Pharmacological aspects of the neuroprotective effects of irreversible MAO-B inhibitors, selegiline and rasagiline, in Parkinson’s disease

Szökő, Éva; Tábi, Tamás; Riederer, Peter; Vécsei, László; Magyar, K.

doi:10.1007/s00702-018-1853-9

Cited by 85 publications

(46 citation statements)

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“…These side effects are mainly produced by intestinal MAO A inhibition, since the tyramine oxidation occurs exclusively by intestinal MAO A, which prompted research to develop and characterize selective inhibitors. Along these premises, selective MAO B inhibitors, such as selegiline (SEL) and rasagiline (RAS) ( Figure 1 ), do not have such high incidence for fatal side effects, which warrants their use without the restriction of a low-tyramine diet [ 24 ].…”

Section: Introductionmentioning

confidence: 99%

Hydride Abstraction as the Rate-Limiting Step of the Irreversible Inhibition of Monoamine Oxidase B by Rasagiline and Selegiline: A Computational Empirical Valence Bond Study

Tandarić

Prah

Stare

et al. 2020

IJMS

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Monoamine oxidases (MAOs) catalyze the degradation of a very broad range of biogenic and dietary amines including many neurotransmitters in the brain, whose imbalance is extensively linked with the biochemical pathology of various neurological disorders, and are, accordingly, used as primary pharmacological targets to treat these debilitating cognitive diseases. Still, despite this practical significance, the precise molecular mechanism underlying the irreversible MAO inhibition with clinically used propargylamine inhibitors rasagiline and selegiline is still not unambiguously determined, which hinders the rational design of improved inhibitors devoid of side effects current drugs are experiencing. To address this challenge, we present empirical valence bond QM/MM simulations of the rate-limiting step of the MAO inhibition involving the hydride anion transfer from the inhibitor α-carbon onto the N5 atom of the flavin adenin dinucleotide (FAD) cofactor. The proposed mechanism is strongly supported by the obtained free energy profiles, which confirm a higher reactivity of selegiline over rasagiline, while the calculated difference in the activation Gibbs energies of ΔΔG‡ = 3.1 kcal mol−1 is found to be in very good agreement with that from the measured literature kinact values that predict a 1.7 kcal mol−1 higher selegiline reactivity. Given the similarity with the hydride transfer mechanism during the MAO catalytic activity, these results verify that both rasagiline and selegiline are mechanism-based irreversible inhibitors and offer guidelines in designing new and improved inhibitors, which are all clinically employed in treating a variety of neuropsychiatric and neurodegenerative conditions.

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Section: Introductionmentioning

confidence: 99%

Hydride Abstraction as the Rate-Limiting Step of the Irreversible Inhibition of Monoamine Oxidase B by Rasagiline and Selegiline: A Computational Empirical Valence Bond Study

Tandarić

Prah

Stare

et al. 2020

IJMS

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“…All these properties may contribute to its neuroprotective activity. These preclinical findings were previously thoroughly reviewed (Gerlach et al 1996;Magyar et al 2004Magyar et al , 2006Naoi and Maruyama 2010;Maruyama and Naoi 2013;Szoko et al 2018).…”

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confidence: 99%

Selegiline: a molecule with innovative potential

et al. 2019

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Monoamine oxidase B (MAO-B) inhibitors have an established role in the treatment of Parkinson's disease as monotherapy or adjuvant to levodopa. Two major recognitions were required for their introduction into this therapeutic field. The first was the elucidation of the novel pharmacological properties of selegiline as a selective MAO-B inhibitor by Knoll and Magyar and the original idea of Riederer and Youdim, supported by Birkmayer, to explore its effect in parkinsonian patients with on-off phases. In the 1960s, MAO inhibitors were mainly studied as potential antidepressants, but Birkmayer found that combined use of levodopa and various MAO inhibitors improved akinesia in Parkinson's disease. However, the serious side effects of the first non-selective MAO inhibitors prevented their further use. Later studies demonstrated that MAO-B, mainly located in glial cells, is important for dopamine metabolism in the brain. Recently, cell and molecular studies revealed interesting properties of selegiline opening new possibilities for neuroprotective mechanisms and a disease-modifying effect of MAO-B inhibitors.

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“…Широкий спектр биологической активности изатина реализуется путём взаимодействия с многочисленными изатин-связывающими белками, многие из которых были идентифицированы в ходе протеомного профилирования препаратов мозга мышей и крыс [1, [5][6][7]. В контексте нейропротекторного эффекта [1], действие изатина сопоставимо с эффектами депрениласелективного механизм-активируемого ингибитора моноаминоксидазы Б (МАО Б) и известного нейропротекторного препарата, применяющегося для лечения болезни Паркинсона [8,9]. В случае экспериментального паркинсонизма, развитие которого обусловлено биоактивацией протоксина 1-метил-4-фенил-1,2,3,6-тетрагидропиридина (МФТП) под действием МАО Б, эффект и депренила [8,9], и, по-видимому, изатина [10] связан с ингибированием этого фермента и сниженным образованием нейротоксина 1-метил-4-пиридиния (МФП + ).…”

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“…В контексте нейропротекторного эффекта [1], действие изатина сопоставимо с эффектами депрениласелективного механизм-активируемого ингибитора моноаминоксидазы Б (МАО Б) и известного нейропротекторного препарата, применяющегося для лечения болезни Паркинсона [8,9]. В случае экспериментального паркинсонизма, развитие которого обусловлено биоактивацией протоксина 1-метил-4-фенил-1,2,3,6-тетрагидропиридина (МФТП) под действием МАО Б, эффект и депренила [8,9], и, по-видимому, изатина [10] связан с ингибированием этого фермента и сниженным образованием нейротоксина 1-метил-4-пиридиния (МФП + ). Однако, торможение МАО Б, очевидно, не единственное звено нейропротекторных механизмов этих веществ [8][9][10].…”

unclassified

“…В случае экспериментального паркинсонизма, развитие которого обусловлено биоактивацией протоксина 1-метил-4-фенил-1,2,3,6-тетрагидропиридина (МФТП) под действием МАО Б, эффект и депренила [8,9], и, по-видимому, изатина [10] связан с ингибированием этого фермента и сниженным образованием нейротоксина 1-метил-4-пиридиния (МФП + ). Однако, торможение МАО Б, очевидно, не единственное звено нейропротекторных механизмов этих веществ [8][9][10]. Например, депренил [11][12][13] и изатин [14] взаимодействуют с глицеральдегид-3-фосфатдегидрогеназой (ГАФД) -гликолитическим ферментом, которому свойственны важные, не связанные с гликолизом функции [15].…”

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The effect of deprenyl and isatin administration to mice on the proteomic profile of liver isatin-binding proteins

et al. 2018

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Isatin (indol-2,3-dione) is an endogenous indole found in the brain, peripheral tissues and biological body fluids of humans and animals. Its wide spectrum of biological activity is realized via interaction with numerous isatin-binding proteins; these include proteins playing an important role in the development of neurodegenerative pathology. In the context of the neuroprotective effect, the effect of isatin is comparable to the effects of deprenyl, a pharmacological agent used for treatment of Parkinson's disease. In this study, the effects of the course of deprenyl (1 mg/kg) and isatin (20 mg/kg) administration for 21 days on the profile of the isatin-binding proteins of the liver of mice have been investigated. Proteomic profiling of liver isatin-binding proteins of control mice by means of 5-aminocaproylisatin as an affinity ligand resulted in identification of 105 proteins. Treatment of animals with a low dose of isatin slightly decreased (up to 91), while injections of deprenyl slightly increased (up to 120) the total number of isatin-binding proteins. 75 proteins were common for all three groups; they represented from 62.5% (in deprenyl treated mice) and 71% (in control mice), to 82% (isatin treated mice) of the total number of identified liver isatin-binding proteins. Proteomic analysis of the isatin-binding proteins of mice treated with isatin (20 mg/kg) or deprenyl (1 mg/kg) for 21 days revealed a representative group of proteins (n=30) that were sensitive to the administration of these substances. Taking into account the previously obtained results, it is reasonable to suggest that the change in the profile of isatin-binding proteins may be attributed to accumulation of isatin and deprenyl in the liver and interaction with target proteins prevents their subsequent binding to the affinity sorbent. In this context, the identified isatin-binding liver proteins of control animals that do not bind to the affinity sorbent (immobilized isatin analogue) after treatment of animals with either deprenyl or isatin appear to be specific targets directly interacting with isatin in vivo.

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Pharmacological aspects of the neuroprotective effects of irreversible MAO-B inhibitors, selegiline and rasagiline, in Parkinson’s disease

Cited by 85 publications

References 155 publications

Hydride Abstraction as the Rate-Limiting Step of the Irreversible Inhibition of Monoamine Oxidase B by Rasagiline and Selegiline: A Computational Empirical Valence Bond Study

Hydride Abstraction as the Rate-Limiting Step of the Irreversible Inhibition of Monoamine Oxidase B by Rasagiline and Selegiline: A Computational Empirical Valence Bond Study

Selegiline: a molecule with innovative potential

The effect of deprenyl and isatin administration to mice on the proteomic profile of liver isatin-binding proteins

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