Showing papers on "Monoamine oxidase B published in 2012"
TL;DR: Those genes that are highly expressed during the first year of postnatal life may influence and orchestrate the early development of cortical neural circuitry while genes portraying a pattern of increasing expression with age may indicate a role in DLPFC maturation and attainment of adult levels of cognitive function.
Abstract: Dopamine is integral to cognition, learning and memory, and dysfunctions of the frontal cortical dopamine system have been implicated in several developmental neuropsychiatric disorders. The dorsolateral prefrontal cortex (DLPFC) is critical for working memory which does not fully mature until the third decade of life. Few studies have reported on the normal development of the dopamine system in human DLPFC during postnatal life. We assessed pre- and postsynaptic components of the dopamine system including tyrosine hydroxylase, the dopamine receptors (D1, D2 short and D2 long isoforms, D4, D5), catechol-O-methyltransferase, and monoamine oxidase (A and B) in the developing human DLPFC (6 weeks -50 years). Gene expression was first analysed by microarray and then by quantitative real-time PCR. Protein expression was analysed by western blot. Protein levels for tyrosine hydroxylase peaked during the first year of life (p < 0.001) then gradually declined to adulthood. Similarly, mRNA levels of dopamine receptors D2S (p < 0.001) and D2L (p = 0.003) isoforms, monoamine oxidase A (p < 0.001) and catechol-O-methyltransferase (p = 0.024) were significantly higher in neonates and infants as was catechol-O-methyltransferase protein (32 kDa, p = 0.027). In contrast, dopamine D1 receptor mRNA correlated positively with age (p = 0.002) and dopamine D1 receptor protein expression increased throughout development (p < 0.001) with adults having the highest D1 protein levels (p ≤ 0.01). Monoamine oxidase B mRNA and protein (p < 0.001) levels also increased significantly throughout development. Interestingly, dopamine D5 receptor mRNA levels negatively correlated with age (r = -0.31, p = 0.018) in an expression profile opposite to that of the dopamine D1 receptor. We find distinct developmental changes in key components of the dopamine system in DLPFC over postnatal life. Those genes that are highly expressed during the first year of postnatal life may influence and orchestrate the early development of cortical neural circuitry while genes portraying a pattern of increasing expression with age may indicate a role in DLPFC maturation and attainment of adult levels of cognitive function.
87 citations
TL;DR: Results suggest that pioglitazone may have utility as a "re-purposed" neuro-protectant drug in retarding the progression of disease in Parkinson's patients and provide new insights for the development of reversible isoenzyme-specific MAO inhibitors.
Abstract: The widely employed anti-diabetic drug pioglitazone (Actos) is shown to be a specific and reversible inhibitor of human monoamine oxidase B (MAO B). The crystal structure of the enzyme-inhibitor complex shows the R-enantiomer is bound with the thiazolidinedione ring near the flavin. The molecule occupies both substrate and entrance cavities of the active site establishing non-covalent interactions with the surrounding amino acids. These binding properties differentiate pioglitazone from the clinically used MAO inhibitors, which act through covalent inhibition mechanisms and do not exhibit a high degree of MAO A versus B selectivity. Rosiglitazone (Avandia) and troglitazone, other members of the glitazone class, are less selective in that they are weaker inhibitors of both MAO A and MAO B These results suggest that pioglitazone may have utility as a "re-purposed" neuro-protectant drug in retarding the progression of disease in Parkinson's patients. They also provide new insights for the development of reversible isoenzyme-specific MAO inhibitors.
82 citations
TL;DR: In this review article, MAO is examined in terms of function and genetic organization, with special focus on recent discoveries related to the transcriptional regulation of MAO.
Abstract: Monoamine oxidases play an integral role in brain function. Both monoamine oxidase A (MAO-A) and monoamine oxidase B (MAO-B) regulate neurochemistry by degrading monoamine neurotransmitters (serotonin, dopamine, and norepinephrine). Any alteration in MAO levels can have devastating effects on the brain and behavior by lowering or raising neurotransmitter levels and producing toxic reactive oxygen species. In this review article, MAO is examined in terms of function and genetic organization, with special focus on recent discoveries related to the transcriptional regulation of MAO. In recent studies, transcriptional regulation involves a repressor protein, R1, for MAO-A and an activator protein, KLF11 (a Kruppel-like factor; also referred to as transforming growth factor-beta early inducible gene 2, TIEG2), for both MAO-A and MAO-B, by binding to Sp/KLF sites in the core promoters of MAO and regulating MAO gene expression. Furthermore, KLF11 may influence MAO-B expression and augment glyceraldehyde-3 phosphate dehydrogenase (GAPDH) to upregulate MAO-B transcription upon exposure to ethanol. Finally, we review recent progress in MAO research and highlight the roles that MAOs play in several psychiatric conditions, including chronic stress, major depressive disorder and alcohol dependence. Further research in this area is needed to better understand MAOs, their transcription factors and signaling pathways in psychiatric illnesses in order to develop new strategies for pharmacological advancement.
73 citations
TL;DR: Tory evidence is offered that the amine is most likely to be present in the active site in its protonated form, which is similar to the conclusion from experimental studies of MAO A, which can allow for the design of novel and improved MAO B inhibitors.
Abstract: Monoamine oxidase (MAO), which exists in two isozymic forms, MAO A and MAO B, is an important flavoenzyme responsible for the metabolism of amine neurotransmitters such as dopamine, serotonin, and ...
66 citations
TL;DR: The pharmacological effects on the Central Nervous System of some plant extracts and their isolated chemical components due to their monoamine oxidase (MAO) activity are dealt with.
Abstract: Drugs of natural origin still play a major role in the treatment of many diseases and as lead structures for the development of new synthetic drug substances. This review article deals the pharmacological effects on the Central Nervous System (CNS) of some plant extracts and their isolated chemical components due to their monoamine oxidase (MAO) activity. Herbs and herbal preparations containing MAO-A inhibitors have been widely used as an effective alternative in the treatment of neuropsychiatric diseases such as depression. Inhibitors of MAO-B not only enhance dopaminergic neurotransmission but also prevent activation of toxin and free radical formation, alleviating the process of neuron denaturalization, on account of which they are used in Parkinson disease (PD). Several methods have been developed for monitoring MAO activity and its inhibitor screening of bioactive natural products.
45 citations
TL;DR: It is suggested that Mao-B platelet protein level may serve as a biomarker for age-related dementia, especially AD.
44 citations
TL;DR: Results indicate that TF might be beneficial in mitigating MPTP-induced damage of dopaminergic neurons, possibly via its neuroprotective and its antioxidant potential.
41 citations
TL;DR: Several novel compounds were identified, with potencies in the low nanomolar and low micromolar range, and it was found that derivatives of the natural product sulfuretin are potent MAO-A andMAO-B inhibitors.
38 citations
TL;DR: The design and synthesis of a new class of fluorogenic probes based on monoamine oxidase-triggered oxidative C-O bond cleavage and the selectivity of probe P1 towards MAO-B was 22-fold higher than that towardsMAO-A.
36 citations
TL;DR: Repeat treatment with agmatine during 5 consecutive days increased the survival rate and protection against the MPTP-induced decrease of hippocampal glutamate uptake and loss of dopaminergic neurons in the substantia nigra pars compacta of aging mice, without altering brain monoamine oxidase B (MAO-B) activity.
35 citations
TL;DR: The increased melatonin level in ApoE4‐C6 cells results from up‐regulation of NAT expression, a key enzyme for melatonin synthesis, and down-regulation of MAOA and MAOB expression, the metabolic enzyme for its precursor serotonin.
Abstract: Previous studies have demonstrated that apolipoprotein E (ApoE) genotype and melatonin are closely associated with Alzheimer's disease (AD). However, the relationship between ApoE genotype and melatonin remains unclear. Recently, we reported that cultured rat cortical astrocytes and glioma C6 cells synthesize melatonin. In the current study, we investigated the effect of ApoE genotype on melatonin biosynthesis. C6 cells with stable expression of ApoE isoforms (ApoE 2, 3 and 4) were established. A higher level of melatonin was demonstrated in cultured ApoE4-C6 cells than that in ApoE3-C6 cells. In addition, we found that N-acetyltransferase (NAT) protein level was up-regulated in ApoE4-C6 cells compared with ApoE3-C6 cells. Further study suggested that mRNA expression of monoamine oxidase A (MAOA) and monoamine oxidase B (MAOB) decreased in ApoE4-C6 cells. In conclusion, the increased melatonin level in ApoE4-C6 cells results from up-regulation of NAT expression, a key enzyme for melatonin synthesis, and down-regulation of MAOA and MAOB expression, the metabolic enzyme for its precursor serotonin.
TL;DR: Results showed that MAO-B seems to exert a critical role in the development of postoperative and neuropathic pain, and selegiline showed an anti-allodynic effect.
TL;DR: It is demonstrated for the first time that G/A dimorphism in intron 13 sequence creates splicing enhancer thus stimulating intron13 removal efficiency, which might serve as a surrogate marker for – Parkinson disease.
TL;DR: The preliminary findings could suggest that severity of affective flattening may be associated by modifier variants of MAOA and MAOB genes in female Mexican patients with schizophrenia, however, further large-scale studies using quantitative symptom-based phenotypes and several candidate variants should be analyzed to obtain a final conclusion.
Abstract: Given that schizophrenia is a heterogeneous disorder, the analysis of clinical characteristics could help to identify homogeneous phenotypes that may be of relevance in genetic studies. Linkage and association studies have suggested that a locus predisposing to schizophrenia may reside within Xp11. We analyzed uVNTR and rs1137070, polymorphisms from MAOA and rs1799836 of MAOB genes to perform single SNP case-control association study in a sample of 344 schizophrenia patients and 124 control subjects. Single polymorphism analysis of uVNTR, rs1137070 and rs1799836 SNPs did not show statistical differences between cases and controls. Multivariate ANOVA analysis of clinical characteristics showed statistical differences between MAOB/rs1799836 and affective flattening scores (F = 4.852, P = 0.009), and significant association between MAOA/uVNTR and affective flattening in female schizophrenia patients (F = 4.236, P = 0.016) after Bonferroni's correction. Our preliminary findings could suggest that severity of affective flattening may be associated by modifier variants of MAOA and MAOB genes in female Mexican patients with schizophrenia. However, further large-scale studies using quantitative symptom-based phenotypes and several candidate variants should be analyzed to obtain a final conclusion.
Journal Article•
TL;DR: The present data suggest that pharmacokinetic or pharmacodynamic factors other than the investigated genetic variants of the MAOB and COMT enzymes seem to determine the response to levodopa in the Iranian PD patients.
Abstract: Parkinson's disease (PD) patients vary widely in their response to levodopa treatment, and this may be partially genetic in origin. Recent studies suggest that catechol-O-methyltransferase (COMT), G1947A and monoamine oxidase B (MAOB), A644G polymorphisms might influence the risk and treatment of PD. Herein, we aimed to test the possible influence of MAOB and COMT genetic polymorphisms on the effective daily dose of levodopa administered in the fifth year of treatment. We also examined the effect of COMT and MAOB haplotypes on levodopa therapy outcome. There were 31 females and 72 males of Iranian origin diagnosed with sporadic PD included into the study. The patients were divided into two groups. Group 1: patients received daily doses of levodopa below 500 mg in the fifth year of treatment. Group 2: those patients receiving daily doses exceeding 500 mg in the fifth year of treatment. MAOB and COMT polymorphism genotyping was performed by using PCR-based restriction fragment length polymorphism (RFLP) analyses. Our data show that the first group suffered less frequently from dyskinesia than patients from the second group. No statistically significant differences were found in allele frequencies and genotype distributions of the studied genes between two groups. In addition, the incidence of the specific haplotypes between the two groups did not show any difference. The present data suggest that pharmacokinetic or pharmacodynamic factors other than the investigated genetic variants of the MAOB and COMT enzymes seem to determine the response to levodopa in the Iranian PD patients.
TL;DR: An initial summary and framework to understand the potential impact of psychotropic drugs on PD-relevant genes is provided and lithium and bupropion may augment risk, through MAPT, GBA, CCDC62, HIP1R, BDNF, and DRD2 transcription.
Abstract: Objectives Psychotropic drugs are widely prescribed in Parkinson's disease (PD) without regard to their pathobiological effects, and these drugs affect the transcription of a large number of genes. Effects of these drugs on PD risk gene transcription were therefore surveyed. Methods Results summarize a comprehensive survey of psychotropic effects on messenger ribonucleic acid (mRNA) expression evident in published data for 70 genes linked to PD risk. Results Psychotropic drugs can meaningfully affect PD risk gene mRNA transcription, including antipsychotics (upregulate dopamine receptors D2 and D3 (DRD2, DRD3); downregulate low-density lipoprotein receptor-related protein 8 (LRP8), ubiquitin carboxyl-terminal esterase L1 (UCHL1, also known as PARK5)), haloperidol (upregulates DRD3, parkin (PRKN, also known as PARK2), DRD2; downregulates brain-derived neurotrophic factor (BDNF)), risperidone (upregulates monoamine oxidase B (MAOB), DRD2), olanzapine (upregulates transmembrane protein 163 (TMEM163), BDNF, glutathione S-transferase mu 1 (GSTM1), MAOB, DRD2, solute carrier organic anion transporter family, member 3A1 (SLCO3A1)), aripiprazole (upregulates DRD2), quetiapine, paliperidone, lurasidone, carbamazepine, and many antidepressants (upregulate BDNF), lithium and bupropion (downregulate BDNF), amitriptyline (upregulates DRD3, DRD2), imipramine (upregulates BDNF, DRD3, DRD2), desipramine (upregulates BDNF, DRD3), and fluoxetine (upregulates acid beta-glucosidase (GBA), coiled-coil domain containing 62 (CCDC62), BDNF, DRD3, UCHL1, unc-13 homolog B (UNC13B), and perhaps huntingtin interacting protein 1 related (HIP1R); downregulates microtubule-associated protein tau (MAPT), methylcrotonoyl-coenzyme A carboxylase I (MCCC1), GSTM1, 28 kDa calbindin 1 (CALB1)). Fluoxetine effects on BDNF and UCHL1 in GEO Profiles were statistically robust. Conclusions This report provides an initial summary and framework to understand the potential impact of psychotropic drugs on PD-relevant genes. Antipsychotics and serotoninergic antidepressants may potentially attenuate PD risk, and lithium and bupropion may augment risk, through MAPT, GBA, CCDC62, HIP1R, BDNF, and DRD2 transcription, with MAPT, GBA, and CCDC62 being strongly associated with PD risk in recent meta-analyses. Limitations of these findings and a research agenda to better relate them to the nigrostriatum and PD are discussed.
TL;DR: In this article, the effect of stress on the levels of transcripts related to brain monoamine metabolism was quantified using quantitative real-time PCR to quantify the mRNA levels of serotonin reuptake transporter (SERT), norepinephrine transporter (NET), monoamine oxidase-B (MAOB), tryptophan hydroxylase (TPH), and tyrosine hydroxylease (TH) in various brain regions of ovariectomized (OVX) rats which had been exposed for 4 weeks to chronic aversive stimuli (CAS), such
Abstract: Estrogen deficiency increases the risk of anxiety and mood disorders, presumably by deranging metabolism of the monoamine neurotransmitters and the expression of their reuptake transporters in the brain. Although estrogen-deficient individuals were also susceptible to stress, little was known regarding the effect of stress on the levels of transcripts related to brain monoamine metabolism. Herein, we used quantitative real-time PCR to quantify the mRNA levels of serotonin reuptake transporter (SERT), norepinephrine transporter (NET), monoamine oxidase-B (MAOB), tryptophan hydroxylase (TPH), and tyrosine hydroxylase (TH) in various brain regions of ovariectomized (OVX) rats which had been exposed for 4 weeks to chronic aversive stimuli (CAS), such as water deprivation, cage tilt, and illumination. We found that CAS induced stress responses in OVX rats as indicated by increases in the adrenal gland weight and sucrose intake. After CAS exposure, mRNA levels of SERT and NET were upregulated in the frontal cortex, hippocampus, amygdala, and periaqueductal gray. In addition, CAS also increased the mRNA levels of MAOB, an enzyme for dopamine degradation, in the same brain regions. However, CAS did not alter the mRNA levels of TPH or TH, both of which are rate-limiting enzymes for the synthesis of serotonin and norepinephrine in the dorsal raphe and locus coeruleus, respectively. Interestingly, mRNA expression of brain-derived neurotrophic factor precursor was upregulated in the hippocampus of CAS-exposed OVX rats, suggesting a compensatory mechanism which might counteract the stress-induced depression. Therefore, the present data have provided evidence to explain how stress affected brain monoamine metabolism in estrogen-deficient stressed patients.
TL;DR: The design and synthesis of two series of 8-(substituted styrol-formamido)phenyl-xanthine derivatives are described and results suggest that such compounds may be utilized for the development of new candidate MAO-B inhibitors for treatment of Parkinson's disease.
Abstract: The design and synthesis of two series of 8-(substituted styrol-formamido)phenyl-xanthine derivatives are described. Their in vitro monoamine oxidase B (MAO-B) inhibition were tested and the effect of substituents on the N-7, phenyl and the substituted positions are discussed. It was observed that compound 9b displayed significant MAO-B inhibition activity and selectivity, fluorine substitution plays a key role in the selectivity of MAO-B inhibition, and the styrol-formamido group at position-3' may enhance the activity and selectivity of 8-phenyl-xanthine analogues. These results suggest that such compounds may be utilized for the development of new candidate MAO-B inhibitors for treatment of Parkinson's disease.
TL;DR: This work identified a new family of potential MAO-B inhibitors and mapped important residues for intermolecular interactions between this enzyme and ligands and used the program ‘molegro virtual docker’ in all simulations described here.
Abstract: Monoamine oxidase (MAO) is an enzyme of major importance in neurochemistry, because it catalyzes the inactivation pathway for the catecholamine neurotransmitters, noradrenaline, adrenaline and dopamine. In the last decade it was demonstrated that imidazoline derivatives were able to inhibit MAO activity. Furthermore, crystallographic studies identified the imidazoline-binding domain on monoamine oxidase B (MAO-B), which opens the possibility of molecular docking studies focused on this binding site. The goal of the present study is to identify new potential inhibitors for MAO-B. In addition, we are also interested in establishing a fast and reliable computation methodology to pave the way for future molecular docking simulations focused on the imidazoline-binding site of this enzyme. We used the program 'molegro virtual docker' (MVD) in all simulations described here. All results indicate that simplex evolution algorithm is able to succesfully simulate the protein-ligand interactions for MAO-B. In addition, a scoring function implemented in the program MVD presents high correlation coefficient with experimental activity of MAO-B inhibitors. Taken together, our results identified a new family of potential MAO-B inhibitors and mapped important residues for intermolecular interactions between this enzyme and ligands.
TL;DR: This re-examination of ADHD scores in a nonclinical sample suggests that effects of MAOA-VNTR and 5HTT-LPR are moderated by platelet MAOB activity.
Abstract: The monoamine systems have been suggested to play a role in the biological basis of attention-deficit hyperactivity disorder (ADHD) symptoms Thus, polymorphisms, for example, in the monoamine oxidase A (MAOA) and the serotonin transporter (5HTT) genes have been associated with ADHD-like phenotypes Furthermore, platelet monoamine oxidase B (MAOB) activity has frequently been linked to impulsiveness-related traits In this study, we have studied ADHD symptoms with regard to the combination of platelet MAOB activity and MAOA-variable number of tandem repeats (VNTR) or 5HTT-LPR genotype The study group consisted of 156 adolescent twin pairs, that is, 312 individuals, who participated in a previous study ADHD symptoms were scored with a structured clinical interview of both the twins and a parent using Kiddie Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime Version The presence of a short 5HTT-LPR or short MAOA-VNTR allele, in combination with high levels of platelet MAOB enzyme activity was associated with higher scores of ADHD-like problems (P<0001 and 001, respectively) This re-examination of ADHD scores in a nonclinical sample suggests that effects of MAOA-VNTR and 5HTT-LPR are moderated by platelet MAOB activity
Journal Article•
TL;DR: In this article, the effect of genetic variants of the MAOB and COMT enzymes on the response to levodopa therapy in Iranian patients with Parkinson's disease was investigated. But, no statistically significant differences were found in allele frequencies and genotype distributions of the studied genes between two groups.
Abstract: Parkinson’s disease (PD) patients vary widely in their response to levodopa treatment, and this may be partially genetic in origin. Recent studies suggest that catechol-O-methyltransferase (COMT), G1947A and monoamine oxidase B (MAOB), A644G polymorphisms might influence the risk and treatment of PD. Herein, we aimed to test the possible influence of MAOB and COMT genetic polymorphisms on the effective daily dose of levodopa administered in the fifth year of treatment. We also examined the effect of COMT and MAOB haplotypes on levodopa therapy outcome. There were 31 females and 72 males of Iranian origin diagnosed with sporadic PD included into the study. The patients were divided into two groups. Group 1: patients received daily doses of levodopa below 500 mg in the fifth year of treatment. Group 2: those patients receiving daily doses exceeding 500 mg in the fifth year of treatment. MAOB and COMT polymorphism genotyping was performed by using PCR-based restriction fragment length polymorphism (RFLP) analyses. Our data show that the first group suffered less frequently from dyskinesia than patients from the second group. No statistically significant differences were found in allele frequencies and genotype distributions of the studied genes between two groups. In addition, the incidence of the specific haplotypes between the two groups did not show any difference. The present data suggest that pharmacokinetic or pharmacodynamic factors other than the investigated genetic variants of the MAOB and COMT enzymes seem to determine the response to levodopa in the Iranian PD patients.
TL;DR: In mice, overall developmental expression pattern of MAOB, SLC25A14 and TUBB3 in the PFC were comparable to the pattern observed in humans (p<0.05), and mice selectively bred for high fear did not exhibit normal developmental changes ofMAOB and Tubb3.
Abstract: A growing body of evidence suggests that mitochondrial function may be important in brain development and psychiatric disorders. However, detailed expression profiles of those genes in human brain development and fear-related behavior remain unclear. Using microarray data available from the public domain and the Gene Ontology analysis, we identified the genes and the functional categories associated with chronological age in the prefrontal cortex (PFC) and the caudate nucleus (CN) of psychiatrically normal humans ranging in age from birth to 50 years. Among those, we found that a substantial number of genes in the PFC (115) and the CN (117) are associated with the GO term: mitochondrion (FDR qv <0.05). A greater number of the genes in the PFC (91%) than the genes in the CN (62%) showed a linear increase in expression during postnatal development. Using quantitative PCR, we validated the developmental expression pattern of four genes including monoamine oxidase B (MAOB), NADH dehydrogenase flavoprotein (NDUFV1), mitochondrial uncoupling protein 5 (SLC25A14) and tubulin beta-3 chain (TUBB3). In mice, overall developmental expression pattern of MAOB, SLC25A14 and TUBB3 in the PFC were comparable to the pattern observed in humans (p<0.05). However, mice selectively bred for high fear did not exhibit normal developmental changes of MAOB and TUBB3. These findings suggest that the genes associated with mitochondrial function in the PFC play a significant role in brain development and fear-related behavior.
TL;DR: In this paper, a case-control study of the association between Parkinson's disease susceptibility and a genetic polymorphism of MAOB and COMT, both separately and in combination, in Iranians was performed.
Abstract: Genetic polymorphisms have been shown to be involved in dopaminergic neurotransmission. This may influence susceptibility to Parkinson's disease (PD). We performed a case-control study of the association between PD susceptibility and a genetic polymorphism of MAOB and COMT, both separately and in combination, in Iranians. The study enrolled 103 Iranian patients with PD and 70 healthy individuals. Polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) methods were used for genotyping. Our data indicated that the MAOB genotype frequencies in PD patients did not differ significantly from the control group. However, the frequency of MAOB GG genotype was significantly lower in female patients. It has been shown that the distribution of MAOB allele A was slightly higher in PD patients. No statistically significant differences were found in the COMT allele and genotype distribution in PD patients in comparison to the controls. The combined haplotype of the MAOB A, A/A and COMT LL genotype showed a slight increase in the risk of PD in female patients in this Iranian population. The data may suggest that the MAOB and COMT genetic polymorphisms do not play any role in the pathogenesis of PD in Iranians. In addition, the combined haplotype of MAOB and COMT genes did not significantly affect the susceptibility to PD. Future studies involving larger control and case populations will undoubtedly lead to a more thorough understanding of the role of the polymorphisms involved in the dopamine pathway in PD.
Journal Article•
TL;DR: It is indicated that the MAOB genotype frequencies in PD patients did not differ significantly from the control group, however, the frequency of MAOB GG genotype was significantly lower in female patients, and the combined haplotype ofMAOB and COMT genes did not significantly affect the susceptibility to PD.
Abstract: A b s t r a c t Genetic polymorphisms have been shown to be involved in dopaminergic neurotransmission. This may influence sus ceptibility to Parkinson’s disease (PD). We performed a case-control study of the association between PD susceptibil ity and a genetic polymorphism of MAOB and COMT, both separately and in combination, in Iranians. The study enrolled 103 Iranian patients with PD and 70 healthy individuals. Polymerase chain reaction restriction fragment length poly morphism (PCR-RFLP) methods were used for genotyping. Our data indicated that the MAOB genotype frequencies in PD patients did not differ significantly from the control group. However, the frequency of MAOB GG genotype was significantly lower in female patients. It has been shown that the distribution of MAOB allele A was slightly higher in PD patients. No statistically significant differences were found in the COMT allele and genotype distribution in PD patients in comparison to the controls. The combined haplotype of the MAOB A, A/A and COMT LL genotype showed a slight increase in the risk of PD in female patients in this Iranian population. The data may suggest that the MAOB and COMT genetic polymorphisms do not play any role in the pathogenesis of PD in Iranians. In addition, the combined haplo type of MAOB and COMT genes did not significantly affect the susceptibility to PD. Future studies involving larger con trol and case populations will undoubtedly lead to a more thorough understanding of the role of the polymorphisms involved in the dopamine pathway in PD.
TL;DR: A linear correlation was demonstrated between the affinity for MAO A, but not MAO B, and the levels of 3,4-dihydroxyphenylacetic acid (DOPAC) and 3-methoxytyramine (3-MT) in the striatum.
Abstract: A series of para-substituted 4-phenylpiperidines/piperazines have been synthesized and their affinity to recombinant rat cerebral cortex monoamine oxidases A (MAO A) and B (MAO B) determined. Para-substituents with low dipole moment increased the affinity to MAO A, whereas groups with high dipole moment yielded compounds with no or weak affinity. In contrast, the properties affecting MAO B affinity were the polarity and bulk of the para-substituent, with large hydrophobic substituents producing compounds with high MAO B affinity. In addition, these compounds were tested in freely moving rats and the effect on the post-mortem neurochemistry was measured. A linear correlation was demonstrated between the affinity for MAO A, but not MAO B, and the levels of 3,4-dihydroxyphenylacetic acid (DOPAC) and 3-methoxytyramine (3-MT) in the striatum.
TL;DR: It is important to determine whether these actions contribute to the possible disease modifying effect of MAO-B inhibitors in PD in man, as both selegiline and rasagiline also are associated with neuroprotective and/or disease modifying activities.
Abstract: The cause of cell death in Parkinson’s disease (PD) remains unclear but it is multifactorial with a complex interaction between a range of pathogenic mechanisms. However, alterations in mitochondrial function have been clearly linked to nigral dopaminergic loss in sporadic PD and to the effects of gene mutations in familial forms of the illness. These may underlie the onset of oxidative and nitrative stress, a failure of protein degradation and apoptotic degeneration of dopaminergic cells in PD. Perhaps importantly, monoamine oxidase B (MAO-B) is located in the mitochondrial wall and plays a significant role in dopamine degradation in PD. This can explain the symptomatic actions of MAO-B inhibitors, such as selegiline and rasagiline on motor symptoms of PD. However, both selegiline and rasagiline also are associated with neuroprotective and/or disease modifying activities. The second generation MAO-B inhibitor, rasagiline can prevent multiple pathways that lead to apoptotic cell death and it is effective in in vitro and in vivo models of neuronal degeneration. However, there may be contributions from its major metabolite, aminoindan and non-MAO-B mediated actions on mitochondria may also contribute to these effects. It is important to determine whether these actions contribute to the possible disease modifying effect of MAO-B inhibitors in PD in man.
TL;DR: It is shown that it is possible to predict in vivo metabolic clearance from in vitro metabolic data for drugs metabolized by the enzyme monoamine oxidase, and an in vitro-in vivo correlation (IVIVC) could be described for compounds cleared by MAO-A.
Abstract: Oxidative deamination of the GABAA partial agonist CP-409,092 and sumatriptan represents a major metabolic pathway and seems to play an important role for the clearance of these two compounds.Similar to sumatriptan, human mitochondrial incubations with deprenyl and clorgyline, probe inhibitors of monoamine oxidase B and monoamine oxidase A (MAO-B and MAO-A), respectively, showed that CP-409,092 was metabolized to a large extent by the enzyme MAO-A.The metabolism of CP-409,092 and sumatriptan was therefore studied in human liver mitochondria and in vitro intrinsic clearance (CLint) values were determined and compared to the corresponding in vivo oral clearance (CLPO) values. The overall objective was to determine whether an in vitro-in vivo correlation (IVIVC) could be described for compounds cleared by MAO-A.The intrinsic clearance, CLint, of CP-409,092 was approximately 4-fold greater than that of sumatriptan (CLint, values were calculated as 0.008 and 0.002 ml/mg/min for CP-409,092 and sumatriptan, resp...
TL;DR: Even though a diet low in tyramine, phenylethylamine, and dopa/dopamine is necessary for long-term management, it will not rescue the abnormal monoamine profile seen in combined MAOA and MAOB deficiency.
TL;DR: The results revealed that MAO-B was activated by BA, DEBA, TBA, T U, and ATU, and the activation was structural, concentration, and time dependent, but was inhibited by VA in a noncompetitive and irreversible manner.
Abstract: The effects of some pyrimidine compounds (PCs) including barbituric acid (BA) 5,5-diethyl barbituric acid (DEBA), 2-thiobarbituric acid (TBA), violuric acid (VA), 2-thiouracil (TU), and 6-amino-2-thiouracil (ATU) on the activity of rat brain monoamine oxidase-B (MAO-B) were investigated. The results revealed that MAO-B was activated by BA, DEBA, TBA, TU, and ATU, and the activation was structural, concentration, and time dependent. However, MAO-B was inhibited by VA in a noncompetitive and irreversible manner with an enzyme–inhibitor dissociation constant (K
i value) of 32 nM and IC50 equals to 19 nM. All the studied PCs changed both the optimum pH and temperature of MAO-B.
TL;DR: The results document that the evaluated compounds are potent and selective MAO-B inhibitors with most homologues possessing IC(50) values in the nanomolar range and 4-[(4-bromobenzyl)sulfanyl]phthalonitrile is a particularly promising inhibitor, which may serve as a lead for the development of therapies for neurodegenerative disorders such as Parkinson's disease.