Type-B monoamine oxidase inhibitors in neurological diseases:clinical applications based on preclinical findings

Type-B monoamine oxidase inhibitors,encompassing selegiline,rasagiline,and safinamide,are available to treat Parkinson's disease.These drugs ameliorate motor symptoms and improve motor fluctuation in the advanced stages of the disease.There is also evidence suppo rting the benefit of type-B monoamine oxidase inhibitors on non-motor symptoms of Parkinson's disease,such as mood deflection,cognitive impairment,sleep disturbances,and fatigue.Preclinical studies indicate that type-B monoamine oxidase inhibitors hold a strong neuroprotective potential in Parkinson's disease and other neurodegenerative diseases for reducing oxidative stress and stimulating the production and release of neurotrophic factors,particularly glial cell line-derived neurotrophic factor,which suppo rt dopaminergic neurons.Besides,safinamide may interfere with neurodegenerative mechanisms,countera cting excessive glutamate overdrive in basal ganglia motor circuit and reducing death from excitotoxicity.Due to the dual mechanism of action,the new generation of type-B monoamine oxidase inhibitors,including safinamide,is gaining interest in other neurological pathologies,and many supporting preclinical studies are now available.The potential fields of application concern epilepsy,Duchenne muscular dystrophy,multiple scle rosis,and above all,ischemic brain injury.The purpose of this review is to investigate the preclinical and clinical pharmacology of selegiline,rasagiline,and safinamide in Parkinson's disease and beyond,focusing on possible future therapeutic applications.

A Strategy to Employ Clitoria ternatea as a Prospective Brain Drug Confronting Monoamine Oxidase (MAO) Against Neurodegenerative Diseases and Depression

Ayurveda is a renowned traditional medicine practiced in India from ancient times and Clitoria ternatea is one such prospective medicinal herb incorporated as an essential constituent in a brain tonic called as medhya rasayan for treating neurological disorders.This work emphasises the significance of the plant as a brain drug there by upholding Indian medicine.The phytochemicals from the root extract were extricated using gas chromatography–mass spectrometry assay and molecular docking against the protein Monoamine oxidase was performed with four potential compounds along with four reference compounds of the plant.This persuades the prospect of C.ternatea as a remedy for neurodegenerative diseases and depression.The in silico assay enumerates that a major compound(Z)-9,17-octadecadienal obtained from the chromatogram with a elevated retention time of 32.99 furnished a minimum binding affinity energy value of-6.5 kcal/mol against monoamine oxidase(MAO-A).The interactions with the amino acid residues ALA 68,TYR 60 and TYR 69 were analogous to the reference compound kaempferol-3-monoglucoside with a least score of-13.90/-12.95 kcal/mol against the isoforms(MAO)A and B.This study fortifies the phytocompounds of C.ternatea as MAO-inhibitors and to acquire a pharmaceutical approach in rejuvenating Ayurvedic medicine.

Tyramine in Malt Beverages Interfering with Monoamine Oxidase Inhibitor Drugs

The objective of this review is the determination of tyramine in 13 nonalcoholic beers (Maoshaieer) of Tehran market and survey of it’s probably interaction with monoamine oxidase inhibitor drugs (MAOIs) has been investigated. Tyramine was at the highest levels in Baltika (111.34 ± 8.19 μg/ml) and at the lowest level in Bitmalt (8.01 ± 2.09 μg/ml). Comparing different flavors of malt drinks, the highest tyramine content was shown for classic or normal flavor (average 72.99 ± 30.87 μg/ml), while the lowest value belonged to cantaloupe flavored drinks (average 10.55 ± 1.29 μg/ml). In our study, it is seen that there is a significant difference between import and Iranian non-alcoholic beers, the import ones has more tyramine than Iranians. A number of 10 kinds of 13 samples interact whit MAOIs in one serving (250 ml) usage 18.50 mg. The highest tyramine content of Iranian ones is 17.74 mg/250ml and for import ones is 27.83 mg/250ml.

A fluorogenic-inhibitor-based probe for profiling and imaging of monoamine oxidase A in live human glioma cells and clinical tissues

Monoamine oxidase A(MAO-A)plays a critical role in the development of glioma and other neurological disorders.Specific analysis of MAO-A activities and its drug interactions in intact tissue is important for biological and pharmacological research,but highly challenging with current chemical tools.Fluorogenic-inhibitor-based probes offer improved selectivity,sensitivity,and effectiveness to image and profile endogenous targets in an activity-based manner from mammalian cells,which are however rare.Herein,we report HD1 as the first fluorogenic-inhibitor-based probe that can selectively label endogenous MAO-A from various mammalian cells and clinical tissues.The probe was delicately designed based on N-propargyl tetrahydropyridine,a small MAO-A-specific fluorogenic and inhibitory war-head,so that the probe becomes fluorescent upon in situ enzymatic oxidation and covalent labeling of MAO-A.With the excellent binding affinity(in vitro K_(i)=285 n M)and fluorogenic properties,HD1 offers a promising approach to simultaneously image endogenous MAO-A activities by super-resolution fluorescence microscopy and study its drug interactions by subsequent activity-based protein profiling,in both live cells and human glioma tissues.

Specific tracking of monoamine oxidase A in heart failure models by a far-red fluorescent probe with an ultra large Stokes shift

Monoamine oxidase A(MAO-A) is a prominent myocardial source of reactive oxygen species(ROS), and its expression and activity are strongly increased in failing hearts. Therefore, accurate evaluation of MAOA activity in cardiomyocytes is of great importance for understanding its biological functions and early diagnosing the progression of heart failure. However, so far, there is no report on the fluorescent diagnosis of heart failure by a specific probe for MAO-A. In this work, two far-red emissive fluorescent turn-on probes(KXS-M1 and KXS-M2) for the highly selective and sensitive detection of MAO-A were fabricated.Both probes exhibit good response to MAO-A, one of which, KXS-M2, performs better than the other one in terms of a fluorescence increment and sensitivity. Using the pioneering probe KXS-M2, specific fluorescence imaging of MAO-A in glucose-deprived H9c2 cardiac cells, zebrafish and isoprenaline-induced failing heart tissues was achieved, proving that KXS-M2 can serve as a powerful tool for the diagnosis and treatment of heart failure.

Determination of dietary copper requirement by the monoamine oxidase activity in kidney of broilers from 1 to 21 days of age

The current dietary copper(Cu)requirement(8 mg/kg)of broilers is mainly based on growth,hemoglobin concentration,or hematocrit,which might not be the most sensitive indices to evaluate dietary Cu requirements of broilers.The present study was carried out to estimate dietary Cu requirements of broilers fed a conventional corn-soybean meal diet from 1 to 21 d of age using biochemical or molecular biomarkers.A total of 3841-d-old Arbor Acres male broilers were randomly allocated to 1 of 6 treatments with 8 replicates and fed a Cu-unsupplemented corn-soybean meal basal diet containing 5.17 mg Cu/kg by analysis and the basal diet supplemented with 3,6,9,12 or 15 mg Cu/kg as CuSO4,5H2O for 21 d.Regression analysis was performed to estimate the optimal dietary Cu level using the broken-line model.Dietary supplemental Cu level affected(P<0.05)Cu contents in serum and liver and kidney monoamine oxidase(MAO)activity,but had no effects(P>0.05)on the growth performance,Cu contents in heart,kidney,pancreas and spleen,Cu-and zinc-containing superoxide dismutase(CuZnSOD)activity and ceruloplasmin content in serum,CuZnSOD and cytochrome c oxidase(COX)activities and ceruloplasmin,CuZnSOD,MAO A,MAO B,COX 4I1 and COX 1 mRNA and protein expressions in the above tissues of broilers.As dietary supplemental Cu levels increased,Cu contents in serum and liver increased linearly(P<0.05),but kidney MAO activity decreased linearly and quadratically(P<0.05).The estimated dietary Cu requirement based on the fitted broken-line model(P=0.035)of kidney MAO activity was 11.30 mg/kg.In conclusion,kidney MAO activity is a new and sensitive criterion to evaluate the dietary Cu requirement of broilers,and the dietary Cu requirement was 11.30 mg/kg for broilers fed the conventional corn-soybean meal diet from 1 to 21 d of age,which is higher than the current National Research Council(NRC)Cu requirement(8 mg/kg)of broilers.

Promising drug targets and associated therapeutic interventions in Parkinson's disease

Parkinson's disease(PD) is one of the most debilitating brain diseases. Despite the availability of symptomatic treatments, response towards the health of PD patients remains scarce. To fulfil the medical needs of the PD patients, an efficacious and etiological treatment is required. In this review, we have compiled the information covering limitations of current therapeutic options in PD, novel drug targets for PD, and finally, the role of some critical beneficial natural products to control the progression of PD.

Zhichan powder regulates nigrostriatal dopamine synthesis and metabolism in Parkinson's disease rats

In this study, rat models of Parkinson＇s disease induced by substantia nigra injection of 6-hydroxy-dopamine were intragastrically administered Zhichan powder daily for 50 days. Reverse transcription PCR results showed that tyrosine hydroxylase mRNA expression in the rat substantia nigra was significantly increased, while monoamine oxidase B mRNA expression was significantly decreased in the Zhichan powder group, compared with the model group. In addition, the levels of striatal dopamine and homovanillic acid, the ratio of dopamine to homovanillic acid, and the activity of blood superoxide dismutase were all higher in the Zhichan powder group than in the model group but the content of malondialdehyde in blood was lower. Our experimental findings indicate that Zhichan powder has an antioxidant effect, it can regulate the expression of monoamine oxidase B and tyrosine hydroxylase in the substantia nigra of Parkinson＇s disease rats, and it can facilitate the secretion of striatal dopamine and its metabolite homovanillic acid.

Evaluation of antidepressant activity of methanolic and hydroalcoholic extracts of Acorus calamus L.rhizome through tail suspension test and forced swimming test of mice

Objective:Acorus calamus(AC)L.(Araceae)is an annual semi-aquatic and aromatic plant found in Europe,North America and Asia.Its rhizomes are often used by Native Americans,Americans,and Chinese as well as by other cultures.Ethnobotanical studies and documents have shown their use in various disease treatments,such as insomnia,mental disorders,diabetes mellitus,epilepsy,inflammation,asthma,neuropathic pain,and diarrhea.In this study,the antidepressant activity of methanolic and hydroalcoholic extracts of the AC rhizome part in mice was investigated.Methods:Three doses of methanolic extract of AC rhizome(MEACR)(25,50 and 100 mg/kg b.wt),three doses of hydroalcoholic extract of AC rhizome(HAACR)(100,200 and 400 mg/kg b.wt),and standards(imipramine,15 mg/kg b.wt and fluoxetine,20 mg/kg b.wt)was daily oral administration to the mice for consecutive 14 days.The extract effect on the immobility time was monitored by a tail suspension test(TST)and a forced swimming test(FST).Monoamine oxidase(MAO)levels were also analyzed using standard methods.Results:The optimum antidepressant activity was viewed at 100 mg/kg b.wt of MEACR extract and400 mg/kg b.wt of HAACR extract with 23.82%and 20.59%immobility period reduction,respectively.Besides,the extracts weakened the FST-induced elevation of MAO activity significantly and returned to near-normal levels of neurotransmitters in the brain.100 mg/kg b.wt or above of MEACR extract significantly prevented the MAO-A and MAO-B activities in mice brain at a dose-dependent fashion.But,just 400 mg/kg b.wt of HAACR extract prevented the activity of MAO-A and MAO-B.Fluoxetine and imipramine showed a tendency to prevent the activity of MAO-A and MAO-B.Conclusion:This study suggests that AC rhizome extract mediated antidepressant activity by modulating the central neurochemical and hypothalamic-pituitary-adrenal(HPA)axis in response to FST and TSTinduced stress.Therefore,AC rhizome extract can be used as a valuable plant supplement to treat depressive disorders.

No synergism between bis(propyl)-cognitin and rasagiline on protecting dopaminergic neurons in Parkinson's disease mice

Rasagiline,a monoamine oxidase-B inhibitor,and bis（propyl）-cognitin（B3C）,a novel dimer are reported to be neuroprotective.Herein,the synergistical neuroprotection produced by rasagiline and B3 C was investigated in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine（MPTP）-induced mice of Parkinsonism.By using neurobehavioural tests,high-performance liquid chromatography and western blot assay,we showed that B3 C at 0.3 mg/kg,rasagiline at 0.02 mg/kg,as well as co-treatment with B3 C and rasagiline prevented MPTP-induced behavioural abnormities,increased the concentrations of dopamine and its metabolites in the striatum,and up-regulated the expression of tyrosine hydroxylase in the substantia nigra.However,the neuroprotective effects of co-treatment were not significantly improved when compared with those of B3 C or rasagiline alone.Collectively,we have demonstrated that B3 C at 0.3 mg/kg and rasagline at 0.02 mg/kg could not produce synergistic neuroprotective effects.

Mechanisms of repetitive transcranial magnetic stimulation for antidepression: Evidence from preclinical studies

This review summarizes the anti-depressant mechanisms of repetitive transcranial magnetic stimulation in preclinical studies,including anti-inflammatory effects mediated by activation of nuclear factor-E2-related factor 2 signaling pathway,anti-oxidative stress effects,enhancement of synaptic plasticity and neurogenesis via activation of the endocannabinoid system and brain derived neurotrophic factor signaling pathway,increasing the content of monoamine neurotransmitters via inhibition of Sirtuin 1/monoamine oxidase A signaling pathway,and reducing the activity of the hypothalamic-pituitary-adrenocortical axis.We also discuss the shortcomings of transcranial magnetic stimulation in preclinical studies such as inaccurate positioning,shallow depth of stimulation,and difficulty in elucidating the neural circuit mechanism up-and down-stream of the stimulation target brain region.

High-throughput discovery of highly selective reversible hMAO-B inhibitors based on at-line nanofractionation

Human monoamine oxidase B(hMAO-B)has emerged as a pivotal therapeutic target for Parkinson's disease.Due to adverse effects and shortage of commercial drugs,there is a need for novel,highly selective,and reversible hMAO-B inhibitors with good blood-brain barrier permeability.In this study,a high-throughput at-line nanofractionation screening platform was established with extracts from Chuanxiong Rhizoma,which resulted in the discovery of 75 active compounds,including phenolic acids,volatile oils,and phthalides,two of which were highly selective novel natural phthalide hMAO-B inhibitors that were potent,selective,reversible and had good blood‒brain permeability.Molecular docking and molecular dynamics simulations elucidated the inhibition mechanism.Sedanolide(IC_(50)=103 nmol/L;SI=645)and neocnidilide(IC_(50)=131 nmol/L;SI=207)demonstrated their excellent potential as hMAO-B inhibitors.They offset the limitations of deactivating enzymes associated with irreversible hMAO-B inhibitors such as rasagiline.In SH-SY5Y cell assays,sedanolide(EC_(50)=0.962μmol/L)and neocnidilide(EC_(50)=1.161μmol/L)exhibited significant neuroprotective effects,comparable to the positive drugs rasagiline(EC_(50)=0.896μmol/L)and safinamide(EC_(50)=1.079μmol/L).These findings underscore the potential of sedanolide as a novel natural hMAO-B inhibitor that warrants further development as a promising drug candidate.

8-Hydroxyquinolylnitrones as multifunctional ligands for the therapy of neurodegenerative diseases

We describe the development of quinolylnitrones(QNs)as multifunctional ligands inhibiting cholinesterases(ChEs:acetylcholinesterase and butyrylcholinesterase—h BChE)and monoamine oxidases(hMAO-A/B)for the therapy of neurodegenerative diseases.We identified QN 19,a simple,low molecular weight nitrone,that is readily synthesized from commercially available 8-hydroxyquinoline-2-carbaldehyde.Quinolylnitrone 19 has no typical pharmacophoric element to suggest ChE or MAO inhibition,yet unexpectedly showed potent inhibition of h BChE(IC50=1.06±0.31 nmol/L)and h MAO-B(IC_(50)=4.46±0.18μmol/L).The crystal structures of 19 with hBChE and hMAO-B provided the structural basis for potent binding,which was further studied by enzyme kinetics.Compound 19 acted as a free radical scavenger and biometal chelator,crossed the blood—brain barrier,was not cytotoxic,and showed neuroprotective properties in a 6-hydroxydopamine cell model of Parkinson's disease.In addition,in vivo studies showed the anti-amnesic effect of 19 in the scopolamine-induced mouse model of AD without adverse effects on motoric function and coordination.Importantly,chronic treatment of double transgenic APPswe-PS1δE9 mice with 19 reduced amyloid plaque load in the hippocampus and cortex of female mice,underscoring the disease-modifying effect of QN 19.

Effects of nimodipine and fructose-1,6-diphosphate on cerebral damage in carbon monoxide poisoning mice

Objective To study the dose- and time- dependent protective effects and the synergistic effects of nimodipine (NMDP) and fructose-1,6-diphosphate (FDP) against cerebral damage induced by acute carbon monoxide (CO) poisoning in mice. Methods Male mice were exposed to CO 170 mL/kg, i.p. After CO intraperitonealy exposure, mortality of mice, change in memory function estimated by passive avoidance test, the pathomorphologic observation of brain tissue slices, as well as changes of activities of monoamine oxidase (MAO)-B and Ca 2+-Mg 2+-ATPase in cerebral tissue were studied. In dose-dependent protective effect study, NMDP (10.6, 5.3, 2.7 mg/kg) and FDP (2.6, 1.3, 0.67 g/kg) was injected ip, respectively 15 min after CO exposure. To study the time-effect relationship of drugs, NMDP (5.3 mg/kg) and FDP (1.3 g/kg) were administered ip respectively 15 minutes, 45 minutes and 120 minutes after CO exposure. The combination of NMDP (2.7 mg/kg) and FDP (0.67 g/kg) was administered ip15 minutes, 45 min and 120 minutes after CO exposure to study the synergism of the two drugs. Results Either NMDP (10.6, 5.3 mg/kg) or FDP (2.6, 1.3 g/kg) administered ip within 15 minutes after CO exposure significantly decreased the impairment of memory function and mortality rate induced by CO, inhibited the decrease of Ca 2+-Mg 2+-ATPase activity, blunted the rising of MAO-B activity and prevented the delayed hippocampal neuronal death in poisoning mice. To our surprise, the combined use of NMDP (2.7 mg/kg) and FDP (0.67 g/kg) within 15 minutes after CO exposure had similar effects to that in NMDP (10.6, 5.3 mg/kg) and FDP (2.6, 1.3 g/kg). Conclusions These results suggest that the impairment of CO on brain can be attenuated if NMDP or FDP are administered sufficiently and quickly as soon as possible after CO exposure and there exists a synergism of FDP and NMDP against CO poisoning damage.

Neuromodulatory effects of ethyl acetate fraction of Zingiber officinale Roscoe extract in rats with lead-induced oxidative stress

Objective: This study investigated the ameliorative potential of Zingiber officinale Roscoe extract against lead-induced brain damage in rats.Methods: Thirty male rats were divided into 5 groups of 6 rats each. Lead-acetate toxicity was induced by intraperitoneal injection(10 mg/kg body weight(b.w.)) in Groups B–E. Group A(control) and Group B(lead-acetate) were left untreated; vitamin C(200 mg/kg b.w.) was administered to Group C; ethyl acetate fraction from Z. officinale extract(200 and 100 mg/kg b.w.) was administered to Group D and E by oral gavage once daily for 7 days. Changes in the content of some key marker enzymes such as acetylcholinesterase(AChE), butyrylcholinesterase(BChE), monoamine oxidase(MAO), epinephrine, dopamine,Na^+/K^+-ATPase, catalase(CAT), superoxide dismutase(SOD) and glutathione peroxidase(GPx) as well as malonaldehyde(MDA) levels were determined in serum.Results: Exposure to lead acetate resulted in a significant decrease(P < 0.05) in the activities of BChE,AChE, Na^+/K^+-ATPase, SOD, CAT and GPx with a corresponding increase in the levels of MDA, xanthine oxidase, epinephrine, dopamine and MAO relative to the control group. Levels of all disrupted parameters were alleviated by co-administration of Z. officinale fraction and by the standard drug, vitamin C.Conclusion: These results suggest that ethyl acetate fraction of Z. officinale extract attenuates leadinduced brain damage and might have therapeutic potential as a supplement that can be applied in lead poisoning.

Effect of Kangshuai Yizhi Formula Ⅰ (抗衰益智方Ⅰ) on Learning and Memory Dysfunction Induced by Scopolamine in Mice

Objective：To evaluate the improvement of Kangshuai Yizhi FormulaⅠ（抗衰益智方Ⅰ,KYFⅠ）on the learning and memory dysfunction in mice,and on the mechanism of the hippocampal cholinergic system and the nervous system of monoamine which are closely related to learning and memory function.Methods：Mice in the low-,middle-,and high-dose KYFⅠgroups were given low-,middle-,and high-dose KYF,respectively, by gastrogavage for 35 successive days.Animals in the control group and the model group were treated with distilled water.The acute learning and memory dysfunction model was established by injection of scopolamine from day 31,and Morris water maze was used to assess the behavior performance of scopolamine-induced model mice for five days.The activities of acetylcholinesterase（AChE）,choline acetyl transferase（ChaT） and the content of monoamine neurotransmitters in hippocampus were measured.The activity of monoamine oxidase（MAO）in hippocampus and serum was also detected.Results：（1）Compared with the control group,the mean escape latency was shortened,and the frequency across the platform and the staying time at the platform area on the 5th day were decreased in the model group by Morris water maze test.The activities of AChE and MAO were increased,and the ChaT activity and monoamine neurotransmitter content were decreased as well.（2） The escape latency for 4 days in the low-,middle-,and high-dose KYFⅠgroups was significantly shortened than that in the model group,with the shortest latency in the high-dose KYFⅠgroup（P〈0.05,P〈0.01）.The frequency across the platform was significantly increased and the staying time at the platform was significantly prolonged in the middle-and high-dose KYFⅠgroups（P〈0.05,P〈0.01）.（3）As compared with the model group,the activity of ChaT and the content of monoamine neurotransmitters in the hippocampus were significantly increased, and the activities of AchE and MAO were significantly decreased in the hippocampus in the high-dose KYFⅠgroup（P〈0.01）.Conclusions：High-dose KYFⅠcan significantly improve the learning and memory dysfunction induced by scopolamine in mice.Its mechanism may be related to improving the central cholinergic system and regulating the hippocampal monoamine neurotransmitters.