LSD1 in drug discovery: From biological function to clinical application.

Lysine-specific demethylase 1 (LSD1) is a flavin adenine dinucleotide (FAD) dependent monoamine oxidase (MAO) that erases the mono-, and dimethylation of histone 3 lysine 4 (H3K4), resulting in the suppression of target gene transcriptions. Besides, it can also demethylate some nonhistone substrates to regulate their biological functions. As reported, LSD1 is widely upregulated and plays a key role in several kinds of cancers, pharmacological or genetic ablation of LSD1 in cancer cells suppresses cell aggressiveness by several distinct mechanisms. Therefore, numerous LSD1 inhibitors, including covalent and noncovalent, have been developed and several of them have entered clinical trials. Herein, we systemically reviewed and discussed the biological function of LSD1 in tumors, lymphocytes as well as LSD1-targeting inhibitors in clinical trials, hoping to benefit the field of LSD1 and its inhibitors.

Virus infection participates in the occurrence and development of human diseases through monoamine oxidase.

Monoamine oxidase (MAO) is a membrane-bound mitochondrial enzyme that maintains the steady state of neurotransmitters and other biogenic amines in biological systems through catalytic oxidation and deamination. MAO dysfunction is closely related to human neurological and psychiatric diseases and cancers. However, little is known about the relationship between MAO and viral infections in humans. This review summarises current research on how viral infections participate in the occurrence and development of human diseases through MAO. The viruses discussed in this review include hepatitis C virus, dengue virus, severe acute respiratory syndrome coronavirus 2, human immunodeficiency virus, Japanese encephalitis virus, Epstein-Barr virus, and human papillomavirus. This review also describes the effects of MAO inhibitors such as phenelzine, clorgyline, selegiline, M-30, and isatin on viral infectious diseases. This information will not only help us to better understand the role of MAO in the pathogenesis of viruses but will also provide new insights into the treatment and diagnosis of these viral diseases.

Effect of Hydroxytyrosol Derivatives of Donepezil on the Activity of Enzymes Involved in Neurodegenerative Diseases and Oxidative Damage.

Monoamine oxidase and xanthine oxidase inhibitors represent useful multi-target drugs for the prevention, attenuation, and treatment of oxidative damage and neurodegenerative disorders. Chimeric molecules, constituted by naturally derived compounds linked to drugs, represent lead compounds to be explored for the discovery of new synthetic drugs acting as enzyme inhibitors. We have previously reported that seven hydroxytyrosol-donepezil hybrid compounds play a protective role in an in vitro neuronal cell model of Alzheimer's disease. In this work, we analyzed the effects exerted by the hybrid compounds on the activity of monoamine oxidase A (MAO-A) and B (MAO-B), as well as on xanthine oxidase (XO), enzymes involved in both neurodegenerative disorders and oxidative stress. The results pointed to the identification, among the compounds tested, of selective inhibitors between the two classes of enzymes. While the 4-hydroxy-3-methoxyphenethyl 1-benzylpiperidine-4-carboxylate- (HT3) and the 4-hydroxyphenethyl 1-benzylpiperidine-4-carboxylate- donepezil derivatives (HT4) represented the best inhibitors of MAO-A, with a scarce effect on MAO-B, they were almost ineffective on XO. On the other hand, the 4,5-dihydroxy-2-nitrophenethyl 1-benzylpiperidine-4-carboxylate donepezil derivative (HT2), the least efficient MAO inhibitor, acted like the best XO inhibitor. Therefore, the differential enzymatic targets identified among the hybrid compounds synthesized enhance the possible applications of these polyphenol-donepezil hybrids in neurodegenerative disorders and oxidative stress.

Monoamine Oxidase Inhibitors for Trichotillomania: A Case Series.

PURPOSE/BACKGROUND: Despite several decades of research, there are no US Food and Drug Administration-approved medications for trichotillomania or medications generally approved in other geographical jurisdictions. Monoamine oxidase inhibitors show efficacy in the treatment of depression and some possible promise for obsessive compulsive disorder. METHODS/PROCEDURES: We present new data from a case series collected in a specialty clinical practice over a 4-year period. FINDINGS/RESULTS: In 5 treatment-resistant patients whose trichotillomania had not improved with at least 1 course of cognitive behavior therapy and trials of n -acetyl cysteine, an antipsychotic, and a serotonin selective reuptake inhibitor, 2 had marked clinical improvement (>40% improvement) on phenelzine, 1 improved on tranylcypromine, and 2 showed no improvement (<10%) on phenelzine. In 2 of the 3 patients who experienced improvement, there was co-occurring depression. IMPLICATIONS/CONCLUSIONS: Monoamine oxidase inhibitors in trichotillomania may deserve large-scale randomized controlled trials, particularly in specialist settings where first-line interventions have proven inadequate to manage severe symptoms.

Clinical benefit of MAO-B and COMT inhibition in Parkinson's disease: practical considerations.

Inhibitors of monoamine oxidase B (MAO-B) and catechol-O-methyltransferase (COMT) are major strategies to reduce levodopa degradation and thus to increase and prolong its effect in striatal dopaminergic neurotransmission in Parkinson's disease patients. While selegiline/rasagiline and tolcapone/entacapone have been available on the market for more than one decade, safinamide and opicapone have been approved in 2015 and 2016, respectively. Meanwhile, comprehensive data from several post-authorization studies have described the use and specific characteristics of the individual substances in clinical practice under real-life conditions. Here, we summarize current knowledge on both medication classes, with a focus on the added clinical value in Parkinson's disease. Furthermore, we outline practical considerations in the treatment of motor fluctuations and provide an outlook on ongoing studies with MAO-B and COMT inhibitors.

Comparative efficacy and safety of monoamine oxidase type B inhibitors plus channel blockers and monoamine oxidase type B inhibitors as adjuvant therapy to levodopa in the treatment of Parkinson's disease: a network meta-analysis of randomized controlled trials.

BACKGROUND AND PURPOSE: The monoamine oxidase type B inhibitors plus channel blockers (MAO-BIs plus) are a new class of antiparkinsonian drug with additional mechanisms of action for their property as ion channel blockers. The present study aimed to compare the efficacy and safety of MAO-BIs plus and conventional MAO-BIs, as well as their corresponding doses, as adjuvant therapy to levodopa in the treatment of Parkinson's disease (PD). METHOD: Randomized controlled trials enrolling PD patients treated with selegiline, rasagiline, safinamide or zonisamide as adjuvant therapy to levodopa were identified. Bayesian network meta-analysis was conducted. RESULTS: Thirty-one randomized controlled trials comprising 7142 PD patients were included. Compared with levodopa monotherapy, the combination therapy of MAO-BIs and levodopa was significantly more effective, with a mean difference of 2.74 (1.26-4.18) on the Unified Parkinson's Disease Rating Scale (UPDRS) III score change for selegiline, 2.67 (1.45-3.87) for safinamide, 2.2 (0.98-3.64) for zonisamide and 2.04 (1.24-2.87) for rasagiline. No significant difference was detected amongst MAO-BIs. The surface under the cumulative ranking results showed that safinamide 100 mg and rasagiline 1 mg ranked first in improving UPDRS III and UPDRS II, respectively. Zonisamide 100 mg ranked first in reducing OFF time. For safety outcomes, rasagiline was associated with a higher incidence of adverse events than placebo and safinamide. MAO-BIs plus had a higher probability of being safer agents compared to conventional MAO-BIs. CONCLUSIONS: Monoamine oxidase type B inhibitors plus, conventional MAO-BIs and the corresponding doses are similar in efficacy in PD treatment. MAO-BIs plus might be safer than conventional MAO-BIs. Head-to-head comparisons are needed for further investigation.

Exploration of the novel phthalimide-hydroxypyridinone derivatives as multifunctional drug candidates against Alzheimer's disease.

A novel series of phthalimide-hydroxypyridinone derivatives were rationally designed and evaluated as potential anti-Alzheimer's disease (AD) agents. Bioactivity tests showed that all compounds displayed great iron ions-chelating activity (pFe3+ = 17.07-19.52), in addition to potent inhibition of human monoamine oxidase B (hMAO-B). Compound 11n emerged as the most effective anti-AD lead compound with a pFe3+ value of 18.51, along with selective hMAO-B inhibitory activity (IC50 = 0.79 ± 0.05 µM, SI > 25.3). The results of cytotoxicity assays demonstrated that 11n showed extremely weak toxicity in PC12 cell line at 50 µM. Additionally, compound 11n displayed a cytoprotective effect against H2O2-induced oxidative damage. Moreover, compound 11n exhibited ideal blood-brain barrier (BBB) permeability in the parallel artificial membrane permeation assay (PAMPA), and significantly improved scopolamine-induced cognitive and memory impairment in mice behavioral experiments. In conclusion, these favorable experimental results suggested compound 11n deserved further investigation as an anti-AD lead compound.

Effects of monotherapy with a monoamine oxidase B inhibitor on motor symptoms in Parkinson's disease are dependent on frontal function.

BACKGROUND: Monotherapy with monoamine oxidase B (MAO-B) inhibitors enhances the level of endogenous dopamine in treatment for Parkinson's disease (PD) and provides some benefits. Certain neuropsychiatric functions are also regulated by central dopaminergic activity. AIM: To investigate the relationship of the efficacy of monotherapy with MAO-B inhibitors on motor symptoms in PD with baseline cognitive function. PATIENTS AND METHODS: Outcomes were examined for 27 consecutive drug-naïve PD patients who received initial treatment with a MAO-B inhibitor (selegiline: 11, rasagiline: 16). Selegiline was titrated to an optimal dose. The dose of rasagiline was fixed at 1 mg/day. Motor symptoms were assessed using the Movement Disorder Society-Unified Parkinson's Disease Rating Scale part III before treatment and after the efficacy reached a plateau within 19 weeks after drug initiation, and the % improvement in motor symptoms was calculated. Pre-treatment cognitive function was assessed using the Montreal Cognitive Assessment (MoCA) and Frontal Assessment Battery (FAB). Correlations of % improvement in motor symptoms and baseline cognitive assessments were examined using Spearman correlation coefficients and multiple regression analysis. RESULTS: In all patients, the mean % improvement in motor symptoms was 46.5% (range 0-83.3%). Spearman correlation coefficients showed the % improvement in motor symptoms was correlated with FAB (r = 0.631, p < 0.001). In multiple regression analysis with patient background factors as independent variables, only FAB was associated with improvement in motor symptoms in the MAO-B group. CONCLUSION: Better FAB scores predict a significant improvement in motor symptoms with treatment with MAO-B inhibitors, suggesting high activity of endogenous dopamine.

Structure-Guided Design of N-Methylpropargylamino-Quinazoline Derivatives as Multipotent Agents for the Treatment of Alzheimer's Disease.

Alzheimer's disease (AD) is a complex disease with an unknown etiology. Available treatments, limited to cholinesterase inhibitors and N-methyl-d-aspartate receptor (NMDAR) antagonists, provide symptomatic relief only. As single-target therapies have not proven effective, rational specific-targeted combination into a single molecule represents a more promising approach for treating AD, and is expected to yield greater benefits in alleviating symptoms and slowing disease progression. In the present study, we designed, synthesized, and biologically evaluated 24 novel N-methylpropargylamino-quinazoline derivatives. Initially, compounds were thoroughly inspected by in silico techniques determining their oral and CNS availabilities. We tested, in vitro, the compounds' effects on cholinesterases and monoamine oxidase A/B (MAO-A/B), as well as their impacts on NMDAR antagonism, dehydrogenase activity, and glutathione levels. In addition, we inspected selected compounds for their cytotoxicity on undifferentiated and differentiated neuroblastoma SH-SY5Y cells. We collectively highlighted II-6h as the best candidate endowed with a selective MAO-B inhibition profile, NMDAR antagonism, an acceptable cytotoxicity profile, and the potential to permeate through BBB. The structure-guided drug design strategy applied in this study imposed a novel concept for rational drug discovery and enhances our understanding on the development of novel therapeutic agents for treating AD.

Data-Driven Approaches Used for Compound Library Design for the Treatment of Parkinson's Disease.

Parkinson's disease (PD) is the second most common neurodegenerative disease in older individuals worldwide. Pharmacological treatment for such a disease consists of drugs such as monoamine oxidase B (MAO-B) inhibitors to increase dopamine concentration in the brain. However, such drugs have adverse reactions that limit their use for extended periods; thus, the design of less toxic and more efficient compounds may be explored. In this context, cheminformatics and computational chemistry have recently contributed to developing new drugs and the search for new therapeutic targets. Therefore, through a data-driven approach, we used cheminformatic tools to find and optimize novel compounds with pharmacological activity against MAO-B for treating PD. First, we retrieved from the literature 3316 original articles published between 2015-2021 that experimentally tested 215 natural compounds against PD. From such compounds, we built a pharmacological network that showed rosmarinic acid, chrysin, naringenin, and cordycepin as the most connected nodes of the network. From such compounds, we performed fingerprinting analysis and developed evolutionary libraries to obtain novel derived structures. We filtered these compounds through a docking test against MAO-B and obtained five derived compounds with higher affinity and lead likeness potential. Then we evaluated its antioxidant and pharmacokinetic potential through a docking analysis (NADPH oxidase and CYP450) and physiologically-based pharmacokinetic (PBPK modeling). Interestingly, only one compound showed dual activity (antioxidant and MAO-B inhibitors) and pharmacokinetic potential to be considered a possible candidate for PD treatment and further experimental analysis.

A need for clinical trial: re-purposing the Monoamine Oxidase Inhibitors (MAO-I) for rheumatoid arthritis (RA).

There is a group of enzymes called monoamine oxidase(s) (MAOs) that help with the oxidation of amines found in both our diet and our bodies. Currently, monoamine oxidase inhibitors (MAO-Is) are utilized to manage conditions like depression, Parkinson's disease, and other psychiatric disorders. Rheumatoid arthritis (RA) is an auto-immune disease that has been linked to negative changes in mental health, such as depression. When depression co-occurs with RA, it can further worsen the outcome of the disease. Inhibiting monoamine oxidases could potentially treat RA by improving its pathological markers. Using existing pre-clinical and clinical data on safety and toxicity makes drug re-purposing advantageous. Hence, the pre-clinical validation of MAO-I's effectiveness in managing RA requires urgent regulatory intervention to commence clinical trials. Back in 1983, a clinical case report put forward the idea of repurposing MAO-I for RA treatment. Although MAO-I had been used for depression, it was observed to have a significant reduction in joint pain and stiffness. However, no significant clinical research has been conducted on this matter since then. In this commentary article, we provide a summary of the pre-clinical data that is currently available. The main focus of our discussion is on the significance of clinical trials for MAO-I, repurposing it for RA, and using it for the simultaneous management of depression and RA.

Investigation on Novel E/Z 2-Benzylideneindan-1-One-Based Photoswitches with AChE and MAO-B Dual Inhibitory Activity.

The multitarget therapeutic strategy, as opposed to the more traditional 'one disease-one target-one drug', may hold promise in treating multifactorial neurodegenerative syndromes, such as Alzheimer's disease (AD) and related dementias. Recently, combining a photopharmacology approach with the multitarget-directed ligand (MTDL) design strategy, we disclosed a novel donepezil-like compound, namely 2-(4-((diethylamino)methyl)benzylidene)-5-methoxy-2,3-dihydro-1H-inden-1-one (1a), which in the E isomeric form (and about tenfold less in the UV-B photo-induced isomer Z) showed the best activity as dual inhibitor of the AD-related targets acetylcholinesterase (AChE) and monoamine oxidase B (MAO-B). Herein, we investigated further photoisomerizable 2-benzylideneindan-1-one analogs 1b-h with the unconjugated tertiary amino moiety bearing alkyls of different bulkiness and lipophilicity. For each compound, the thermal stable E geometric isomer, along with the E/Z mixture as produced by UV-B light irradiation in the photostationary state (PSS, 75% Z), was investigated for the inhibition of human ChEs and MAOs. The pure E-isomer of the N-benzyl(ethyl)amino analog 1h achieved low nanomolar AChE and high nanomolar MAO-B inhibition potencies (IC50s 39 and 355 nM, respectively), whereas photoisomerization to the Z isomer (75% Z in the PSS mixture) resulted in a decrease (about 30%) of AChE inhibitory potency, and not in the MAO-B one. Molecular docking studies were performed to rationalize the different E/Z selectivity of 1h toward the two target enzymes.

Monoamine Oxidase-B Inhibition Facilitates α-Synuclein Secretion In Vitro and Delays Its Aggregation in rAAV-Based Rat Models of Parkinson's Disease.

Cell-to-cell transmission of α-synuclein (α-syn) pathology is considered to underlie the spread of neurodegeneration in Parkinson's disease (PD). Previous studies have demonstrated that α-syn is secreted under physiological conditions in neuronal cell lines and primary neurons. However, the molecular mechanisms that regulate extracellular α-syn secretion remain unclear. In this study, we found that inhibition of monoamine oxidase-B (MAO-B) enzymatic activity facilitated α-syn secretion in human neuroblastoma SH-SY5Y cells. Both inhibition of MAO-B by selegiline or rasagiline and siRNA-mediated knock-down of MAO-B facilitated α-syn secretion. However, TVP-1022, the S-isomer of rasagiline that is 1000 times less active, failed to facilitate α-syn secretion. Additionally, the MAO-B inhibition-induced increase in α-syn secretion was unaffected by brefeldin A, which inhibits endoplasmic reticulum (ER)/Golgi transport, but was blocked by probenecid and glyburide, which inhibit ATP-binding cassette (ABC) transporter function. MAO-B inhibition preferentially facilitated the secretion of detergent-insoluble α-syn protein and decreased its intracellular accumulation under chloroquine-induced lysosomal dysfunction. Moreover, in a rat model (male Sprague Dawley rats) generated by injecting recombinant adeno-associated virus (rAAV)-A53T α-syn, subcutaneous administration of selegiline delayed the striatal formation of Ser129-phosphorylated α-syn aggregates, and mitigated loss of nigrostriatal dopaminergic neurons. Selegiline also delayed α-syn aggregation and dopaminergic neuronal loss in a cell-to-cell transmission rat model (male Sprague Dawley rats) generated by injecting rAAV-wild-type α-syn and externally inoculating α-syn fibrils into the striatum. These findings suggest that MAO-B inhibition modulates the intracellular clearance of detergent-insoluble α-syn via the ABC transporter-mediated non-classical secretion pathway, and temporarily suppresses the formation and transmission of α-syn aggregates.SIGNIFICANCE STATEMENT The identification of a neuroprotective agent that slows or stops the progression of motor impairments is required to treat Parkinson's disease (PD). The process of α-synuclein (α-syn) aggregation is thought to underlie neurodegeneration in PD. Here, we demonstrated that pharmacological inhibition or knock-down of monoamine oxidase-B (MAO-B) in SH-SY5Y cells facilitated α-syn secretion via a non-classical pathway involving an ATP-binding cassette (ABC) transporter. MAO-B inhibition preferentially facilitated secretion of detergent-insoluble α-syn protein and reduced its intracellular accumulation under chloroquine-induced lysosomal dysfunction. Additionally, MAO-B inhibition by selegiline protected A53T α-syn-induced nigrostriatal dopaminergic neuronal loss and suppressed the formation and cell-to-cell transmission of α-syn aggregates in rat models. We therefore propose a new function of MAO-B inhibition that modulates α-syn secretion and aggregation.

Re-Analysis of the STEADY-PD II Trial-Evidence for Slowing the Progression of Parkinson's Disease.

BACKGROUND: Recent examination of the STEADY-PD III isradipine clinical trial data concluded that early-stage Parkinson's disease (PD) participants who had longer exposure to isradipine had a significant delay in their need for symptomatic medication, as well as a lower medication burden at the end of the trial. These findings suggest that greater exposure to isradipine might slow disease progression. OBJECTIVES: To test this hypothesis, the data from the STEADY-PD II isradipine clinical trial, in which an extended-release (ER) formulation of the drug was used, was re-examined. METHODS: The re-analysis of the STEADY-PD II data was restricted to participants assigned placebo or tolerable isradipine treatment (10 mg isradipine/day or less). The effect of isradipine treatment was assessed by Unified Parkinson's Disease Rating Scale (UPDRS) at the end of the 52-week trial, rather than by last observation carried forward at the beginning of symptomatic therapy. RESULTS: Participant cohorts were well-matched for baseline disability, initial disease progression, and time to initiation of symptomatic therapy. Participants given 10 mg/day ER isradipine had significantly smaller total and part 3 UPDRS scores at the end of the trial than did the placebo cohort. Post hoc adjustment for symptomatic therapy diminished the statistical significance of these differences. In those participants not taking a monoamine oxidase B inhibitor, the progression in UPDRS scores also was significantly reduced. CONCLUSIONS: These results are consistent with the recent secondary analysis of the STEADY-PD III clinical trial-suggesting that clinically attainable brain exposure to isradipine may slow early-stage PD progression. © 2021 International Parkinson and Movement Disorder Society.

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

Since the 1980s, the MAO-B inhibitors have gained considerable status in the therapy of the Parkinson's disease. In addition to the symptomatic effect in mono- and combination therapies, a neuroprotective effect has repeatedly been a matter of some discussion, which has unfortunately led to a good many misunderstandings. Due to potential interactions, selegiline has declined in significance in the field. For the MAO-B inhibitor safinamide, recently introduced to the market, an additional inhibition of pathological release of glutamate has been postulated. At present, rasagiline and selegiline are being administered in early therapy as well as in combination with levodopa. Safinamide has been approved only for combination therapy with levodopa when motor fluctuations have occurred. MAO-B inhibitors are a significant therapeutic option for Parkinson's disease, an option which is too often not appreciated properly.

The evaluation of N-propargylamine-2-aminotetralin as an inhibitor of monoamine oxidase.

Monoamine oxidase B (MAO-B) inhibitors are established therapy for Parkinson's disease and act, in part, by blocking the MAO-catalysed metabolism of dopamine in the brain. Two propargylamine-containing MAO-B inhibitors, selegiline [(R)-deprenyl] and rasagiline, are currently used in the clinic for this purpose. These compounds are mechanism-based inactivators and, after oxidative activation, form covalent adducts with the FAD co-factor. An important consideration is that selegiline and rasagiline display specificity for MAO-B over the MAO-A isoform thus reducing the risk of tyramine-induced changes in blood-pressure. In the interest of discovering new propargylamine MAO inhibitors, the present study synthesises racemic N-propargylamine-2-aminotetralin (2-PAT), a compound that may be considered as both a six-membered ring analogue of rasagiline and a semi-rigid N-desmethyl ring-closed analogue of selegiline. The in vitro human MAO inhibition properties of this compound were measured and the results showed that 2-PAT is a 20-fold more potent inhibitor of MAO-A (IC50 = 0.721 µM) compared to MAO-B (IC50 = 14.6 µM). Interestingly, dialysis studies found that 2-PAT is a reversible MAO-A inhibitor, while acting as an inactivator of MAO-B. Since reversible MAO-A inhibitors are much less liable to potentiate tyramine-induced side effects than MAO-A inactivators, it is reasonable to suggest that 2-PAT could be a useful and safe therapeutic agent for disorders such as Parkinson's disease and depression.

6-Benzyloxyphthalides as selective and reversible monoamine oxidase B inhibitors with antioxidant and anti-neuroinflammatory activities for Parkinson's disease treatment.

A series of 6-benzyloxyphthalides were designed and synthesized as potent monoamine oxidase B inhibitors with antioxidant and anti-neuroinflammatory activities. The representative compounds 8f and 14a exhibited excellent selective MAO-B inhibition activity (IC50 = 1.33 nM, SI = 865; IC50 = 0.02 nM, SI = 40250, respectively) and moderate antioxidant activity (0.34 and 0.36 Trolox equivalent, respectively). Further studies showed that they were competitive and quasi-reversible MAO-B inhibitors. In cellular experiments, they could significantly decrease the production of NO and TNF-α in LPS-stimulated BV-2 cells to perform their in vitro anti-neuroinflammatory activities. Moreover, BBB permeability study and the predicted physicochemical properties indicated they were suitable for the CNS. Finally, in in vivo acute and subacute MPTP-induced mice model of PD, 8f and 14a could significantly improve most behavioral disorders, restore the DA content and decrease the MDA content in the mice striatum, exhibiting better anti-PD effects than clinically used safinamide. Hence, compounds 8f and 14a are identified in our studies as prospective prototype in the research of innovative multifunctional drugs for Parkinson's disease treatment.

Rasagiline, sleep quality and well-being in Parkinson's disease: a pilot study.

Sleep disordersand excessive daytime sleepiness are among the commonest nonmotor symptoms in Parkinson disease (PD) and can contribute to significantly lower quality of life in affected patients. Various antiparkinson drugs exert a relevant influence on sleep quality, daily vigilance and well-being. In the latest years, administration of monoamine oxidase type B inhibitor (iMAO-B) medications in PD, especially rasagiline, has gained importance due to the hypothesized neuroprotective effect of these agents. Whereas the 'wakepromoting' effect of selegine, due to its activating amphetamine-like compounds, has been already described, less is known regarding the effect of rasagiline, a world-wide used iMAO-B drug. A pilot study was carried out to analyze the effects of rasagiline on sleep and healthrelated quality of life in a small cohort of PD patients. According to our results, PD patients treated with rasagiline referred better sleep quality, required less frequently hypnotic medication, complained of lower daytime sleepiness and presented higher scores in social functioning, perceived energy levels and emotional well-being. Albeit limited by the small sample size, our study suggests an intriguing role of rasagiline in improving sleep and quality of life in PD patients. Further studies are necessary to confirm our preliminary observations.

Insufficient recovery of monoamine oxidase in a bioequivalence study of the monoamine oxidase inhibitor tranylcypromine: Recommendation of the tranylcypromine enantiomer test.

OBJECTIVE: To investigate the recovery of monoamine oxidase (MAO) activity in the liver and gut of healthy subjects after a dose of 10 mg of the irreversible MAO inhibitor tranylcypromine (TCP). MATERIALS AND METHODS: A bioequivalence study of TCP with a wash-out of 1 week between 2 doses of 10 mg TCP was re-analyzed for changes of the plasma concentrations of TCP enantiomers. Plasma concentrations of (+)-TCP and the ratio of (+)-TCP and (-)-TCP plasma concentrations were used as a measure of MAO activity because (+)-TCP is a more effective suicide inhibitor of MAO than (-)-TCP and, therefore considerably more metabolized by MAO. RESULTS: The area under the curve from the first to the last measured concentration (AUCt) and the maximum plasma concentration (Cmax) of (+)-TCP increased significantly in the second dose (p < 0.0001) by 43.1% (11.8%) and 66.5% (26.4%), respectively, (mean with 95%CI in each case). The ratios (+)-TCP/(-)-TCP of AUCt and Cmax also increased significantly (p < 0.0001) by 27.3% (6.4%) and 25.9% (6.2%), respectively. No changes were found for the half-lives (T1/2) of both enantiomers. CONCLUSION: For the first dose, MAO is the main drug-metabolizing enzyme of (+)-TCP. MAO activity in the liver and gut is not completely recovered within 1 week after 1 dose of TCP. One week of wash-out may be insufficient in bioequivalence studies of irreversible MAO inhibitors. Prolonged inhibition of MAO after the treatment with irreversible MAO inhibitors may explain drug interactions during the switch from another MAO inhibitor to TCP. Enantiomer plasma concentrations of TCP after a dose of racemic TCP may be used as a test for gastrointestinal and hepatic MAO activity.

Differences in CSF Biomarkers Profile of Patients with Parkinson's Disease Treated with MAO-B Inhibitors in Add-On.

BACKGROUND: Monoamine oxidase type B inhibitors (iMAO-Bs) are a class of largely-used antiparkinsonian agents that, based on experimental evidence, are supposed to exert different degrees of neuroprotection in Parkinson's disease (PD). However, clinical proofs on this regard are very scarce. Since cerebrospinal fluid (CSF) reflects pathological changes occurring at brain level, we examined the neurodegeneration-related CSF biomarkers profile of PD patients under chronic treatment with different iMAO-Bs to identify biochemical signatures suggestive for differential neurobiological effects. METHODS: Thirty-five PD patients under chronic treatment with different iMAO-Bs in add-on to levodopa were enrolled and grouped in rasagiline (n = 13), selegiline (n = 9), safinamide (n = 13). Respective standard clinical scores for motor and non-motor disturbances, together with CSF biomarkers of neurodegeneration levels (amyloid- ß -42, amyloid- ß -40, total and 181-phosphorylated tau, and lactate) were collected and compared among the three iMAO-B groups. RESULTS: No significant clinical differences emerged among the iMAO-B groups. CSF levels of tau proteins and lactate were instead different, resulting higher in patients under selegiline than in those under rasagiline and safinamide. CONCLUSIONS: Although preliminary and limited, this study indicates that patients under different iMAO-Bs may present distinct profiles of CSF neurodegeneration-related biomarkers, probably because of the differential neurobiological effects of the drugs. Larger studies are now needed to confirm and extend these initial observations.