In vitro and in vivo Biological Evaluation of Newly Tacrine-Selegiline Hybrids as Multi-Target Inhibitors of Cholinesterases and Monoamine Oxidases for Alzheimer's Disease.

Purpose: Alzheimer's disease (AD) is the most common neurodegenerative disease, and its multifactorial nature increases the difficulty of medical research. To explore an effective treatment for AD, a series of novel tacrine-selegiline hybrids with ChEs and MAOs inhibitory activities were designed and synthesized as multifunctional drugs. Methods: All designed compounds were evaluated in vitro for their inhibition of cholinesterases (AChE/BuChE) and monoamine oxidases (MAO-A/B) along with their blood-brain barrier permeability. Then, further biological activities of the optimizing compound 7d were determined, including molecular model analysis, in vitro cytotoxicity, acute toxicity studies in vivo, and pharmacokinetic and pharmacodynamic property studies in vivo. Results: Most synthesized compounds demonstrated potent inhibitory activity against ChEs/MAOs. Particularly, compound 7d exhibited good and well-balanced activity against ChEs (hAChE: IC50 = 1.57 µM, hBuChE: IC50 = 0.43 µM) and MAOs (hMAO-A: IC50 = 2.30 µM, hMAO-B: IC50 = 4.75 µM). Molecular modeling analysis demonstrated that 7d could interact simultaneously with both the catalytic active site (CAS) and peripheral anionic site (PAS) of AChE in a mixed-type manner and also exhibits binding affinity towards BuChE and MAO-B. Additionally, 7d displayed excellent permeability of the blood-brain barrier, and under the experimental conditions, it elicited low or no toxicity toward PC12 and BV-2 cells. Furthermore, 7d was not acutely toxic in mice at doses up to 2500 mg/kg and could improve the cognitive function of mice with scopolamine-induced memory impairment. Lastly, 7d possessed well pharmacokinetic characteristics. Conclusion: In light of these results, it is clear that 7d could potentially serve as a promising multi-functional drug for the treatment of AD.

The novel design of an intelligent anti-depression transdermal drug delivery system.

Depression is a type of mental disorder with a significant and persistent low mood as the main clinical feature. It is often accompanied by symptoms such as slow thinking, decreased will, loss of appetite, and weight loss. The current treatment methods for depression are mainly medical treatment, psychotherapy, and physical therapy. These treatments are dependent on the patient's autonomy and the patients may suspend treatment due to forgetting or refusing. Therefore, an anti-depressant intelligent drug release system was designed, which can achieve autonomously controlled doses for the treatment of depression by transdermal drug delivery system. The work of this study is as follows: (1) The first module: the electrothermal material heating layer. Several preparation methods were screened, and multiple sets of graphene (GE) electric thermogenic layers were successfully prepared. After increasing the actual energization area to 1 cm × 1 cm, the GE electric thermogenic layer is used as the heating layer of the electrothermal material of the system, and can reach a uniform surface temperature of (45 ± 0.5) °C within 15 s at a voltage of 6 V keeping the temperature fluctuation range not exceeding ±0.03 °C, and the resistance fluctuation range not exceeding ±20 Ω, which plays a role in controlling the temperature and heat treatment of the drug loaded gel layer. (2) The second module: the drug-loaded gel layer. Based on the L16 (45) orthogonal test, the best formulation and process of N-Isopropyl acrylamide-Acrylamide copolymer (P(NIPAAm-co-AAm)) hydrogel was determined. Then, the percutaneous permeability of Selegiline liposome was studied in vitro. (3) A rat model of depression was established using chronic unpredictable mild stress (CUMS) combined with separation. From the aspects of behavior (body weight, sucrose preference test, forced swimming test, open field test) and biochemical indexes (serum proinflammatory cytokines (IL-1ß, TNF-α), hippocampus HE staining observation), the therapeutic effect of hyperthermia, Selegiline oral administration and transdermal administration was discussed.

Classics in Chemical Neuroscience: Selegiline, Isocarboxazid, Phenelzine, and Tranylcypromine.

The discovery of monoamine oxidase inhibitors (MAOIs) in the 1950s marked a significant breakthrough in medicine, creating a powerful new category of drug: the antidepressant. In the years and decades that followed, MAOIs have been used in the treatment of several pathologies including Parkinson's disease, Alzheimer's disease, and various cancers and as anti-inflammatory agents. Despite once enjoying widespread use, MAOIs have dwindled in popularity due to side effects, food-drug interactions, and the introduction of other antidepressant drug classes such as tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs). The recently published prescriber's guide for the use of MAOIs in treating depression has kindled a resurgence of their use in the clinical space. It is therefore timely to review key aspects of the four "classic" MAOIs: high-dose selegiline, isocarboxazid, phenelzine, and tranylcypromine. This review discusses their chemical synthesis, metabolism, pharmacology, adverse effects, and the history and importance of these drugs within the broader field of chemical neuroscience.

Striking Neurochemical and Behavioral Differences in the Mode of Action of Selegiline and Rasagiline.

Selegiline and rasagiline are two selective monoamine oxidase B (MAO-B) inhibitors used in the treatment of Parkinson's disease. In their clinical application, however, differences in L-dopa-sparing potencies have been observed. The aim of this study was to find neurochemical and behavioral explanations for the antiparkinsonian effects of these drugs. We found that selegiline possesses a dopaminergic enhancer effect: it stimulated the electrically induced [3H]dopamine release without influencing the resting [3H]dopamine release from rat striatal slices in 10-10-10-9 mol/L concentrations. Rasagiline added in 10-13 to 10-5 mol/L concentrations did not alter the resting or electrically stimulated [3H]dopamine release. Rasagiline (10-9 mol/L), however, suspended the stimulatory effect of selegiline on the electrically induced [3H]dopamine release. The trace amine-associated receptor 1 (TAAR1) antagonist EPPTB (10-8-10-7 mol/L) also inhibited the stimulatory effect of selegiline on [3H]dopamine release. The effect of selegiline in its enhancer dose (5.33 nmol/kg) against tetrabenazine-induced learning deficit measured in a shuttle box apparatus was abolished by a 5.84 nmol/kg dose of rasagiline. The selegiline metabolite (-)methamphetamine (10-9 mol/L) also exhibited enhancer activity on [3H]dopamine release. We have concluded that selegiline acts as an MAO-B inhibitor and a dopaminergic enhancer drug, and the latter relates to an agonist effect on TAAR1. In contrast, rasagiline is devoid of enhancer activity but may act as an antagonist on TAAR1.

Inhibition of MAOB Ameliorated High-Fat-Diet-Induced Atherosclerosis by Inhibiting Endothelial Dysfunction and Modulating Gut Microbiota.

In this study, monoamine oxidase B (MAOB) was activated under pathological conditions, and was the novel source of cardiovascular reactive oxygen species (ROS). ROS-induced endothelial dysfunction results in sustained and chronic vascular inflammation, which is central to atherosclerotic diseases. However, whether MAOB regulates endothelial oxidative stress and its related mechanism and whether gut microbiota mediates the anti-atherosclerosis effect of MAOB inhibitor remains unclear. In our study, MAOB expressions were elevated in high-fat diet (HFD) fed mice aortas, but only in vascular endothelial cells (not in smooth muscle cells). MAOB small interfering RNA significantly attenuated the palmitic-acid (PA)-induced endothelial oxidative stress and dysfunction. Furthermore, RNA-sequencing data revealed that MAOB knockdown decreased the levels of proinflammatory and apoptotic gene induced by PA. Microarray analysis and qPCR assay showed that miR-3620-5p was significantly decreased under the HFD condition. The dual-luciferase reporter, Western blot and qPCR assay confirmed that miR-3620-5p directly regulated MAOB by binding to its mRNA 3'UTR. Moreover, inhibition of MAOB by selegiline significantly ameliorated endothelial dysfunction and reduced atherosclerotic burden in HFD-fed ApoE-/- mice. Finally, 16S rRNA sequencing showed that selegiline significantly altered the community compositional structure of gut microbiota. Specifically, selegiline treatment enriched the abundance of Faecalibaculum and Akkermansia, decreased the abundance of unclassified_f__Lachnospiraceae, Desulfovibrio, and Blautia, and these genera were significantly correlated with the serum biochemical indices. Taken together, our findings showed that MAOB controlled endothelial oxidative stress homeostasis, and revealed the anti-atherosclerotic effect of selegiline by ameliorating endothelial dysfunction and modulating the composition and function of gut microbiota.

Selegiline ameliorated dyslipidemia and hepatic steatosis in high-fat diet mice.

Certain monoamine oxidase (MAO) inhibitors exhibit beneficial effects, such as reducing adiposity and metabolic disorders; however, their effects on hepatic lipid metabolism have not been revealed. This study aimed to investigate the effects of a selective MAO-B inhibitor, selegiline, on dyslipidemia and hepatic steatosis in mice induced by a high-fat diet (HFD). Administration of selegiline (0.6 mg/kg body weight) by intraperitoneal injection was found to reduce HFD-induced body weight gain and increases in liver and adiposity coefficients, blood lipids and fatty acid levels. Furthermore, selegiline dramatically reduced the total triglyceride (TG) and cholesterol (TC) levels and lipid accumulation in the livers of HFD-fed mice and palmitic acid (PA)-treated AML-12 hepatocytes. In vivo and in vitro results indicated that selegiline protects against HFD- and PA-induced hepatic inflammation by reducing the expression of proinflammatory cytokines, namely IL-6, TNF-α, IL-1ß, and IL-1α. Additionally, selegiline exhibited antioxidative effects on HFD and PA exposure in mouse liver and AML-12 cells by decreasing the levels of reactive oxygen species (ROS) and malonaldehyde (MDA) and increasing superoxide dismutase (SOD) activity. Further study showed that selegiline administration mitigated the expression of Srebf-1, Fasn, and Acaca and downregulated the expression of Cpt-1 and Pparα in HFD-fed mouse livers and PA-treated AML-12 cells. In conclusion, our findings suggest that selegiline exerts protective effects against HFD-induced dyslipidemia and hepatic steatosis, which may be related to an improved inflammatory response, oxidative stress, and hepatic lipid metabolism.

Low Dose Betahistine in Combination With Selegiline Increases Cochlear Blood Flow in Guinea Pigs.

OBJECTIVE: Betahistine is frequently used in the pharmacotherapy for Menière's Disease (MD). Little is known about its mode of action and prescribed dosages vary. While betahistine had an increasing effect on cochlear microcirculation in earlier studies, low dose betahistine of 0.01 mg/kg bw or less was not able to effect this. Selegiline inhibits monoaminooxidase B and therefore potentially the breakdown of betahistine. The goal of this study was to examine whether the addition of selegiline to low dose betahistine leads to increased cochlear blood flow. METHODS: Twelve Dunkin-Hartley guinea pigs were anesthetized, the cochlea was exposed and a window opened to the stria vascularis. Blood plasma was visualized by injecting fluoresceinisothiocyanate-dextrane and vessel diameter and erythrocyte velocity were evaluated over 20 minutes. One group received low dose betahistine (0.01 mg/kg bw) and selegiline (1 mg/kg bw) i.v. while the other group received only selegiline (1 mg/kg bw) and saline (0.9% NaCl) as placebo i.v. RESULTS: Cochlear microcirculation increased significantly (P < .001) in guinea pigs treated with low dose betahistine combined with selegiline by up to 58.3 ± 38.7% above baseline over a period of up to 11 minutes. In one guinea pig, the increase was 104.6%. Treatment with Selegiline alone did not affect microcirculation significantly. CONCLUSIONS: Low dose betahistine increased cochlear microcirculation significantly when combined with selegiline. This should be investigated in further studies regarding dose-effect relation in comparison to betahistine alone. Side effects, in particular regarding circulation, should be considered carefully in view of the clinical applicability of a combination therapy in patients with MD.

The Role of Monoamine Oxidase B Inhibitors in the Treatment of Parkinson's Disease - An Update.

Parkinson's disease (PD) is a progressive neurodegenerative disease characterised by reduced dopamine levels 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 monoamine oxidase B (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 inhibitor 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 is scarce and warrants further investigation.

Monoamine-oxidase Type B Inhibitors and Cognitive Functions in Parkinson's Disease: Beyond the Primary Mechanism of Action.

Symptoms of cognitive impairment are rather common since the early stage of Parkinson's disease (PD); they aggravate with disease progression and may lead to dementia in a significant proportion of cases. Worsening of cognitive symptoms in PD patients depends on the progression of subcortical dopaminergic damage as well as the involvement of other brain neurotransmitter systems in cortical and subcortical regions. Beyond the negative impact on disability and quality of life, the presence and severity of cognitive symptoms may limit adjustments of dopamine replacement therapy along the disease course. This review focuses on the consequences of the administration of monoamine-oxidase type Binhibitors (MAOB-I) on cognition in PD patients. Two drugs (selegiline and rasagiline) are available for the treatment of motor symptoms of PD as monotherapy or in combination with L-DOPA or dopamine agonists in stable and fluctuating patients; a further drug (safinamide) is usable in fluctuating subjects solely. The results of available studies indicate differential effects according to disease stage and drug features. In early, non-fluctuating patients, selegiline and rasagiline ameliorated prefrontal executive functions, similarly to other dopaminergic drugs. Benefit on some executive functions was maintained in more advanced, fluctuating patients, despite the tendency of worsening prefrontal inhibitory control activity. Interestingly, high-dose safinamide improved inhibitory control in fluctuating patients. The benefit of high-dose safinamide on prefrontal inhibitory control mechanisms may stem from its dual mechanism of action, allowing reduction of excessive glutamatergic transmission, in turn secondary to increased cortical dopaminergic input.

Effect of selegiline as a monomine oxidase B inhibitor on the expression of neurotrophin mRNA levels in a contusion rat model of spinal cord injury.

OBJECTIVE: Spinal cord injury (SCI) is followed by a cascade of events at the site of injury, including vascular ischemia, an increase in free radicals, inflammation, and neuronal death. In these individuals, protection of nerves and supporting cells, as well as prevention of neuronal damage, may improve recovery opportunities. Neurotrophins are a family of polypeptides that regulate nerve differentiation, growth, and survival. Selegiline is a selective monoamine oxidase B (MAO-B) inhibitor used to treat Parkinson's disease. Selegiline has been found to have neuroprotective properties and may be useful for the expression of neurotrophins. The aim of this study was to evaluate the expression levels of neurotrophin genes in spinal cord rats treated with selegiline. METHODS: Rats were divided into four groups: injury (control), laminectomy, sham (injured rat received 1 ml saline intraperitoneally) and treatment (injured rat received 5 mg/kg selegiline intraperitoneally for 7 days; once a day). The BBB scale (Basso, Beattie and Bresnahan) was performed once a week for 4 weeks to assess motor function after a spinal cord injury. On day 28 after SCI, the rat was sacrificed and the spinal cord lesion removed. A real-time PCR approach was used to assess neurotrophin gene expression. RESULTS: The results showed that administration of selegiline improves locomotor function and increases mRNA levels of BDNF, GDNF, NT-3, and NT-4. CONCLUSION: In summary, the results of this study suggest that selegiline may be an appropriate treatment for spinal cord injuries.

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.

Neuroprotective Function of Rasagiline and Selegiline, Inhibitors of Type B Monoamine Oxidase, and Role of Monoamine Oxidases in Synucleinopathies.

Synucleinopathies are a group of neurodegenerative disorders caused by the accumulation of toxic species of α-synuclein. The common clinical features are chronic progressive decline of motor, cognitive, behavioral, and autonomic functions. They include Parkinson's disease, dementia with Lewy body, and multiple system atrophy. Their etiology has not been clarified and multiple pathogenic factors include oxidative stress, mitochondrial dysfunction, impaired protein degradation systems, and neuroinflammation. Current available therapy cannot prevent progressive neurodegeneration and "disease-modifying or neuroprotective" therapy has been proposed. This paper presents the molecular mechanisms of neuroprotection by the inhibitors of type B monoamine oxidase, rasagiline and selegiline. They prevent mitochondrial apoptosis, induce anti-apoptotic Bcl-2 protein family, and pro-survival brain- and glial cell line-derived neurotrophic factors. They also prevent toxic oligomerization and aggregation of α-synuclein. Monoamine oxidase is involved in neurodegeneration and neuroprotection, independently of the catalytic activity. Type A monoamine oxidases mediates rasagiline-activated signaling pathways to induce neuroprotective genes in neuronal cells. Multi-targeting propargylamine derivatives have been developed for therapy in various neurodegenerative diseases. Preclinical studies have presented neuroprotection of rasagiline and selegiline, but beneficial effects have been scarcely presented. Strategy to improve clinical trials is discussed to achieve disease-modification in synucleinopathies.

The Relationship between Procyanidin Structure and Their Protective Effect in a Parkinson's Disease Model.

This study evaluated the effect of grape seed-derived monomer, dimeric, and trimeric procyanidins on rat pheochromocytoma cell line (PC12) cells and in a zebrafish Parkinson's disease (PD) model. PC12 cells were cultured with grape seed-derived procyanidins or deprenyl for 24 h and then exposed to 1.5 mm 1-methyl-4-phenylpyridinium (MPP+) for 24 h. Zebrafish larvae (AB strain) 3 days post-fertilization were incubated with deprenyl or grape seed-derived procyanidins in 400 µM 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) for 4 days. The results showed that the procyanidin dimers procyanidin B1 (B1), procyanidin B2 (B2), procyanidin B3 (B3), procyanidin B4 (B4), procyanidin B1-3-O-gallate (B1-G), procyanidin B2-3-O-gallate (B2-G), and the procyanidin trimer procyanidin C1 (C1) had a protective effect on PC12 cells, decreasing the damaged dopaminergic neurons and motor impairment in zebrafish. In PC12 cells and the zebrafish PD model, procyanidin (B1, B2, B3, B4, B1-G, B2-G, C1) treatment decreased the content of reactive oxygen species (ROS) and malondialdehyde (MDA), increased the activity of antioxidant enzymes glutathione peroxidase (GSH-Px), catalase (CAT), and superoxide dismutase (SOD), and upregulated the expression of nuclear factor-erythroid 2-related factor (Nrf2), NAD(P)H: quinone oxidoreductase 1 (NQO1), and heme oxygenase-1 (HO-1). These results suggest that in PC12 cells and the zebrafish PD model, the neuroprotective effects of the procyanidins were positively correlated with their degree of polymerization.

Monoamine oxidase inhibitors: A concise review with special emphasis on structure activity relationship studies.

Monoamine oxidase enzyme is necessary for the management of brain functions. It oxidatively metabolizes monoamines and produces ammonia, aldehyde and hydrogen peroxide as by-products. Excessive production of by-products of monoamine metabolism generates free radicals which cause cellular apoptosis and several neurodegenerative disorders for example Alzheimer's disease, Parkinson's disease, depression and autism. The inhibition of MAOs is an attractive target for the treatment of neurological disorders. Clinically approved MAO inhibitors for example selegiline, rasagiline, clorgyline, pargyline etc. are irreversible in nature and cause some adverse effects while recently studied reversible MAO inhibitors are devoid of harmful effects of old monoamine oxidase inhibitors. In this review article we have listed various synthesized molecules containing different moieties like coumarin, chalcone, thiazole, thiourea, caffeine, pyrazole, chromone etc. along with their activity, mode of action, structure activity relationship and molecular docking studies.

Intrathecal pramipexole and selegiline for sensory and motor block in rats.

BACKGROUND: The purpose of the study was to investigate spinal sensory and motor block by antiparkinsonian drugs (pramipexole and selegiline), and the combination of pramipexole and the local anesthetic lidocaine. METHODS: Using a technique of spinal blockade in rats, the effects of pramipexole, selegiline, and coadministration of pramipexole and lidocaine on spinal blockades of motor and sensory function were investigated. RESULTS: Under a concentration of 100 mM, pramipexole displayed more potent and had a longer duration of nociceptive, proprioceptive, and motor block than selegiline, whereas pramipexole and selegiline were less potent in comparison to lidocaine. Pramipexole produced spinal nociceptive, proprioceptive, and motor blocks in a dose-related manner. On the ED50 (50% effective dose) basis, the rank-order potency on nociceptive, proprioceptive, and motor block was pramipexole < lidocaine. The spinal block duration of pramipexole was greater than lidocaine at every equipotent dose tested (ED25, ED50, and ED75). Coadministration of lidocaine (ED50 or ED95) with pramipexole (4.5 µmol/kg) improved the effect (efficacy) and duration of the spinal block. CONCLUSIONS: Pramipexole and selegiline were less potent than lidocaine to block sensory and motor responses. The duration of the spinal anesthetic effect of pramipexole was longer than lidocaine. At a non-effective dose, pramipexole increased the duration of efficacy of lidocaine.

Antibody-Mediated Screening of Peptide Inhibitors for Monoamine Oxidase-B (MAO-B) from an Autodisplayed FV Library.

Inhibitors for monoamine oxidase-B (MAO-B) were screened from an FV library with a randomized complementarity-determining region 3 (CDR3) region using a monoclonal antibody against dopamine. As the first step, the FV library was expressed on the outer membrane of E. coli by site-directed mutagenesis of the randomized CDR3 region. Among the FV library, variants with a binding affinity to monoclonal antibodies against dopamine were screened and cloned. From the comparison of the binding activity of the screened clones to a control clone with a modified FV antibody (only with CDR1 and CDR2), the CDR3 regions of screened clones were determined to directly interact with the monoclonal antibody against dopamine. These CDR3 sequences were then synthesized as mimotopes (mimicking peptides) of dopamine. The inhibitory activity of two mimotopes against MAO-B was analyzed using HeLa cells overexpressing MAO-B, as well as using activated human astrocytes; their inhibitory activity was compared to that of a commercial inhibitor of MAO-B, selegiline. The inhibition efficiency of the two mimotopes (in comparison with selegiline) was estimated to be 67.2% and 69.4% in the HeLa cells and 64.4% and 58.0% in the human astrocytes. The gene expression pattern in astrocytes after treatment with the two mimotopes was also analyzed and compared with that in the human astrocytes treated with selegiline. Finally, the interaction between two mimotopes and MAO-B was analyzed using docking simulation, and the candidate regions of MAO-B for the interaction with each mimotope were explored through the docking simulation.

Mitigated Oxidative Stress and Cognitive Impairments in Transient Global Ischemia using Niosomal Selegiline-NBP delivery.

Stroke is the most common reason for adult disabilities and the second ground for death worldwide. Our previous study revealed that selegiline serves as an alternative candidate in transient hypoxia-ischemia. However, aggressive and restless behavior was observed in stroke-induced rats receiving 4 mg/kg selegiline. In comparison, 1 mg/kg selegiline could induce negligible therapeutic effects on mitochondrial dysfunction and histopathological changes. Therefore, we designed oral noisome-based selegiline attached to 4-(4-nitrobenzyl) pyridine to improve transient global ischemia by attenuating cognitive impairments, oxidative stress, and histopathological injury. The investigation was performed in transient hypoxia-ischemia-induced rats by oral administration of nanoformulation containing selegiline (0.25-1 mg/kg) for 4 weeks (3 times a week). Novel object recognition (NOR) was considered to evaluate their cognitive dysfunction. Oxidative stress parameters and brain histopathological assessments were determined following the scarification of rats. Outstandingly, our data demonstrated slower selegiline release from niosomes relative to free drug, which was also in a controlled manner. Our data confirmed significant improvement in cognitive behavior in the NOR test, an increase in glutathione level and total antioxidant power, a decline in MDA and protein carbonyl level, as well as a decreased number of dead cells in histopathological assessment after being exposed to (0.5-1 mg/kg) selegiline-NBP nanoformulation. These data manifested that the selegiline-NBP nanoformulation (0.5-1 mg/kg) could significantly reduce oxidative damage, cognitive dysfunction, and histopathological damage compared to transient hypoxia-ischemia rats, which is 20 times lower than the therapeutic dose in humans. Therefore, the proposed nanoformulation would be capable as an alternative candidate without side effects in stroke.

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.

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.