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Biomedicines ◽  
2022 ◽  
Vol 10 (1) ◽  
pp. 154
Author(s):  
Shofiul Azam ◽  
Ju-Young Park ◽  
In-Su Kim ◽  
Dong-Kug Choi

Piperine (PIP) is an active alkaloid of black and long peppers. An increasing amount of evidence is suggesting that PIP and its metabolite’s could be a potential therapeutic to intervene different disease conditions including chronic inflammation, cardiac and hepatic diseases, neurodegenerative diseases, and cancer. In addition, the omnipresence of PIP in food and beverages made this compound an important investigational material. It has now become essential to understand PIP pharmacology and toxicology to determine its merits and demerits, especially its effect on the central nervous system (CNS). Although several earlier reports documented that PIP has poor pharmacokinetic properties, such as absorption, bioavailability, and blood–brain barrier permeability. However, its interaction with metabolic enzyme cytochrome P450 superfamily and competitive hydrophobic interaction at Monoamine oxide B (MAO-B) active site have made PIP both a xenobiotics bioenhancer and a potential MAO-B inhibitor. Moreover, recent advancements in pharmaceutical technology have overcome several of PIP’s limitations, including bioavailability and blood–brain barrier permeability, even at low doses. Contrarily, the structure activity relationship (SAR) study of PIP suggesting that its several metabolites are reactive and plausibly responsible for acute toxicity or have pharmacological potentiality. Considering the importance of PIP and its metabolites as an emerging drug target, this study aims to combine the current knowledge of PIP pharmacology and biochemistry with neurodegenerative and neurological disease therapy.


2022 ◽  
Vol 12 (1) ◽  
Author(s):  
Youhei Obata ◽  
Mie Kubota-Sakashita ◽  
Takaoki Kasahara ◽  
Masafumi Mizuno ◽  
Takahiro Nemoto ◽  
...  

AbstractMonoamine oxidase (MAO) is a key enzyme responsible for the degradation of neurotransmitters and trace amines. MAO has two subtypes (MAO-A and MAO-B) that are encoded by different genes. In the brain, MAO-B is highly expressed in the paraventricular thalamic nucleus (PVT); however, its substrate in PVT remains unclear. To identify the MAO-B substrate in PVT, we generated Maob knockout (KO) mice and measured five candidate substrates (i.e., noradrenaline, dopamine, 3-methoxytyramine, serotonin, and phenethylamine [PEA]) by liquid chromatography tandem mass spectrometry. We showed that only PEA levels were markedly elevated in the PVT of Maob KO mice. To exclude the influence of peripheral MAO-B deficiency, we developed brain-specific Maob KO mice, finding that PEA in the PVT was increased in brain-specific Maob KO mice, whereas the extent of PEA increase was less than that in global Maob KO mice. Given that plasma PEA levels were elevated in global KO mice, but not in brain–specific KO mice, and that PEA passes across the blood–brain barrier, the substantial accumulation of PEA in the PVT of Maob KO mice was likely due to the increase in plasma PEA. These data suggest that PEA is a substrate of MAO-B in the PVT as well as other tissues.


Pharmacia ◽  
2022 ◽  
Vol 69 (1) ◽  
pp. 15-20
Author(s):  
Alexandrina Mateeva ◽  
Lily Peikova ◽  
Magdalena Kondeva-Burdina ◽  
Maya Georgieva

In this research, a new rapid PR- HPLC method was developed for the determination of metabolites in isolated rat hapatocytes. The chromatographic parameters, including the stationary and mobile phases, outlet pressure, temperature and flow rate, were optimized. The method identified two initial from the synthesis molecules in higher concentration and one new unidentified structure as products of the hepatocytic processing of the evaluated analyte. The results identified as first step of metabolism the hydrolysis of the hydrazone group. Further investigations should be aimed into determining the next metabolic transformations, predicted by the in silico application of the web server SMARTCyp.


Author(s):  
Zhi Xin Chew ◽  
Chooi Ling Lim ◽  
Khuen Yen Ng ◽  
Soi Moi Chye ◽  
Anna Pick Kiong Ling ◽  
...  

Abstract: Parkinson's disease (PD) is a progressive neurodegenerative disease characterised by reduced dopamine level in the substantial nigra. This may lead to typical motor features such as bradykinesia, resting tremors and rigid muscles; as well as non-motor symptoms such as neuropsychiatric symptoms, sleep disorders, autonomic dysfunction, and sensory disturbances. Inhibitors of MAO-B are used to alleviate symptoms by reducing monoamine oxidase-catalysed degradation of dopamine; hence, preserving functional levels of dopamine. The very first MAO-B used therapeutically was selegiline, followed by rasagiline, its indane derivative which has superior efficacy and selectivity. Both inhibitors can be used as monotherapy or in combination with other anti-Parkinson drugs. Safinamide, a reversible MAO-B inhibitor that utilises both dopaminergic and non-dopaminergic mechanisms, was recently approved by the European Medicines Agency (EMA) (2015) and U.S. FDA (2017) as an add-on therapy for patients with mid- or late-stage Parkinson’s disease. Furthermore, MAO-B inhibitors were found to be associated with potential neuroprotective and disease modifying effects. However, evidence of their efficacy and role in PD models are scarce and warrants further investigation.


2021 ◽  
pp. 089198872110600
Author(s):  
Danielle, Nimmons ◽  
Cini Bhanu ◽  
Mine Orlu ◽  
Anette Schrag ◽  
Kate Walters

Background Orthostatic hypotension (OH) is multifactorial in Parkinson’s disease (PD). Antiparkinsonian medication can contribute to OH, leading to increased risk of falls, weakness and fatigue. Methods We conducted a systematic review and meta-analysis of randomised controlled trials (RCTs) of antiparkinsonian drugs associated with OH as an adverse effect, compared to placebo. We searched EMBASE, MEDLINE and Web of Science databases until November 2020. Analysis used fixed-effects models and the GRADE tool to rate quality of evidence. Meta-analysis was performed if 3 or more studies of a drug group were available. Results Twenty-one RCTs including 3783 patients were included comparing 6 PD drug groups to placebo (MAO-B inhibitors, dopamine agonists, levodopa, COMT inhibitors, levodopa and adenosine receptor antagonists). OH was recorded as an adverse event or measurement of vital signs, without further specification on how this was defined or operationalised. Meta-analysis was performed for MAO-B inhibitors and dopamine agonists, as there were 3 or more studies for these drug groups. In this analysis, compared with placebo, neither MAO-B inhibitors or dopamine agonists were associated with increased risk of OH, (OR 2.28 [95% CI:0.81–6.46]), (OR 1.39 [95% CI:0.97–1.98]). Conclusions Most studies did not specifically report OH, or reporting of OH was limited, including how and when it was measured. Furthermore, studies specifically reporting OH included participants that were younger than typical PD populations without multimorbidity. Future trials should address this, for example,, by including individuals over the age of 75, to improve estimations of how antiparkinsonian medications affect risk of OH.


2021 ◽  
pp. 1-17
Author(s):  
Yu-Yan Tan ◽  
Peter Jenner ◽  
Sheng-Di Chen

Monoamine oxidase-B (MAO-B) inhibitors are commonly used for the symptomatic treatment of Parkinson’s disease (PD). MAO-B inhibitor monotherapy has been shown to be effective and safe for the treatment of early-stage PD, while MAO-B inhibitors as adjuvant drugs have been widely applied for the treatment of the advanced stages of the illness. MAO-B inhibitors can effectively improve patients’ motor and non-motor symptoms, reduce “OFF” time, and may potentially prevent/delay disease progression. In this review, we discuss the effects of MAO-B inhibitors on motor and non-motor symptoms in PD patients, their mechanism of action, and the future development of MAO-B inhibitor therapy.


2021 ◽  
Vol 29 ◽  
pp. 1-26
Author(s):  
Joice Silva de Oliveira ◽  
Luciana Fernandes Pastana Ramos
Keyword(s):  
Mao B ◽  

Introdução. A Doença de Parkinson (DP) é uma patologia neurológica caracterizada pela degeneração crônica e progressiva de neurônios dopaminérgicos na substância negra pars compacta (SNpc) e é a segunda desordem neurodegenerativa mais comum, sendo a idade o principal fator de risco. A L-3,4-dihidroxifenilanina (L-DOPA) tem sido amplamente utilizada como o principal tratamento de DP. Todavia, a maioria dos pacientes cronicamente tratados com L-DOPA apresentam efeitos adversos motores e psiquiátricos. Assim, várias estratégias terapêuticas têm sido testadas a fim de repor dopamina estriatal de maneira mais fisiológica, dentre elas a utilização de inibidores da Monoamina Oxidase B (MAO-B). Objetivo. Obter modelos teóricos de novos inibidores da MAO-B, com características físico-químicas para o desenvolvimento de fármacos para o tratamento da DP. Método. Foi realizada uma triagem virtual baseada na estrutura do inibidor cristalográfico Safinamida, com aplicação de filtro para avaliação da passagem pela barreira hematoencefálica, bem como simulações de docking e validação de re-docking. Resultados. Os inibidores teóricos foram: (7R,8S,8'R)-7-Hydroxy-3,4,3',4'-tetramethoxy-8,8'-neolignan, Oxovirolin and 3-oxo-skimmiarepin, que exibiram afinidade para o sítio de ligação da MAO-B melhor ou semelhante ao do inibidor de referência. Todos os compostos exibiram propriedades físico-químicas favoráveis ​​à biodisponibilidade oral, de acordo com os descritores de Lipinski e Veber. Conclusão. Os inibidores teóricos encontrados são alvos potenciais para o planejamento e desenvolvimento de medicamentos para a doença de Parkinson. Porém, por se tratar de um estudo in silico, é necessário que mais pesquisas e testes sejam feitos para avaliar in vitro e, posteriormente, in vivo o comportamento dessas moléculas.


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