A critical appraisal of MAO-B inhibitors in the treatment of Parkinson’s disease

Jost, Wolfgang H.

doi:10.1007/s00702-022-02465-w

Cited by 34 publications

(30 citation statements)

References 114 publications

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“…We have previously identified 2-phenyloxazole (PHOX) derivatives as selective monoamine oxidase B (MAO-B) inhibitors (Di Paolo et al, 2019) ( Figure 2A ). MAO-B inhibitors are used to treat Parkinson’s disease and are also considered potential drug candidates for the treatment of AD (Jost, 2022; Park et al, 2019). In accordance with the concept of polypharmacology, i.e., the use of a single drug acting on multiple targets or disease pathways (Anighoro et al, 2014), we searched for possible additional targets of the PHOX compounds through integrated 2D (MACCS and ECFP4 fingerprints; OpenEye Toolkits 2020.2.2 OpenEye Scientific Software, Santa Fe, NM.…”

Section: Resultsmentioning

confidence: 99%

Quantitative live cell imaging of a tauopathy model enables the identification of a polypharmacological drug candidate that restores physiological microtubule regulation

Pinzi¹,

Conze²,

Bisi³

et al. 2022

Preprint

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Tauopathies such as Alzheimers disease are characterized by the aggregation and increased phosphorylation of the microtubule-associated protein tau. The pathological changes in tau are closely linked to neurodegeneration, making tau a prime candidate for intervention. However, the multiple facets of tau function and the lack of cellular tauopathy models that could support mechanism-based drug development hampers progress. Here we report the development of a live-cell imaging approach to quantitatively monitor pathological changes of human tau as it interacts with axonal microtubules. We show that a full-length aggregation-prone tau construct exhibits reduced interaction with microtubules as it increasingly aggregates. Through chemoinformatic analyses, we identified 2-phenyloxazole (PHOX) derivatives as putative polypharmacological small molecules that inhibit tau aggregation and modulate tau phosphorylation. We found that PHOX15 restores the physiological microtubule interaction of aggregation-prone tau in neurons and inhibits the first phase of tau aggregation in vitro. Furthermore, we report that PHOX15 inhibits the tau kinases GSK3beta and Cdk5, alters the kinome activity of model neurons, and reduces tau phosphorylation at disease-relevant sites. Molecular dynamics simulations highlight cryptic channel-like pockets crossing tau protofilaments and indicate that the binding of PHOX15 in one of the channels reduces the protofilaments ability to adopt a PHF-like conformation. The data show that our imaging approach provides a useful tool for identifying compounds that modulate tau-microtubule interaction in axons. We demonstrate that a polypharmacological approach to simultaneously treat tau aggregation and tau phosphorylation is able to restore physiological microtubule regulation, identifying PHOX15 as a promising drug candidate to counteract tau-induced neurodegeneration.

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Section: Resultsmentioning

confidence: 99%

Quantitative live cell imaging of a tauopathy model enables the identification of a polypharmacological drug candidate that restores physiological microtubule regulation

Pinzi¹,

Conze²,

Bisi³

et al. 2022

Preprint

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“…Deprenyl, also known as selegiline, has been used to treat Parkinson’s disease [ 26 ]. It is an irreversible and selective inhibitor of MAO B, and it can increase dopamine concentrations in the synaptic gap, primarily when used in combination with levodopa.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of monoamine oxidase B reduces atherosclerosis and fatty liver in mice

et al. 2023

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Oxidative stress is vital for pathophysiology of atherosclerosis and non-alcoholic fatty liver disease (NAFLD). Monoamine oxidase (MAO) is an important source of oxidative stress in the vascular system and liver. However, the effect of MAO inhibition on atherosclerosis and NAFLD has not been explored. In this study, MAO A and B expressions were increased in atherosclerotic plaques in human and apolipoprotein E (ApoE)-deficient mice. Inhibition of MAO B (by deprenyl), but not MAO A (by clorgyline), reduced the atheroma area in the thoracic aorta and aortic sinus in ApoE-deficient mice fed the cholesterol-enriched diet for 15 weeks. MAO B inhibition attenuated oxidative stress, expression of adhesion molecules, production of inflammatory cytokines, and macrophage infiltration in atherosclerotic plaques and decreased plasma triglyceride and low-density lipoprotein (LDL) cholesterol concentrations. MAO B inhibition had no therapeutic effect on restenosis in the femoral artery wire-induced injury model in C57BL/6 mice. In the NAFLD mouse model, MAO B inhibition reduced lipid droplet deposition in the liver and hepatic total cholesterol and triglyceride levels in C57BL/6 mice fed high-fat diets for 10 weeks. Key enzymes for triglyceride and cholesterol biosynthesis (fatty acid synthase and 3-hydroxy-3-methylglutaryl-CoA reductase, HMGCR) and inflammatory markers were inhibited, and cholesterol clearance was upregulated (increased LDL receptor expression and reduced proprotein convertase subtilisin/kexin type 9, PCSK9, expression) by MAO B inhibition in the liver. These results were also demonstrated in the HepG2 liver cell model. Our data suggest that MAO B inhibition is a potential and novel treatment for atherosclerosis and NAFLD

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“…49 Rasagiline is more bioavailable than selegiline and may have neuroprotective qualities in vitro. 49 , 50 It has been shown to improve morning OFF as well as wearing OFF, and post-hoc analyses have suggested a possible benefit in measures of depression, cognition and fatigue. 51 Safinamide is unique in its mechanism of action by also working at voltage-gated sodium and N-type calcium channels to inhibit release of glutamate.…”

Section: Prolonging Levodopa Plasma Half-lifementioning

confidence: 99%

Effective Management of “OFF” Episodes in Parkinson’s Disease: Emerging Treatment Strategies and Unmet Clinical Needs

Masood

Jimenez-Shahed

2023

NDT

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Motor complications related to the chronic administration of levodopa and failure to prevent the neurodegenerative disease process counterbalance the pivotal discovery of levodopa as the cornerstone of PD treatment. Excellent motor control is offered early during the course of treatment, but this diminishes as pathological changes in the striatum lead to synaptic dopamine levels becoming completely dependent on exogenous dopamine. This non-physiologic stimulation of dopamine receptors eventually manifests as OFF episodes. As no disease modifying therapy exists for PD that can disrupt these pathological changes, most research and treatment focuses on optimization of dopaminergic stimulation of striatal receptors so that they mimic tonic, physiologic stimulation as closely as possible. Strategies focusing on these challenges have included non-pharmacologic approaches, optimizing levodopa pharmacokinetics, using adjunctive treatments including those with non-dopaminergic mechanisms, and implementing rescue therapies. Device aided therapies, including surgery, are also available. In this review, we will focus on effective management of motor symptoms related to OFF periods, including emerging strategies. Unmet clinical needs will be discussed, including non-motor symptoms, targeted molecular therapies and disease modifying therapy.

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A critical appraisal of MAO-B inhibitors in the treatment of Parkinson’s disease

Cited by 34 publications

References 114 publications

Quantitative live cell imaging of a tauopathy model enables the identification of a polypharmacological drug candidate that restores physiological microtubule regulation

Quantitative live cell imaging of a tauopathy model enables the identification of a polypharmacological drug candidate that restores physiological microtubule regulation

Inhibition of monoamine oxidase B reduces atherosclerosis and fatty liver in mice

Effective Management of “OFF” Episodes in Parkinson’s Disease: Emerging Treatment Strategies and Unmet Clinical Needs

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