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 ...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.展开更多
Monoamine oxidase is flavoenzymes, widely distributed in mammals. It is well recognized that MAOs serve an important role in metabolism that they have close relationship with health .Along with the discoveries between...Monoamine oxidase is flavoenzymes, widely distributed in mammals. It is well recognized that MAOs serve an important role in metabolism that they have close relationship with health .Along with the discoveries between MAOs and neurotic disease, more and more studies have been jumped in .In this paper, we design a new probe for assaying the activities of MAOs. The results showed that the probe [7-（3-aminopropoxy）coumarin] is simple, effective and sensitive for MAOB.展开更多
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...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.展开更多
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...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.展开更多
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 inv...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.展开更多
Monoamine oxidases(MAOs)are a class of flavin enzymes that are mainly present in the outer membrane of mitochondria and play a crucial role in maintaining the homeostasis of monoamine neurotransmitters in the central ...Monoamine oxidases(MAOs)are a class of flavin enzymes that are mainly present in the outer membrane of mitochondria and play a crucial role in maintaining the homeostasis of monoamine neurotransmitters in the central nervous system.Furthermore,expression of MAOs is associated with the functions of peripheral organs.Dysfunction of MAOs is relevant in a variety of diseases such as neurodegenerative diseases,heart failure,metabolic disor-ders,and cancers.Monoamine oxidases have two isoenzymes,namely,monoamine oxidase A(MAO-A)and monoamine oxidase B(MAO-B).Therefore,the development of reliable and specific methods to detect these two isoenzymes is of great significance for the in-depth understanding of their functions in biological systems,and for further promoting the clinical diag-nosis and treatment of MAO-related diseases.This review mainly focuses on the advances in small molecular probes for the specific imaging of MAO-A and MAO-B,including radiolabeled probes,fluorescent probes,and a 19F magnetic resonance imaging probe.In addition,applications of these probes for detecting MAO expression levels in cells,tissues,animal models,and patients are described.Finally,the challenges and perspectives of developing novel MAO imaging probes are also highlighted.展开更多
Neuroregeneration and remyelination rarely occur in the adult mammalian brain and spinal cord following central nervous system(CNS)injury.The glial scar has been proposed as a major contributor to this failure in the ...Neuroregeneration and remyelination rarely occur in the adult mammalian brain and spinal cord following central nervous system(CNS)injury.The glial scar has been proposed as a major contributor to this failure in the regenerative process.However,its underlying molecular and cellular mechanisms remain unclear.Here,we report that monoamine oxidase B(MAOB)-dependent excessiveγ-aminobutyric acid(GABA)release from reactive astrocytes suppresses the CNS repair system by reducing brain‒derived neurotrophic factor(BDNF)and tropomyosin receptor kinase B(TrkB)expression in severe spinal cord injury(SCI)animal models.Genetic deletion of MAOB in a mouse SCI model promotes both functional and tissue recovery.Notably,the selective MAOB inhibitor,KDS2010,facilitates recovery and regeneration by disinhibiting the BDNF-TrkB axis in a rat SCI model.Its dose-dependent effects were further validated in a monkey SCI model.Moreover,KDS2010 demonstrated a tolerable safety profile and doseproportional pharmacokinetics in healthy humans during a phase 1 clinical trial.This pathway therefore represents a pivotal target for overcoming the intrinsic barriers to CNS repair after injury.Our findings identify the astrocytic MAOB‒GABA axis as a crucial molecular and cellular brake on the CNS repair system following SCI and highlight the translational potential of KDS2010 as a promising therapeutic candidate for SCI treatment.展开更多
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 broil...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.展开更多
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 biologica...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.展开更多
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...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.展开更多
OBJECTIVE: To investigate the antidepressant-likeeffect of active fraction of Polyrhachis vicina Roger(AFPR) in a rat depression model, and to elucidate the underlying mechanism.METHODS: AFPR was extracted with ethano...OBJECTIVE: To investigate the antidepressant-likeeffect of active fraction of Polyrhachis vicina Roger(AFPR) in a rat depression model, and to elucidate the underlying mechanism.METHODS: AFPR was extracted with ethanol followed by petroleum ether. Its antidepressant-like effect was investigated in mice by tail suspension test(TST), forced swimming test(FST) and open field test(OPT). A repeated dose of reserpine(0.5 mg/kg, daily for 14 d) was used to establish a rat depression model. Fluoxetine was used as positive control agent. The effect of AFPR on reserpine-induced ptosis, hypothermia and akinesia, the levels of monoamines and their metabolites, and the activity of monoamine oxidase(MAO) in hippocampus and prefrontal cortex were determined.RESULTS: Administration of AFPR by gavage at 160 and 320 mg/kg significantly reduced the duration of immobility in the FST and TST, and did not affect locomotor activity in the OPT. In the reserpine-induced depression model, AFPR attenuated anhedonia, demonstrated by reversing hypothermia, akinesia and sucrose consumption. AFPR significantly increased the concentration of monoamines, including dopamine, serotonin, noradrenaline and acetylcholine.CONCLUSION: AFPR normalized the metabolism rates of noradrenaline, serotonin and dopamine,and the activity of MAO, which were altered by chronic reserpine exposure. The findings suggest that modulation of the monoaminergic neurotransmitter system likely underlies the antidepressant-like effect of AFPR.展开更多
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 fact...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.展开更多
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 show...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.展开更多
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-a...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.展开更多
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 cult...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.展开更多
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 i...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.展开更多
The prevalence of neurological disorders is high,especially in the elderly,and current therapies only provide temporary relief and elicit serious adverse effects.This study evaluated the neuroprotective effect of Cymb...The prevalence of neurological disorders is high,especially in the elderly,and current therapies only provide temporary relief and elicit serious adverse effects.This study evaluated the neuroprotective effect of Cymbopogon citratus(lemongrass)teas using in vitro and in silico techniques.The inhibitory effect of the infusions from fresh and dry lemongrass was tested against four enzymes implicated in neurological diseases viz;acetylcholinesterase(AChE),butyrylcholinesterase(BChE),β-secretase(BACE-1),and monoamine oxidase(MAO).This was followed by molecular docking and molecular dynamic simulation studies to assess the interactions of the metabolites present in lemongrass on the selected enzymes.The fresh lemongrass tea displayed a better inhibitory effect on the activities of BACE-1(IC_(50):38.24μg/mL)and MAO(IC_(50):78.62μg/mL),and is comparable to the standard drugs.Molecular docking revealed that resulting complexes from 4-oxo-3-phenyl-4H-chromen-7-yl 3-phenylprop-2-enoate(OPCPPE)as well as aspulvinone H(-10.6 kcal/mol),[1,1′-binaphthalen]-2-ol(-12.1 kcal/mol),neocuscutoside C(-10.5 kcal/mol)and aspulvinone H(-11.9 kcal/mol)had the lowest scores for AChE,BChE,BACE-1,and MAO,respectively.A further probe through a 120-ns molecular dynamics simulation on the topperforming metabolites showed that the resulting complexes formed with chamaemeloside(-66.59 kcal/mol),isocarlinoside(-65.79 kcal/mol),neocuscutoside C(-41.09 kcal/mol),and aspulvinone H(-72.28 kcal/mol)against AChE,BChE,BACE-1 and MAO,respectively,had the lowest binding free energy values compared to the respective standards.In conclusion,the fresh lemongrass tea elicited better neuroprotective properties in vitro and its phenolic constituents(especially aspulvinone H and neocuscutoside C)are potent inhibitors of neurological targets in silico.There is a need for further studies on the in vivo neuroprotective potentials of these compounds.展开更多
Monoamine oxidase(MAO)is an enzyme that plays a crucial role in breaking down monoamine neurotransmitters,including serotonin,dopamine,and norepinephrine,thereby regulating their levels in the brain and other tissues....Monoamine oxidase(MAO)is an enzyme that plays a crucial role in breaking down monoamine neurotransmitters,including serotonin,dopamine,and norepinephrine,thereby regulating their levels in the brain and other tissues.A decrease in MAO enzymes leads to a nonfatal neurological condition that can lead to Parkinson’s disease.In this study,compounds from Tecomella undulata that mimic the structure of MAO-A can be used as substitutes for the blood-brain barrier,which was confirmed via in silico approaches.To study protein-ligand interactions,the target protein,MAO-A(Protein Data Bank ID:2Z5Y),was subjected to molecular docking and dynamics studies with high-affinity compounds extracted from T.undulata.Among the 30 phytochemicals that were subjected to molecular docking simulation to examine the behavior of the dynamic protein complex,the compounds with the highest binding affinities were squalene,benzoic acid,4-methyl-[4-(methoxycarbonyl)phenyl]methyl ester,and stigmasterol.In terms of the root mean square deviation(RMSD),root mean square fluctuation,ligand RMSD,radius of gyration,solvent accessible surface area,and H bond,ligand binding demonstrated sustained stability throughout the simulation period.The results suggest that substances derived from T.undulata show important potential for treating Parkinson’s disease,justifying additional research through both in vitro and in vivo experiments.展开更多
Post-traumatic stress disorder(PTSD)remains a debilitating psychiatric condition with limited pharmacological treatment options.Identifying novel therapeutic targets is critical for addressing its unmet clinical needs...Post-traumatic stress disorder(PTSD)remains a debilitating psychiatric condition with limited pharmacological treatment options.Identifying novel therapeutic targets is critical for addressing its unmet clinical needs.Through our comprehensive human clinical research,including both cross-sectional and longitudinal studies,we revealed a compelling link between dysregulated prefrontal gamma-aminobutyric acid(GABA)levels and PTSD symptoms.Notably,elevated prefrontal GABA levels in PTSD patients are associated with impaired cerebral blood flow(CBF)and symptom severity,normalizing with recovery,highlighting GABA dysregulation as a key mechanism in the disorder.Postmortem and PTSD-like mouse models implicated monoamine oxidase B(MAOB)-dependent astrocytic GABA as a primary driver of this imbalance,exacerbating deficit in fear extinction retrieval.展开更多
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) poi...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.展开更多
文摘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.
基金the project sponsored by the Scientific Research Foundation for the Returned Overseas Chinese Scholars Fund,Zhejiang Province(No.Z01105002)Returned Overseas Chinese Scholars Fund.
文摘Monoamine oxidase is flavoenzymes, widely distributed in mammals. It is well recognized that MAOs serve an important role in metabolism that they have close relationship with health .Along with the discoveries between MAOs and neurotic disease, more and more studies have been jumped in .In this paper, we design a new probe for assaying the activities of MAOs. The results showed that the probe [7-（3-aminopropoxy）coumarin] is simple, effective and sensitive for MAOB.
基金supported by the National Natural Science Foundation of China (Nos. 22037002, 22007032 and 21977082)the National Mega-project for Innovative Drugs of China (No.2019ZX09721001-004-003)+1 种基金the Chinese Postdoctoral Science Foundation,China (No. 2019M660083)the Shanghai Sailing Program,China (No. 20YF1411200)。
文摘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.
文摘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.
文摘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.
基金Natural Science Foundation of Jiangsu Province,Grant/Award Number:BK20210062National Natural Science Foundation of China,Grant/Award Number:82172054Project of Key Laboratory of Organic Synthesis of Jiangsu Province,College of Chemistry,Chemical Engineering and Materials Science,Soochow University,Grant/Award Number:KJS2326。
文摘Monoamine oxidases(MAOs)are a class of flavin enzymes that are mainly present in the outer membrane of mitochondria and play a crucial role in maintaining the homeostasis of monoamine neurotransmitters in the central nervous system.Furthermore,expression of MAOs is associated with the functions of peripheral organs.Dysfunction of MAOs is relevant in a variety of diseases such as neurodegenerative diseases,heart failure,metabolic disor-ders,and cancers.Monoamine oxidases have two isoenzymes,namely,monoamine oxidase A(MAO-A)and monoamine oxidase B(MAO-B).Therefore,the development of reliable and specific methods to detect these two isoenzymes is of great significance for the in-depth understanding of their functions in biological systems,and for further promoting the clinical diag-nosis and treatment of MAO-related diseases.This review mainly focuses on the advances in small molecular probes for the specific imaging of MAO-A and MAO-B,including radiolabeled probes,fluorescent probes,and a 19F magnetic resonance imaging probe.In addition,applications of these probes for detecting MAO expression levels in cells,tissues,animal models,and patients are described.Finally,the challenges and perspectives of developing novel MAO imaging probes are also highlighted.
基金supported by a faculty research grant from Yonsei University College of Medicine(6-2018-0161)the National Research Foundation of Korea(NRF)grant funded by the Korea government(MSIT)(RS-2024-00341308)+1 种基金the Center for Cognition and Sociality from Institute for Basic Science(IBS)(IBS-R001-D2)and NeuroBiogen Co.,LTD.
文摘Neuroregeneration and remyelination rarely occur in the adult mammalian brain and spinal cord following central nervous system(CNS)injury.The glial scar has been proposed as a major contributor to this failure in the regenerative process.However,its underlying molecular and cellular mechanisms remain unclear.Here,we report that monoamine oxidase B(MAOB)-dependent excessiveγ-aminobutyric acid(GABA)release from reactive astrocytes suppresses the CNS repair system by reducing brain‒derived neurotrophic factor(BDNF)and tropomyosin receptor kinase B(TrkB)expression in severe spinal cord injury(SCI)animal models.Genetic deletion of MAOB in a mouse SCI model promotes both functional and tissue recovery.Notably,the selective MAOB inhibitor,KDS2010,facilitates recovery and regeneration by disinhibiting the BDNF-TrkB axis in a rat SCI model.Its dose-dependent effects were further validated in a monkey SCI model.Moreover,KDS2010 demonstrated a tolerable safety profile and doseproportional pharmacokinetics in healthy humans during a phase 1 clinical trial.This pathway therefore represents a pivotal target for overcoming the intrinsic barriers to CNS repair after injury.Our findings identify the astrocytic MAOB‒GABA axis as a crucial molecular and cellular brake on the CNS repair system following SCI and highlight the translational potential of KDS2010 as a promising therapeutic candidate for SCI treatment.
基金This work was supported by the China Agriculture Research System of MOF and MARA(CARS-41)the Agricultural Science and Technology Innovation Program(ASTIP-IAS09)+2 种基金the Key Program of the National Natural Science Foundation of China(31630073)the National Natural Science Foundation of China(31972583)the Earmarked Fund for Hebei Chicken Innovation Team of Modern Agro-industry Technology Research System(HBCT2018150203,HBCT2018150206).
文摘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.
基金supported by the National Key R&D Program of China(2020YFA0709900)the National Natural Science Foundation of China(62288102,22077101,22004099)+3 种基金the Joint Research Funds of Department of Science&Technology of Shaanxi Province and Northwestern Polytechnical University(2020GXLH-Z-008,2020GXLH-Z-021,2020GXLH-Z-023)the Natural Science Foundation of Shaanxi Province(2022JM-130)the Key Research and Development Program of Shaanxi(2020ZDLGY13-04)the Fundamental Research Funds for the Central Universities
文摘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.
基金supported by UGC Dr.D.S.Kothari Postdoctoral scheme by awarding the fellowship to SNR(Ref.No-F.4-2/2006(BSR)/BL/19-20/0032)。
文摘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.
基金Supported by Grants from the National Natural Science Foundation of China(No.81560663,81773924,U1402221,81573636)Beijing Natural Science Foundation(7182114)+7 种基金PUMC Youth Fund(3332016058)CAMS Innovation Fund for Medical Sciences(CIFMS)(2016-I2M-1-004)the Scientific Research Foundation of the Higher Education Institutions of Hunan Province(15K091)Project of NDRC and State Administration of Traditional Chinese Medicine(60011000)Hunan Provincial Key Laboratory for Standardization of Important Chinese Herbal Pieces(BG201701,4981-0901020)The State Key Laboratory Fund Open Project(GTZK201610)China Postdoctoral Science Foundation(2013M540066)Beijing Key Laboratory of New Drug Mechanisms and Pharmacological Evaluation Study(BZ0150)
文摘OBJECTIVE: To investigate the antidepressant-likeeffect of active fraction of Polyrhachis vicina Roger(AFPR) in a rat depression model, and to elucidate the underlying mechanism.METHODS: AFPR was extracted with ethanol followed by petroleum ether. Its antidepressant-like effect was investigated in mice by tail suspension test(TST), forced swimming test(FST) and open field test(OPT). A repeated dose of reserpine(0.5 mg/kg, daily for 14 d) was used to establish a rat depression model. Fluoxetine was used as positive control agent. The effect of AFPR on reserpine-induced ptosis, hypothermia and akinesia, the levels of monoamines and their metabolites, and the activity of monoamine oxidase(MAO) in hippocampus and prefrontal cortex were determined.RESULTS: Administration of AFPR by gavage at 160 and 320 mg/kg significantly reduced the duration of immobility in the FST and TST, and did not affect locomotor activity in the OPT. In the reserpine-induced depression model, AFPR attenuated anhedonia, demonstrated by reversing hypothermia, akinesia and sucrose consumption. AFPR significantly increased the concentration of monoamines, including dopamine, serotonin, noradrenaline and acetylcholine.CONCLUSION: AFPR normalized the metabolism rates of noradrenaline, serotonin and dopamine,and the activity of MAO, which were altered by chronic reserpine exposure. The findings suggest that modulation of the monoaminergic neurotransmitter system likely underlies the antidepressant-like effect of AFPR.
基金National Key R and D Program of China,No.2016YFC1306700The Key Projects of National Natural Science Foundation of China,No.81830040+1 种基金Science and Technology Program of Guangdong,China,No.2018B030334001Program of Excellent Talents in Medical Science of Jiangsu Province,China,No.JCRCA2016006.
文摘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.
文摘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.
文摘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.
文摘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.
基金supported by grants from the Natural Science Foundation of Guangdong Province of China,No.2015A030313317a grant from the Science and Technology Program of Guangzhou City of China,No.2014J4100097+3 种基金partially by a grant from the Science and Technology Development Fund(FDCT) of Macao Special Administrative Region,No.134/2014/A3a grant from the Research Committee of University of Macao,No.MYRG139(Y1-L4)-ICMS12-LMY and MYRG2015-00214-ICMS-QRCMgrants from the Research Grants Council of Hong Kong Special Administrative Region of China,No.561011,15101014the Hong Kong Polytechnic University of China,No.G-SB10,G-UC15 and G-YBGQ
文摘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.
基金support of the South African Medical Research Council under a Self-Initiated Research Grantthe National Research Foundation’s Competitive Programme for Rated Researchers Support(SRUG2204193723)to Saheed Sabiu.
文摘The prevalence of neurological disorders is high,especially in the elderly,and current therapies only provide temporary relief and elicit serious adverse effects.This study evaluated the neuroprotective effect of Cymbopogon citratus(lemongrass)teas using in vitro and in silico techniques.The inhibitory effect of the infusions from fresh and dry lemongrass was tested against four enzymes implicated in neurological diseases viz;acetylcholinesterase(AChE),butyrylcholinesterase(BChE),β-secretase(BACE-1),and monoamine oxidase(MAO).This was followed by molecular docking and molecular dynamic simulation studies to assess the interactions of the metabolites present in lemongrass on the selected enzymes.The fresh lemongrass tea displayed a better inhibitory effect on the activities of BACE-1(IC_(50):38.24μg/mL)and MAO(IC_(50):78.62μg/mL),and is comparable to the standard drugs.Molecular docking revealed that resulting complexes from 4-oxo-3-phenyl-4H-chromen-7-yl 3-phenylprop-2-enoate(OPCPPE)as well as aspulvinone H(-10.6 kcal/mol),[1,1′-binaphthalen]-2-ol(-12.1 kcal/mol),neocuscutoside C(-10.5 kcal/mol)and aspulvinone H(-11.9 kcal/mol)had the lowest scores for AChE,BChE,BACE-1,and MAO,respectively.A further probe through a 120-ns molecular dynamics simulation on the topperforming metabolites showed that the resulting complexes formed with chamaemeloside(-66.59 kcal/mol),isocarlinoside(-65.79 kcal/mol),neocuscutoside C(-41.09 kcal/mol),and aspulvinone H(-72.28 kcal/mol)against AChE,BChE,BACE-1 and MAO,respectively,had the lowest binding free energy values compared to the respective standards.In conclusion,the fresh lemongrass tea elicited better neuroprotective properties in vitro and its phenolic constituents(especially aspulvinone H and neocuscutoside C)are potent inhibitors of neurological targets in silico.There is a need for further studies on the in vivo neuroprotective potentials of these compounds.
文摘Monoamine oxidase(MAO)is an enzyme that plays a crucial role in breaking down monoamine neurotransmitters,including serotonin,dopamine,and norepinephrine,thereby regulating their levels in the brain and other tissues.A decrease in MAO enzymes leads to a nonfatal neurological condition that can lead to Parkinson’s disease.In this study,compounds from Tecomella undulata that mimic the structure of MAO-A can be used as substitutes for the blood-brain barrier,which was confirmed via in silico approaches.To study protein-ligand interactions,the target protein,MAO-A(Protein Data Bank ID:2Z5Y),was subjected to molecular docking and dynamics studies with high-affinity compounds extracted from T.undulata.Among the 30 phytochemicals that were subjected to molecular docking simulation to examine the behavior of the dynamic protein complex,the compounds with the highest binding affinities were squalene,benzoic acid,4-methyl-[4-(methoxycarbonyl)phenyl]methyl ester,and stigmasterol.In terms of the root mean square deviation(RMSD),root mean square fluctuation,ligand RMSD,radius of gyration,solvent accessible surface area,and H bond,ligand binding demonstrated sustained stability throughout the simulation period.The results suggest that substances derived from T.undulata show important potential for treating Parkinson’s disease,justifying additional research through both in vitro and in vivo experiments.
基金supported by National Research Foundation of Korea grants funded by the Ministry of Science and ICT(RS-2024-00457381 to I.K.L.2020M3E5D9079742 to H.R.)+2 种基金by the Ministry of Education(2020R1A6A1A03043528 to I.K.L.)This work was also in part supported by the Institute for Basic Science(IBS),Center for Cognition and Sociality(IBS-R001-D2 to C.J.L)This project applied tools developed under NIH grants R01 EB016089,R01 EB023963 and P41 EB031771.
文摘Post-traumatic stress disorder(PTSD)remains a debilitating psychiatric condition with limited pharmacological treatment options.Identifying novel therapeutic targets is critical for addressing its unmet clinical needs.Through our comprehensive human clinical research,including both cross-sectional and longitudinal studies,we revealed a compelling link between dysregulated prefrontal gamma-aminobutyric acid(GABA)levels and PTSD symptoms.Notably,elevated prefrontal GABA levels in PTSD patients are associated with impaired cerebral blood flow(CBF)and symptom severity,normalizing with recovery,highlighting GABA dysregulation as a key mechanism in the disorder.Postmortem and PTSD-like mouse models implicated monoamine oxidase B(MAOB)-dependent astrocytic GABA as a primary driver of this imbalance,exacerbating deficit in fear extinction retrieval.
基金ThisprojectwassupportedbyChongqingScienceandTechnologyCommission (No 99 3 3 3 2 )
文摘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.
