The rat rotenone model reproduces the abnormal pattern of central catecholamine metabolism found in Parkinson's disease

Landau, Regev; Halperin, Reut; Sullivan, Patti; Zibly, Zion; Leibowitz, Avshalom; Goldstein, David S.; Sharabi, Yehonatan

doi:10.1242/dmm.049082

Cited by 13 publications

(9 citation statements)

References 40 publications

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“…Recently, we analyzed the striatal neurochemical profile following systemic administration of rotenone to Sprague Dawley rats, a well-established animal model of Parkinson's disease [21][22][23]. Rotenone caused striatal depletion of dopamine, increased striatal DOPAL, and induced the double hit of decreased vesicular sequestration and decreased ALDH activity [24]. We therefore concluded that the rat rotenone model replicates the changes found in humans and is in line with the neurochemical profile that underlies the catecholaldehyde hypothesis.…”

Section: The Molecular Basis Of the Catecholaldehyde Hypothesissupporting

confidence: 53%

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

Khashab,

Gutman-Sharabi,

Shabtai

et al. 2023

IJMS

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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.

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Section: The Molecular Basis Of the Catecholaldehyde Hypothesissupporting

confidence: 53%

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

Khashab,

Gutman-Sharabi,

Shabtai

et al. 2023

IJMS

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“…A vesicular storage defect would not only deplete releasable neurotransmitter stores but also promote autotoxicity from augmented oxidation of cytoplasmic catecholamines ( 37 – 39 ). Diminished vesicular storage in existing nerve terminals could have any of several causes, such as decreased mitochondrial complex 1 activity ( 40 ), α-synuclein (αS) oligomers ( 37 , 41 ), or decreased VMAT2 availability ( 42 ), all of which are potential therapeutic targets; however, no previous study has determined whether indices of attenuated vesicular sequestration in cardiac sympathetic nerves precede central LBDs in at-risk individuals.…”

Section: Introductionmentioning

confidence: 99%

Cardiac noradrenergic deficiency revealed by 18F-dopamine positron emission tomography identifies preclinical central Lewy body diseases

Goldstein,

Holmes,

Sullivan

et al. 2024

Journal of Clinical Investigation

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BACKGROUND. In Lewy body diseases (LBDs) Parkinson disease (PD), and dementia with Lewy bodies (DLB), by the time parkinsonism or cognitive dysfunction manifests clinically, substantial neurodegeneration has already occurred. Biomarkers are needed to identify central LBDs in a preclinical phase, when neurorescue strategies might forestall symptomatic disease. This phase may involve catecholamine deficiency in the autonomic nervous system. We analyzed data from the prospective, observational, long-term PDRisk study to assess the predictive value of low versus normal cardiac 18 F-dopamine positron emission tomography (PET), an index of myocardial content of the sympathetic neurotransmitter norepinephrine, in at-risk individuals. METHODS. Participants self-reported risk factor information (genetics, olfactory dysfunction, dream enactment behavior, and orthostatic intolerance or hypotension) at a protocol-specific website. Thirty-four with 3 or more confirmed risk factors underwent serial cardiac 18 F-dopamine PET at 1.5-year intervals for up to 7.5 years or until PD was diagnosed. RESULTS. Nine participants had low initial myocardial 18 F-dopamine–derived radioactivity (<6,000 nCi-kg/cc-mCi) and 25 had normal radioactivity. At 7 years of follow-up, 8 of 9 with low initial radioactivity and 1 of 11 with normal radioactivity were diagnosed with a central LBD (LBD+) ( P = 0.0009 by Fisher’s exact test). Conversely, all 9 LBD+ participants had low 18 F-dopamine–derived radioactivity before or at the time of diagnosis of a central LBD, whereas among 25 participants without a central LBD only 1 (4%) had persistently low radioactivity ( P < 0.0001 by Fisher’s exact test). CONCLUSION. Cardiac 18 F-dopamine PET highly efficiently distinguishes at-risk individuals who are diagnosed subsequently with a central LBD from those who are not. TRIAL REGISTRATION. ClinicalTrials.gov NCT00775853. FUNDING. Division of Intramural Research, NIH, NINDS.

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“…In vivo experimental model shows RO induces loss of dopaminergic neurons in the substantia nigra, one of the characteristic features of PD neuropathology. 86 Rotenone also replicates the clinical features of PD, including the aggregation of α-synuclein and the formation of Lewy bodies. 87 …”

Section: Mitochondrial Toxicants and Neurodegenerationmentioning

confidence: 85%

Mitochondrial Toxicant-Induced Neuronal Apoptosis in Parkinson’s Disease: What We Know so Far

Sivagurunathan¹,

Gnanasekaran²,

Latchoumycandane³

2023

DNND

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Parkinson’s disease (PD) is one of the most common progressive neurodegenerative diseases caused by the loss of dopamine-producing neuronal cells in the region of substantia nigra pars compacta of the brain. During biological aging, neuronal cells slowly undergo degeneration, but the rate of cell death increases tremendously under some pathological conditions, leading to irreversible neurodegenerative diseases. By the time symptoms of PD usually appear, more than 50 to 60% of neuronal cells have already been destroyed. PD symptoms often start with tremors, followed by slow movement, stiffness, and postural imbalance. The etiology of PD is still unknown; however, besides genetics, several factors contribute to neurodegenerative disease, including exposure to pesticides, environmental chemicals, solvents, and heavy metals. Postmortem brain tissues of patients with PD show mitochondrial abnormalities, including dysfunction of the electron transport chain. Most chemicals present in our environment have been shown to target the mitochondria; remarkably, patients with PD show a mild deficiency in NADH dehydrogenase activity, signifying a possible link between PD and mitochondrial dysfunction. Inhibition of electron transport complexes generates free radicals that further attack the macromolecules leading to neuropathological conditions. Apart from that, oxidative stress also causes neuroinflammation-mediated neurodegeneration due to the activation of microglial cells. However, the mechanism that causes mitochondrial dysfunction, especially the electron transport chain, in the pathogenesis of PD remains unclear. This review discusses the recent updates and explains the possible mechanisms of mitochondrial toxicant-induced neuroinflammation and neurodegeneration in PD.

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The rat rotenone model reproduces the abnormal pattern of central catecholamine metabolism found in Parkinson's disease

Cited by 13 publications

References 40 publications

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

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

Cardiac noradrenergic deficiency revealed by 18F-dopamine positron emission tomography identifies preclinical central Lewy body diseases

Mitochondrial Toxicant-Induced Neuronal Apoptosis in Parkinson’s Disease: What We Know so Far

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