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Seong Su Kang, Eun Hee Ahn, Zhentao Zhang, Xia Liu, Fredric P Manfredsson, Ivette M Sandoval, Susov Dhakal, P Michael Iuvone, Xuebing Cao, Keqiang Ye
Dopaminergic neurodegeneration in Parkinson's disease (PD) is associated with abnormal dopamine metabolism by MAO-B (monoamine oxidase-B) and intracellular α-Synuclein (α-Syn) aggregates, called the Lewy body. However, the molecular relationship between α-Syn and MAO-B remains unclear. Here, we show that α-Syn directly binds to MAO-B and stimulates its enzymatic activity, which triggers AEP (asparagine endopeptidase; legumain) activation and subsequent α-Syn cleavage at N103, leading to dopaminergic neurodegeneration...
May 16, 2018: EMBO Journal
Nobutaka Hattori, Atsushi Takeda, Shinichi Takeda, Akira Nishimura, Masafumi Kato, Hideki Mochizuki, Masahiro Nagai, Ryosuke Takahashi
INTRODUCTION: Rasagiline, a selective, irreversible monoamine oxidase-B inhibitor, is in development in Japan as adjunctive therapy to levodopa. This Phase 2/3 trial evaluated the efficacy and safety of adjunctive rasagiline in Japanese patients with Parkinson's disease (PD) and wearing-off phenomena. METHODS: Patients aged 30-79 years with diagnosed PD and stable levodopa use were randomized 1:1:1 to rasagiline (0.5/1 mg/day) or placebo for 26 weeks. The primary endpoint was change from baseline in mean daily OFF-time during the treatment period...
April 27, 2018: Parkinsonism & related Disorders
Marc-André Roy, Maxime Doiron, Jessica Talon-Croteau, Nicolas Dupré, Martine Simard
OBJECTIVE: This study aimed to systematically review the effects of currently prescribed antiparkinson medication on cognition in patients with mild-to-moderate Parkinson's disease (PD) who were either cognitively intact or mildly impaired. METHODS: English- and French-language studies published between 1969 and 2017 were accessed via MedLine, PsychNET, EMBASE and EBSCO databases. Methodological quality (MQ) was evaluated with the quality assessment instrument of the Cochrane Collaboration Depression, Anxiety and Neurosis Review (scores from 0% to 44% indicate very low quality; scores from 45% to 64% indicate low quality; scores from 65% to 84% indicate medium quality; and scores from 85% to 100% indicate high quality)...
May 11, 2018: Canadian Journal of Neurological Sciences. le Journal Canadien des Sciences Neurologiques
Susan H Fox, Regina Katzenschlager, Shen-Yang Lim, Brandon Barton, Rob M A de Bie, Klaus Seppi, Miguel Coelho, Cristina Sampaio
OBJECTIVE: The objective of this review was to update evidence-based medicine recommendations for treating motor symptoms of Parkinson's disease (PD). BACKGROUND: The Movement Disorder Society Evidence-Based Medicine Committee recommendations for treatments of PD were first published in 2002 and updated in 2011, and we continued the review to December 31, 2016. METHODS: Level I studies of interventions for motor symptoms were reviewed. Criteria for inclusion and quality scoring were as previously reported...
March 23, 2018: Movement Disorders: Official Journal of the Movement Disorder Society
Dawei Lei, Zhengbo Shao, Xinrong Zhou, Huiping Yuan
Retinal ischemia-reperfusion (RIR) injury causes neuronal degeneration and initiates various optic nerve diseases. This study aimed to investigate the synergistic neuroprotective effect of rasagiline and idebenone against RIR injury. A combination of rasagiline and idebenone was administered intraperitoneally immediately after establishment of the RIR model. Treatment with the combination of the two drugs resulted in a significant restoration of retinal thickness and retinal ganglion cells. Apoptosis of cells in ganglion cell layers was also ameliorated, suggesting that the effect of the two drugs was synergistic and the expression of brain-derived neurotrophic factor increased...
February 23, 2018: Oncotarget
Ruben Smith, Michael Schöll, Elisabet Londos, Tomas Ohlsson, Oskar Hansson
Mixed pathologies of α-synuclein, β-amyloid and tau are relatively common in Parkinson's disease (PD) and Dementia with Lewy Bodies (DLB). We therefore wanted to study the retention patterns of18 F-AV-1451 in PD, PD-dementia (PDD), and DLB. To do this 44 healthy controls, 11 non-demented patients with PD, 18 patients with PDD, and six patients with DLB underwent MRI and18 F-AV-1451 PET scanning and cognitive testing. We found that parietal18 F-AV-1451 retention was increased in patients with DLB compared to controls and PD patients, while18 F-AV-1451 uptake was reduced in the substantia nigra in PDD...
March 16, 2018: Scientific Reports
Dhaval R Kalaria, Mayank Singhal, Vandana Patravale, Virginia Merino, Yogeshvar N Kalia
Effective treatment of Parkinson's disease (PD) involves administration of therapeutic agents with complementary mechanisms of action in order to replenish, sustain or substitute endogenous dopamine. The objective of this study was to investigate anodal co-iontophoresis of pramipexole (PRAM; dopamine agonist) and rasagiline (RAS; MAO-B inhibitor) in vitro and in vivo. Passive permeation of PRAM and RAS (20 mM each) across porcine skin after 6 h was 15.7 ± 1.9 and 16.0 ± 2.9 µg/cm2 , respectively...
June 2018: European Journal of Pharmaceutics and Biopharmaceutics
Dale E Edmondson, Claudia Binda
Monoamine oxidases A and B (MAO A and B) are mammalian flavoenzymes bound to the outer mitochondrial membrane. They were discovered almost a century ago and they have been the subject of many biochemical, structural and pharmacological investigations due to their central role in neurotransmitter metabolism. Currently, the treatment of Parkinson's disease involves the use of selective MAO B inhibitors such as rasagiline and safinamide. MAO inhibition was shown to exert a general neuroprotective effect as a result of the reduction of oxidative stress produced by these enzymes, which seems to be relevant also in non-neuronal contexts...
2018: Sub-cellular Biochemistry
Peter A LeWitt, Leo Verhagen Metman, Robert Rubens, Sarita Khanna, Sherron Kell, Suneel Gupta
OBJECTIVES: Extended-release (ER) carbidopa-levodopa (CD-LD) (IPX066/RYTARY/NUMIENT) produces improvements in "off" time, "on" time without troublesome dyskinesia, and Unified Parkinson Disease Rating Scale scores compared with immediate-release (IR) CD-LD or IR CD-LD plus entacapone (CLE). Post hoc analyses of 2 ER CD-LD phase 3 trials evaluated whether the efficacy and safety of ER CD-LD relative to the respective active comparators were altered by concomitant medications (dopaminergic agonists, monoamine oxidase B [MAO-B] inhibitors, or amantadine)...
March 2018: Clinical Neuropharmacology
Éva Szökő, Tamás Tábi, Peter Riederer, László Vécsei, Kálmán Magyar
The era of MAO-B inhibitors dates back more than 50 years. It began with Kálmán Magyar's outstanding discovery of the selective inhibitor, selegiline. This compound is still regarded as the gold standard of MAO-B inhibition, although newer drugs have also been introduced to the field. It was revealed early on that selective, even irreversible inhibition of MAO-B is free from the severe side effect of the non-selective MAO inhibitors, the potentiation of tyramine, resulting in the so-called 'cheese effect'...
February 7, 2018: Journal of Neural Transmission
Ana B Garcia-Delgado, Lourdes Valdés-Sánchez, Sofia M Calado, Francisco J Diaz-Corrales, Shom S Bhattacharya
AIMS: Retinitis pigmentosa (RP) is an inherited disease characterized by a progressive degeneration of rod photoreceptors. An imbalance between pro- and antiapoptotic factors, such as Bax/Bcl-2, has been involved in retinal degeneration. To date, no cure or effective treatments are available for RP. Rasagiline is an antiparkinsonian drug that has shown neuroprotective effects in part attributed to a modulation of Bax/Bcl-2 expression. In this study, we have evaluated the use of rasagiline as a potential treatment for RP...
May 2018: CNS Neuroscience & Therapeutics
Bao-Dong Li, Jing-Jun Cui, Jia Song, Ce Qi, Pei-Feng Ma, Ya-Rong Wang, Jing Bai
BACKGROUND/AIMS: A network meta-analysis is used to compare the efficacy of ropinirole, rasagiline, rotigotine, entacapone, apomorphine, pramipexole, sumanirole, bromocriptine, piribedil and levodopa, with placebo as a control, for non-motor symptoms in Parkinson's disease (PD). METHODS: PubMed, Embase and the Cochrane Library were searched from their establishment dates up to January 2017 for randomized controlled trials (RCTs) investigating the efficacy of the above ten drugs on the non-motor symptoms of PD...
2018: Cellular Physiology and Biochemistry
Xuan Xiao, Xing-Xing Zhang, Mei-Miao Zhan, Kai Cheng, Shiyu Li, Zhouling Xie, Chenzhong Liao
Parkinson's disease (PD) is associated with elevated levels of hMAO-B in the brain, and MAO-B has been recognized a successful target for developing anti-PD drugs. Herein we report rasagiline derivatives as novel potent and selective hMAO-B inhibitors. They were designed by employing fragment-based drug design strategy to link rasagiline and hydrophobic fragments, which may target a hydrophobic pocket in the entrance cavity of hMAO-B. Different linkers such as -OCH2 -, -SCH2 -, -OCH2 CH2 -, -OCH2 CH2 O-, -OCH2 CH2 CH2 O- were tried...
February 10, 2018: European Journal of Medicinal Chemistry
W Schrempf, M Fauser, M Wienecke, S Brown, A Maaß, C Ossig, K Otto, M D Brandt, M Löhle, U Schwanebeck, X Graehlert, H Reichmann, A Storch
BACKGROUND AND PURPOSE: The aim was to study the effects of rasagiline on sleep quality in patients with Parkinson's disease (PD) with sleep disturbances. Sleep disorders are common in PD. Rasagiline is widely used in patients with PD, but double-blind polysomnographic trials on its effects on sleep disturbances are missing. METHODS: This was a single-center, double-blind, baseline-controlled investigator-initiated clinical trial of rasagiline (1 mg/day) over 8 weeks in patients with PD with sleep disturbances...
April 2018: European Journal of Neurology: the Official Journal of the European Federation of Neurological Societies
Makoto Naoi, Wakako Maruyama, Masayo Shamoto-Nagai
Type A and B monoamine oxidases (MAO-A, -B) mediate and modulate intracellular signal pathways for survival or death of neuronal cells. MAO-A is associated with development of neuronal architecture, synaptic activity, and onset of psychiatric disorders, including depression, and antisocial aggressive impulsive behaviors. MAO-B produces hydrogen peroxide and plays a vital role in neuronal loss of neurodegenerative disorders, such as Parkinson's and Alzheimer's diseases. This review presents a novel role of MAO-A and B, their substrates and inhibitors, and hydrogen peroxide in brain function and neuronal survival and death...
December 26, 2017: Journal of Neural Transmission
Ying Jiang, Xuemei Zhang, Hongjie Mu, Hongchen Hua, Dongyu Duan, Xiuju Yan, Yiyun Wang, Qingqing Meng, Xiaoyan Lu, Aiping Wang, Wanhui Liu, Youxin Li, Kaoxiang Sun
A microsphere-gel in situ forming implant (MS-Gel ISFI) dual-controlled drug delivery system was applied to a high water-soluble small-molecule compound Rasagiline mesylate (RM) for effective treatment of Parkinson's disease. This injectable complex depot system combined an in situ phase transition gel with high drug-loading and encapsulation efficiency RM-MS prepared by a modified emulsion-phase separation method and optimized by Box-Behnken design. It was evaluated for in vitro drug release, in vivo pharmacokinetics, and in vivo pharmacodynamics...
November 2018: Drug Delivery
József Attila Szász, Viorelia Constantin, Péter Alpár Fazakas, Eszter Blényesi, Levente Gábor Grieb, Antal Balla, Mónika Sárig, Kinga Szegedi, Eszter Noémi Bartha, Szabolcs Szatmári
INTRODUCTION: Selective monoamine oxidase B inhibitors have an accurate place in therapeutical strategy of Parkinsons's disease. In the early stages of the disease, especially in younger patients with milder symptoms, the introduction of levodopa substitution could be efficacious in delaying; in advanced stages they are mainly used to treat motor complications, as an adjunct to levodopa. AIM: The evaluation of therapeutical strategies used in the neurology clinics of Tirgu Mures County Emergency Clinical Hospital in order to define the role of monoamine oxidase B inhibitors...
December 2017: Orvosi Hetilap
Wenjia Zhou, Chengzhe Lv, Quanying Zhang, Shunlin Zong, Meng Wang
BACKGROUND AND OBJECTIVES: Rasagiline tablet is an oral MAO-B inhibitor applied in early or advanced Parkinson's disease (PD). However, when patients with PD cannot take their usual oral medications, a rasagiline transdermal patch can be used as a way to offer continuous rasagiline while avoiding plasma concentration peaks and troughs. The objectives of this study were to investigate the pharmacokinetics, pharmacodynamics, and safety of the rasagiline transdermal patch in healthy Chinese subjects...
February 2018: Clinical Drug Investigation
Michele Pistacchi, Manuela Gioulis, Flavio Sanson, Sandro Z Marsala
BACKGROUND: 'Wearing off' refers to the phenomenology of movement disorders in Parkinson's disease (PD) that appears early and is much commoner than generally believed. It may be present in the form of either motor symptoms or non-motor symptoms. AIM: To investigate the utility of wearing-off questionnaire (WOQ-19, Italian version) in the outpatient clinical practice to assess the suitability of different combinations of treatment, in various stages of PD. METHODS: 73 consecutive patients (58% male and 42% female) suffering from PD were recruited through the Santorso Hospital and San Martino Hospital from September 2012 to March 2014...
November 2017: Neurology India
Matt R Adams, Chieh-Hung Tien, Robert McDonald, Alexander W H Speed
The first use of diazaphospholenes as chiral catalysts has been demonstrated with enantioselective imine hydroboration. A chiral diazaphospholene prepared in a simple three-step synthesis from commercial materials has been shown to achieve the highest enantioselectivity for the hydroboration of alkyl imines with pinacolborane reported to date. Enantiomer ratios of up to 88:12 were obtained with low (2 mol %) catalyst loadings. Twenty examples of asymmetric reduction employing this main-group catalysis protocol, including the synthesis of the pharmaceuticals ent-rasagiline and fendiline, are shown...
December 22, 2017: Angewandte Chemie
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