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The Path to Cure in Parkinson’s Disease: Novel Concepts on Mechanisms, Disease Modifying Treatment, and Prevention

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Prof. Dr. Yehonatan Sharabi

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Head, Neuroautonomic Service, Chaim Sheba Medical Center, Tel-HaShomer, Israel and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel
Interests: Parkinson's disease; Lewy bodies; autonomic medicine; catecholamines; neuroprotection; disease-modifying treatment

Prof. Dr. David S. Goldstein

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Guest Editor

Autonomic Medicine Section, NINDS Intramural Research Program, National Institutes of Health, Bethesda, MD 20892, USA
Interests: Parkinson's disease; Lewy bodies; autonomic medicine; catecholamines; neuroprotection; disease-modifying treatment

Special Issue Information

Dear Colleagues,

For many years, treatment for Parkinson's disease has focused on ways to increase the availability of dopamine at its receptors in the striatum. The disadvantages of this approach are inherent, both due to the approach that focuses on symptomatic treatment only and due to the focus on one aspect of a complex disease - the movement disorder. In recent years much information has accumulated about the pathogenesis of the disease and the way in which the disease progresses anatomically and physiologically, with increasing attention to the involvement of non-motor systems in the disease. The vast fund of information allows and enables many researchers to design and try more advanced and sophisticated treatments that are aimed at addressing the underlying dysfunctions of the systems involved in the disease and finding therapeutic strategies that can slow and possibly even prevent the neurodegenerative process.

The purpose of this Special Issue is to compile key articles and reviews on cutting-edge basic and clinical research on this topic and to present advanced concepts that mark promising trends for the future ranging from preclinical to prodromal to advanced disease, with emphasis on disease-modifying strategies.

Prof. Dr. Yehonatan Sharabi
Prof. Dr. David S. Goldstein
Guest Editors

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Research

12 pages, 861 KiB

Open AccessArticle

Dihydroxyphenylacetaldehyde Lowering Treatment Improves Locomotor and Neurochemical Abnormalities in the Rat Rotenone Model: Relevance to the Catecholaldehyde Hypothesis for the Pathogenesis of Parkinson’s Disease

by Rawan Khashab, Naama Gutman-Sharabi, Zehava Shabtai, Regev Landau, Reut Halperin, Tsviya Fay-Karmon, Avshalom Leibowitz and Yehonatan Sharabi

Int. J. Mol. Sci. 2023, 24(15), 12522; https://doi.org/10.3390/ijms241512522 - 7 Aug 2023

Cited by 1 | Viewed by 1702

Abstract

The catecholaldehyde hypothesis for the pathogenesis of Parkinson’s disease centers on accumulation of 3,4-dihydroxyphenylacetaldehyde (DOPAL) in dopaminergic neurons. To test the hypothesis, it is necessary to reduce DOPAL and assess if this improves locomotor abnormalities. Systemic administration of rotenone to rats reproduces the motor and central neurochemical abnormalities characterizing Parkinson’s disease. In this study, we used the monoamine oxidase inhibitor (MAOI) deprenyl to decrease DOPAL production, with or without the antioxidant N-acetylcysteine (NAC). Adult rats received subcutaneous vehicle, rotenone (2 mg/kg/day via a minipump), or rotenone with deprenyl (5 mg/kg/day i.p.) with or without oral NAC (1 mg/kg/day) for 28 days. Motor function tests included measures of open field activity and rearing. Striatal tissue was assayed for contents of dopamine, DOPAL, and other catechols. Compared to vehicle, rotenone reduced locomotor activity (distance, velocity and rearing); increased tissue DOPAL; and decreased dopamine concentrations and inhibited vesicular sequestration of cytoplasmic dopamine and enzymatic breakdown of cytoplasmic DOPAL by aldehyde dehydrogenase (ALDH), as indicated by DA/DOPAL and DOPAC/DOPAL ratios. The addition of deprenyl to rotenone improved all the locomotor indices, increased dopamine and decreased DOPAL contents, and corrected the rotenone-induced vesicular uptake and ALDH abnormalities. The beneficial effects were augmented when NAC was added to deprenyl. Rotenone evokes locomotor and striatal neurochemical abnormalities found in Parkinson’s disease, including DOPAL buildup. Administration of an MAOI attenuates these abnormalities, and NAC augments the beneficial effects. The results indicate a pathogenic role of DOPAL in the rotenone model and suggest that treatment with MAOI+NAC might be beneficial for Parkinson’s disease treatment. Full article

(This article belongs to the Special Issue The Path to Cure in Parkinson’s Disease: Novel Concepts on Mechanisms, Disease Modifying Treatment, and Prevention)

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19 pages, 2071 KiB

Open AccessArticle

Optogenetic Globus Pallidus Stimulation Improves Motor Deficits in 6-Hydroxydopamine-Lesioned Mouse Model of Parkinson’s Disease

by Sonia Di Bisceglie Caballero, Aurelia Ces, Martine Liberge, Frederic Ambroggi, Marianne Amalric and Abdel-Mouttalib Ouagazzal

Int. J. Mol. Sci. 2023, 24(9), 7935; https://doi.org/10.3390/ijms24097935 - 27 Apr 2023

Cited by 1 | Viewed by 2232

Abstract

Excessive inhibition of the external globus pallidus (GPe) by striatal GABAergic neurons is considered a central mechanism contributing to motor symptoms of Parkinson’s disease (PD). While electrophysiological findings support this view, behavioral studies assessing the beneficial effects of global GPe activations are scarce and the reported results are controversial. We used an optogenetic approach and the standard unilateral 6-hydroxydopamine nigrostriatal dopamine (DA) lesion model of PD to explore the effects of GPe photostimulation on motor deficits in mice. Global optogenetic GPe inhibition was used in normal mice to verify whether it reproduced the typical motor impairment induced by DA lesions. GPe activation improved ipsilateral circling, contralateral forelimb akinesia, locomotor hypoactivity, and bradykinesia in 6-OHDA-lesioned mice at ineffective photostimulation parameters (532 nm, 5 Hz, 3 mW) in normal mice. GPe photoinhibition (450 nm, 12 mW) had no effect on locomotor activity and forelimb use in normal mice. Bilateral photoinhibition (450 nm, 6 mW/side) reduced directed exploration and improved working memory performances indicating that recruitment of GPe in physiological conditions may depend on the behavioral task involved. Collectively, these findings shed new light on the functional role of GPe and suggest that it is a promising target for neuromodulatory restoration of motor deficits in PD. Full article

(This article belongs to the Special Issue The Path to Cure in Parkinson’s Disease: Novel Concepts on Mechanisms, Disease Modifying Treatment, and Prevention)

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