idiopathischen parkinson-erkrankung: teil 1: diagnostik, therapierichtlinien, standard-pharmakotherapie und physiotherapie