An inducible MAO-B mouse model of Parkinson’s disease: a tool towards better understanding basic disease mechanisms and developing novel therapeutics

Chamoli, Manish; Chinta, Shankar J.; Andersen, Julie K.

doi:10.1007/s00702-018-1887-z

Cited by 27 publications

(11 citation statements)

References 67 publications

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“…Interestingly, MAO-B has been more in the spotlight in PD research. According to different studies, MAO-B expression exponentially increases with age and it can be upregulated, for instance, in neuroinflammation [96–98]. In PD, MAO-B activity was shown to be enhanced [99].…”

Section: Key Players In the Catecholaldehyde Hypothesismentioning

confidence: 99%

Impaired dopamine metabolism in Parkinson’s disease pathogenesis

Masato

Plotegher

Boassa

et al. 2019

Mol Neurodegeneration

235

144

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A full understanding of Parkinson’s Disease etiopathogenesis and of the causes of the preferential vulnerability of nigrostriatal dopaminergic neurons is still an unsolved puzzle. A multiple-hit hypothesis has been proposed, which may explain the convergence of familial, environmental and idiopathic forms of the disease. Among the various determinants of the degeneration of the neurons in Substantia Nigra pars compacta , in this review we will focus on the endotoxicity associated to dopamine dyshomeostasis. In particular, we will discuss the relevance of the reactive dopamine metabolite 3,4-dihydroxyphenylacetaldehyde (DOPAL) in the catechol-induced neurotoxicity. Indeed, the synergy between the catechol and the aldehyde moieties of DOPAL exacerbates its reactivity, resulting in modification of functional protein residues, protein aggregation, oxidative stress and cell death. Interestingly, αSynuclein, whose altered proteostasis is a recurrent element in Parkinson’s Disease pathology, is considered a preferential target of DOPAL modification. DOPAL triggers αSynuclein oligomerization leading to synapse physiology impairment. Several factors can be responsible for DOPAL accumulation at the pre-synaptic terminals, i.e. dopamine leakage from synaptic vesicles, increased rate of dopamine conversion to DOPAL by upregulated monoamine oxidase and decreased DOPAL degradation by aldehyde dehydrogenases. Various studies report the decreased expression and activity of aldehyde dehydrogenases in parkinsonian brains, as well as genetic variants associated to increased risk in developing the pathology. Thus, we discuss how the deregulation of these enzymes might be considered a contributing element in the pathogenesis of Parkinson’s Disease or a down-stream effect. Finally, we propose that a better understanding of the impaired dopamine metabolism in Parkinson’s Disease would allow a more refined patients stratification and the design of more targeted and successful therapeutic strategies.

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Section: Key Players In the Catecholaldehyde Hypothesismentioning

confidence: 99%

Impaired dopamine metabolism in Parkinson’s disease pathogenesis

Masato

Plotegher

Boassa

et al. 2019

Mol Neurodegeneration

235

144

View full text Add to dashboard Cite

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“…Efforts to improve the in vivo behavior of metabolically trapped MAO substrates for PET imaging will likely require further exploration of alternative 4-aryloxy substituents . As we undertake this work and validate the new radiotracers, future experiments could involve evaluation in animal models of disease, such as the recently reported MAO-B mouse model of Parkinson’s disease, before anticipated translation into clinical studies.…”

Section: Discussionmentioning

confidence: 99%

Deuterium Kinetic Isotope Effect Studies of a Potential in Vivo Metabolic Trapping Agent for Monoamine Oxidase B

Drake

Brooks

Mufarreh

et al. 2018

ACS Chem. Neurosci.

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Visualizing the in vivo activity of monoamine oxidase B (MAO-B) is a valuable tool in the ongoing investigation of astrogliosis in neurodegeneration. Existing strategies for imaging changes in MAO enzyme expression or activity have utilized the irreversible suicide inhibitors or high-affinity reversibly binding inhibitors as positron emission tomography (PET) ligands. As an alternative approach, we developed 4-methyl-7-[(1-[C]methyl-1,2,3,6-tetrahydropyridin-4-yl)oxy]-2 H-chromen-2-one ([C]Cou) as a metabolic trapping agent for MAO-B. Trapping of [C]Cou in rhesus monkey brain demonstrated MAO-B selectivity. In this work, we have attempted to improve on the in vivo pharmacokinetics of [C]Cou by using the deuterium kinetic isotope effect (KIE) to slow the MAO-B-mediated oxidation step and thus reduce the rate of trapping in brain tissues. However, in vitro assays of enzyme kinetics and in vivo PET imaging of pharmacokinetics in primate brain showed no effects of deuterium substitution on the tetrahydropyridine ring of [C]Cou. The results are possibly due to masking of the KIE by a second step in the overall metabolism of the new imaging agent.

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“…Although they share about 70% of structure similarity, MAO‐A and ‐B exhibit different substrate specificity as well as diverse regional distribution in brain tissue . MAO‐B has been regarded as a therapeutic target for PD in clinic because the elevated activity of MAO‐B was observed in the SN of PD patients …”

Section: Methodsmentioning

confidence: 99%

“…9 MAO-B has been regarded as a therapeutic target for PD in clinic because the elevated activity of MAO-B was observed in the SN of PD patients. 10 Currently, Selegiline and Rasagiline, both selective and irreversible MAO-B inhibitors, are used in clinics as a combination therapy with L-dopa ( Figure 1). 11 Both drugs increased the amount of dopamine and efficiency of L-dopa.…”

mentioning

confidence: 99%

Benzoxazoles as Selective Monoamine Oxidase B (MAO‐B) Inhibitors

Sawant

Park

Baek

et al. 2019

Bulletin Korean Chem Soc

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Parkinson's disease (PD) is a central nervous system disorder accompanied by tremor, slow movement, motor impairment, and dementia. 1,2 These symptoms of PD mainly result from the death of dopaminergic neurons in substantia nigra (SN) and the deficiency of dopamine inside the brain. 3 Dopamine is a type of monoamine neurotransmitter and acts as a chemical messenger to regulate neuronal signaling in brain, thereby controls motor functions. 4 Levodopa (L-dopa) is the major treatment for PD and exerts its effect as a dopamine precursor. 5 However, doparesistance or serious complications are observed after an initial period of treatment. 6 Besides L-dopa treatment, another therapeutic way to restore dopamine function is the suppression of dopamine catabolism. Monoamine oxidase (MAO) is involved in down-regulation of dopamine level which catalyzes the deamination and degradation of dopamine. 7 Inhibition of MAO blocks the breakdown of dopamine, thereby prolongs the action of dopamine in the brain. 8 There are two isoforms of MAO-A and MAO-B. Although they share about 70% of structure similarity, MAO-A and -B exhibit different substrate specificity as well as diverse regional distribution in brain tissue. 9 MAO-B has been regarded as a therapeutic target for PD in clinic because the elevated activity of MAO-B was observed in the SN of PD patients. 10

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An inducible MAO-B mouse model of Parkinson’s disease: a tool towards better understanding basic disease mechanisms and developing novel therapeutics

Cited by 27 publications

References 67 publications

Impaired dopamine metabolism in Parkinson’s disease pathogenesis

Impaired dopamine metabolism in Parkinson’s disease pathogenesis

Deuterium Kinetic Isotope Effect Studies of a Potential in Vivo Metabolic Trapping Agent for Monoamine Oxidase B

Benzoxazoles as Selective Monoamine Oxidase B (MAO‐B) Inhibitors

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