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-hBChE) 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 hBChE (IC50 = 1.06 ± 0.31 nmol/L) and hMAO-B (IC50 = 4.46 ± 0.18 μmol/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.

Structure of Gardenia Blue Pigment and Its Inhibitory Activity on Monoamine Oxidase B / 中国实验方剂学杂志

ObjectiveTo study the chemical structure of gardenia blue pigment and its inhibitory activity against monoamine oxidase B （MAO-B）， in order to seek a potential feasible way for rational utilization and value enhancement of iridoids in Gardeniae Fructus. MethodIridoid glycosides in Gardeniae Fructus were hydrolyzed by cellulase to obtain their aglycones and reacted with amino acids. Then， the products were purified by column chromatography packed with D101 macroporous resin and preparative liquid chromatography to obtain gardenia blue pigments， and the gardenia blue pigments were identified by nuclear magnetic resonance （NMR） and mass spectrometry （MS）. Benzylamine was used as the reaction substrate of MAO-B and in vitro incubated with gardenia blue pigment monomers， high performance liquid chromatography （HPLC） was employed to determine the production of benzaldehyde for evaluating the inhibitory effect of gardenia blue pigments on MAO-B， the mobile phase was methanol （A） -50 mmol·L-1 potassium phosphate buffer （B， pH 3.2） （2∶3）， and the detection wavelength was 245 nm. ResultEight compounds of gardenia blue pigment A-H were synthesized and identified. In MAO-B inhibition test， compared with geniposide， the inhibitory activity of gardenia blue pigment D and E was significantly enhanced （P<0.05）. Compared with the 6β-hydroxygeniposide， the inhibitory activity of gardenia blue pigment G and H was significantly enhanced （P<0.05， P<0.01）. All the four gardenia blue pigments showed better MAO-B inhibitory activity than the prototype compounds. ConclusionGardenia blue pigment is a simple compound formed by one molecule of amino acid and one molecule of iridoid. Some gardenia blue pigments have better MAO-B inhibitory activity than the prototype compounds. The activity of gardenia blue pigment produced by different substrates is different， and the high-value gardenia blue pigment can be prepared based on experimental optimization， which can expand the application range of gardenia blue pigment and enrich the comprehensive utilization of iridoids from Gardeniae Fructus.

8-Propyl-6H-[1,3]dioxolo[4,5-g]chromen-6-one: A new coumarin with monoamine oxidase B inhibitory activity and possible anti-parkinsonian effects

Parkinson's disease is a common neurodegenerative disorder. In this study, the monoamine oxidase inhibitory activity and potential anti-parkinsonian effects of 8-propyl-6H-[1,3]dioxolo[4,5-g]chromen-6-one (FCS303), a new synthetic coumarin, were evaluated. To do this, we used the reserpine model of Parkinson's disease, an assay of levodopa/carbidopa potentiation, the catalepsy model of haloperidol, and an in vitro assay against monoamine oxidase (MAO) activity. Additionally, lipid peroxidation and protein carbonyl group quantification was performed in mice brain homogenates previously treated with haloperidol. FCS303 inhibited monoamine oxidase B (MAO-B) with an IC50 of 5.46 ± 0.36 µM; however, there was no effect on monoamine oxidase A (MAO-A). The oral administration of FCS303 led to a significant reversal of hypokinesia in the reserpine model (at 24 h, doses of 100 and 200 mg/kg) and in the levodopa/carbidopa potentiation assay (at 2 and 24 h, dose of 200 mg/kg). In addition, FCS303 (100 mg/kg) showed anti-cataleptic activity against haloperidol. FCS303 (50 mg/kg) significantly decreased lipid peroxidation and protein carbonyl quantification. These results suggest that FCS303 could present anti-parkinsonian activity related to MAO-B inhibitory activity.

Effect of monoamine oxidase B A644G variant on nicotine dependence and/or schizophrenia risk

Abstract Objectives Schizophrenia (Sch) is a severe and chronic mental illness. Smoking prevalence is higher in patients with Sch than general population. We aimed to investigate the effects of MAOB gene A644G variant on nicotine dependence (ND) and Sch+ND risk in Turkish population and to evaluate by bioinformatic analysis. Methods Present study included 161 individuals with ND, 223 patients with Sch+ND, and 96 non-smoker controls. MAOB A644G variant was analyzed using PCR-RFLP method. As the MAOB gene is located on the X chromosome, each gender was analysed separately. Results The total distributions of AA, AG and GG genotypes of MAOB gene A644G were 44.7%, 22.4% and 32.9% in the ND group, 45.3%, 25.1% and 29.6% in the Sch+ND group and, 44.8, 22.9% and 32.3% in non-smoker controls. No significant differences were observed between groups for the MAOB A644G genotype and allele frequencies when female group compared to male group (p > 0.05). Examination of disease associations of SNPs from each miRNA gene region in GWAS databases yielded results for aging, bipolar disorder, autoimmune, and neurological diseases. Discussion Our results indicate that the MAOB gene A644G variant is not associated with ND and/or Sch susceptibility in the Turkish population.

Hypersexuality Induced by Rasagiline Monotherapy in a Patinet with Parkinson's Disease

Impulse control disorders including hypersexuality occur occasionally in Parkinson's disease, especially when treated with dopamine agonist. A 62-year-old male with Parkinson's disease was initially treated with rasagiline monotherapy and presented hypersexuality. After 8 weeks of discontinuation of the drug, his hypersexual behavior was significantly improved. To our knowledge, this is the first reported Asian case of a hypersexuality caused by rasagiline. Our observation emphasizes that patients and caregivers need to be educated on the possibility of hypersexuality resulting from rasagiline.

Combined structure- and ligand-based virtual screening to evaluate caulerpin analogs with potential inhibitory activity against monoamine oxidase B

Abstract Natural marine products can help increase the quality of life in patients with neurological diseases. A large number of marine products act against Alzheimer's disease through varying pathways. According to structure- and ligand-based analyses, caulerpin, an alkaloid primarily isolated from the genus Caulerpa, possesses activity against monoamine oxidase B. To predict the activity of caulerpin, we employed Volsurf descriptors and the machine learning Random Forest algorithm in parallel with a structure-based methodology that included molecular docking. Using caulerpin as a lead compound, a database containing 108 analogs was evaluated, and nine were selected as active. The structures selected as active exhibited polar and non-polar substitutions on the caulerpin skeleton, which were relevant for their activity. Dragon consensus drug-like scoring was applied to identify the active analogs that might serve as good drug candidates, and the entire group presented satisfactory performance. These results indicate the possibility of using these analogs as potential leads against Alzheimer's disease.

Effects of β-amyloid peptide on the monoamine oxidase-B, interleukin-6 in the brain of mice and the interfering effect of traditional Chinese medicine / 中国康复理论与实践

@#ObjectiveTo observe the changes of monoamine oxidase-B (MAO-B), interleukin-6(IL-6) in the cortex and hippocampus of Alzheimer's disease model mice and the effect of traditional Chinese medicine Naofucong.MethodsAlzheimer's disease model was induced in mice by β-amyloid(Aβ)25-35 icv. Space learning and memorial ability was tested in Morris water maze. The activity of MAO-B was measured by colorimetric method. IL-6 was observed with the immnuohistochemical stain.ResultsMice in the model group presented longer latent periods of Morris water maze(81.3±13.4)s, higher activities of MAO-B in brain cortex and hippocampus (120.12±10.15,83.60±5.29) compare with that of the control group, which was (34.2±10.9)s,(93.09±10.54) and (50.39±9.16)(P<0.05～0.01).There were many IL-6 positive cell in dentate gyrus of hippocampus of the model group. After administration with Naofucong grain, latent periods (43.7±12.7) s and activities of MAO-B (47.11 ± 6.57)in hippocampus were recovered(P<0.05～0.01), and the IL-6 positive cell in dentate gyrus decreased.ConclusionNaofucong grain can antagonize the Aβ25-35 toxicity by decreasing the overactivition of MAO-B and the excretion of inflammatory medium by microglia, as well as improve the memory function.

Effects of Pine Needle Butanol Fraction on Acetylcholine (ACh) and Its Related Enzymes in Brain of Rats

This study was designed to investigate the effects of buthanol (BuOH) fraction of pine (Pinus densiflora Sieb et Zucc) needle on cholesterol and lipofuscin (LF) accumulations, acetylcholine (ACh) and its related enzyme activities such as choline acetyltransferase (CAhT) and acetylcholinesterase (AChE), and monoamone oxidase-B (MAO-B) activity, which destroyed the catecholamine-related neurotransmitters in brain membranes of Sprague-Dawley (SD) rats. Male SD rats were fed basic diets (control group) or experimental diets (BuOH-25, BuOH-50 and BuOH-100) for 45 days. Cholesterol accumulations in mitochondria and microsomes were significantly inhibited (about 14 - 17% and 23 - 34%, respectvely) in BuOH-50 and BuOH-100 groups, whereas LF levels were significantly inhibited (about 10 - 14%) in BuOH-50 and BuOH-100 groups compared with control group. ACh levels and ChAT activities were significantly increased (about 11 - 17% and 11 - 23%, respectively) in membranes of BuOH-50 and BuOH-100 groups compared with control group. AChE activities were significantly increased (about 14 - 17%) in membranes of BuOH-50 and BuOH-100 groups. There was no significant difference in MAO-B activities between control and experimental diet groups. The results suggest that butanol fraction of pine needle may play an effective role in an antiaging effect and improving a learning and memory impairments.

Significance of monoamine oxidase B activity in neurodegenerative models / 重庆医科大学学报

Objective:To investigate the changes of monoamine oxidase B(MAO B)activity in variety of neurodegenerative animal models and to discuss their significance.Methods:The neurodegenerative models were built with NIH male mice by means of the cerebral ischemia-reperfusion,aluminum overloading and carbon monoxide intoxication,respectively.The learning and memory ability of mice,MAO B activity of brain homogenates,and pathomorphological changes of hippocampal slices were determined using Morris maze and Step-down tests,MAO B kit,as well as microscopic observation with HE stain.Result:Although the significantly decreasing learning and memory ability and loss and karyopyknosis of hippocampal neurons were observed in three groups of animal models,compared with control group,the changes of MAO B activity were quite different.There was no significant change in cerebral ischemia-reperfusion model,but the unusual elevation was found in both aluminum overloading model and carbon monoxide intoxication model.Conclusion:The abnormal increase of MAO B does not occur in a variety of neurodegenerative animal models,which may indicate that the cerebral ischemia-reperfusion model can be used in the research of dementia and aluminum overloading model and carbon monoxide intoxication model can be used in the research of both dementia and extrapyramidal disease.

Monoamine oxidase B gene and Cytochrome P450 2D6 gene polymorphism in sporadic Korean Parkinson's disease

BACKGROUND: Epidemiological studies have identified that positive family history and frequent exposures to environmental toxins such as 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP) are of prime causative factors for PD. These toxins are mainly metabolized by MAO-B and CYP2D6. Thus, an individual with inherited defect in xenobiotic metabolism could have a higher susceptibility to PD. We performed this study to investigate a possible allelic association of MAO-B and CYP2D6 known to be involved in metabolism of dopamine and other drugs such as debrisoquine in PD. METHODS: We studied polymorphism of MAO-B and CYP2D6 genes in 69 sporadic idiopathic PD patients (31 males and 38 females) and 41 age-matched healthy control (20 males and 21 females) using genomic DNA extracted from peripheral blood white cell with polymerase chain reaction (PCR) amplification and restriction fragment length polymorphism (RFLP). RESULTS: There were eight different alleles of various numbers of GT repeats within the second intron of MAO-B. The frequency of (GT)20 allele was the highest (44.7%) in PD, while the frequencies of (GT)14 allele and (GT)19 allele were the highest in control groups. Furthermore, the odds ratios of (GT)16 allele and (GT)20 allele were 4.93 (95% confidence interval 0.6-107.63) and 6.15 (95% confidence interval; 2.52-15.51), respectively, suggesting a higher susceptibility to PD in (GT)20 allelic group (p<0.001). Polymorphism of CYP2D6 was also examined by PCR amplification followed by digestion with restriction enzymes. However, we were unable to identify G to A substitution at the junction of intron 3 and exon 4 nor base pair deletion in exon 5 from PD and control groups, which have been reported previously. CONCLUSIONS: These results suggest that the MAO-B gene polymorphism could serve as a determinant of genetic susceptibility to PD at least in Korean population. But the susceptibility may not be directly associated with polymorphism of CYP2D gene examined in this study.

Effect of total alkaloids in Equisetum pratense on activity of MAO-B in mice brain / 中草药

Object To study the effects of total alkaloids in Equisetum pratense Ehrh. (TAEP) on the activity of monoamine oxidase B (MAO B) in mice brain, to reveal the mechanism of its inhibitory action on the central nervous system (CNS). Methods The activity of MAO B was determined by UV spectrophotometry. Results TAEP can markedly activate MAO B in cerebrum and antagonise the inhibition of MAO B activity by nialamide. Conclusion TAEP is a MAO B agonist with an action for the evacuation of monoamine, this may be considered as one of the mechanisms of TAEP sedative and tranquilizing action on CNS.

Correlation between aluminum overload-induced brain neurodegeneration and monoamine oxidase B in mouse brain / 重庆医科大学学报

Objective:To adopt the brain lesion model of mouse induced by overload aluminum to study the relationship between monoamine oxidase B disorder and neurodegeneration induced by overload aluminum(Al).Method:Aluminum overload models were established by injection of 3?l AlCl3 into lateral ventricle of miceeach day for 5d.The AlCl3 solutions injected in different modelswere with different concentrations and they were 0.125%,0.25%,0.5%.On d10,d20,and d30 after the final administration of AlCl3 solution,the learning and memory function of mice,pathomorphology of hippocampi,and MAO-B activity were determined.Results:Aluminum overload elevated MAO-B activity,caused karyopyknosis and loss of neurons in CA1 area of hippocampi,in dose-and time-dependent manners.Conclusion:The results indicate that neurodegeneration induced by Al toxicity may be related to the monoamine oxidase B homeostasis interfered by Al overload.