DOCSLIB.ORG

Monoamine Oxidase Inhibitors: Promising Therapeutic Agents for Alzheimer's Disease (Review)

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Monoamine Oxidase Inhibitors: Promising Therapeutic Agents for Alzheimer's Disease (Review) MOLECULAR MEDICINE REPORTS 9: 1533-1541, 2014 Monoamine oxidase inhibitors: Promising therapeutic agents for Alzheimer's disease (Review) ZHIYOU CAI Department of Neurology, The Lu'an Affiliated Hospital of Anhui Medical University, Lu'an People's Hospital, Lu'an, Anhui 237005, P.R. China Received July 2, 2013; Accepted February 10, 2014 DOI: 10.3892/mmr.2014.2040 Abstract. Activated monoamine oxidase (MAO) has a critical 6. MAO activation contributes to cognitive impairment in role in the pathogenesis of Alzheimer's disease (AD), including patients with AD the formation of amyloid plaques from amyloid β peptide (Aβ) 7. Activated MAO contributes to the formation of amyloid production and accumulation, formation of neurofibrillary plaques tangles, and cognitive impairment via the destruction of cholin- 8. Is activated MAO associated with the formation of ergic neurons and disorder of the cholinergic system. Several neurofibrillary tangles? studies have indicated that MAO inhibitors improve cognitive 9. Evidence for the neuroprotective effect of MAO inhibitors deficits and reverse Aβ pathology by modulating proteolytic in AD cleavage of amyloid precursor protein and decreasing Aβ 10. Conclusions and outlook protein fragments. Thus, MAO inhibitors may be considered as promising therapeutic agents for AD. 1. Introduction Monoamine oxidase (MAO) catalyzes the oxidative deamina- Contents tion of biogenic and xenobiotic amines and has an important role in the metabolism of neuroactive and vasoactive amines in 1. Introduction the central nervous system (CNS) and peripheral tissues. The 2. Monoamine oxidase (MAO) enzyme preferentially degrades benzylamine and phenylethyl- 3. Involvement of MAO in neurodegeneration amine and targets a wide variety of specific neurotransmitters 4. Increased MAO activity in the platelets of patients with involved in the primary substrates of MAO in the brain, Alzheimer's disease (AD)? including epinephrine (EP), norepinephrine (NE), dopamine 5. Alterations in MAO levels in the brains of patients with (DA), serotonin (5-HT), and β-phenylethylamine (PEA) (1,2). AD The unique position of MAO in modulating the function of a diverse series of specific neurotransmitters in association with various conditions, including mood disorders (3), anxiety and depression (4,5), schizophrenia (6), attention deficit hyper- activity disorder (7-9), migraine (10), sexual maturation (11) Correspondence to: Dr Zhiyou Cai, Department of Neurology, and neurodegenerative diseases (12), has attracted significant The Lu'an Affiliated Hospital of Anhui Medical University, Lu'an attention to the protein as a therapeutic target. People's Hospital, 21 Wanxi West Road, Lu'an, Anhui 237005, Compelling studies have shown that the involvement of P. R. Ch i na MAO in AD and neurodegenerative diseases plays an impor- E-mail: [email protected] tant role in several key pathophysiological mechanisms (13,14). MAO-B has been proposed as a biomarker, whereas activated Abbreviations: Aβ, amyloid β peptide; AD, Alzheimer's disease; MAO-B leads to cognitive dysfunction, destroys cholinergic APP, amyloid precursor protein; BACE, β-site APP cleavage neurons, causes disorder of the cholinergic system and contrib- enzyme; ChE, cholinesterase; CNS, central nervous system; utes to the formation of amyloid plaques. CSF, cerebrospinal fluid; DA, dopamine; EP, epinephrine; 5‑HT, The present review focused on evidence supporting the serotonin; MAO, monoamine oxidase; MAPK, mitogen-activated protein kinase; MMSE, Mini Mental State Examination; NE, central role that MAO has in AD pathogenesis, including the norepinephrine; NFT, neurofibrillary tangle; PD, Parkinson's formation of amyloid plaques from amyloid β peptide (Aβ) disease; PEA, β-phenylethylamine; PKC, protein kinase C production and neurofibrillary tangles (NFTs), and cognitive impairment via the destruction of cholinergic neurons and Key words: Alzheimer's disease, monoamine oxidase, disorder of the cholinergic system. Studies reporting that MAO neurodegeneration, β-amyloid, tau inhibitors improve cognitive deficits and reverse Aβ pathology by modulating proteolytic cleavage of amyloid precursor protein (APP) and decreasing Aβ protein fragments are also 1534 CAI: MONOAMINE OXIDASE INHIBITORS AS THERAPEUTIC AGENTS FOR ALZHEIMER'S DISEASE discussed. Finally, on the basis of current advances in the use of MAO inhibitors for the treatment of AD, MAO inhibitors are discussed as a promising therapeutic target for AD. 2. MAO Monoamine oxidase (EC1.4.3.4, a flavin‑containing enzyme) is widely distributed in animal tissue and catalyzes the oxidative deamination of primary amines by reaction between dioxygen and R-CH2-NH2 to form R-CHO, NH3 and H2O2 (Fig. 1). MAO Figure 1. General reaction catalyzed by MAO. The reaction of a base (R, removes an amine group by catalyzing the oxidative deamina- arbitrary group) with one ammonia and two hydrogen components plus water tion of monoamines, resulting in the corresponding aldehyde and oxygen, catalyzed by MAO, generates the aldehyde, ammonia and H2O2. and ammonia. MAO exists as two isozymes in humans: MAO, monoamine oxidase. MAO-A and MAO-B, which are distinct due to different amino acid sequences, three-dimensional structures, distribu- tions in organs and tissue, inhibitor sensitivities and substrate oxidation of monoamine substrates (18,33,34). These results specificity. The two isozymes are found in and outside the suggest that MAO is involved in the neurodegenerative patho- CNS. genesis of PD that manifests as increased oxidative stress and With regard to the functions of MAO, a wide range of a major impairment of the glutathione pathway. pathophysiological roles have been suggested, including the Studies have shown that activated MAO in the brains regulation of cardiac function and blood pressure (15), as well of patients with AD is a biomarker for AD (35-37). This as involvement in a number of psychiatric and neurological was demonstrated by [11C]-L-deprenyl using whole hemi- disorders, including mood, depression, schizophrenia, migraine, sphere autoradiography (38-40), epidemiology (41,42), sexual maturation and neurodegenerative diseases. The notable morphology (43), as well as single-photon emission computed role of MAO is in the regulation of neurotransmitter activity, tomography (44). Such studies demonstrated that: i) MAO since the primary substrates of MAO in the brain are specific activity in platelets was significantly increased in patients neurotransmitters, including EP, NE, DA, 5-HT and PEA. with AD and acted as a marker of behavioral characteristics in dementia disorders (41,45-48); ii) there were early and persis- 3. Involvement of MAO in neurodegeneration tent alterations in MAO-A and -B in the brains of patients with AD (49); iii) activated MAO led to cognitive dysfunction (50); An increasing number of studies have demonstrated the iv) activated MAO destroyed cholinergic neurons and caused involvement of MAO in neurodegenerative diseases, including disorders of the cholinergic system (51); v) activated MAO Parkinson's disease (PD) (16,17), AD (18,19), Lewy body contributed to the formation of amyloid plaques (13,14) and diseases with dementia (20) and depression (17,21). MAO is vi) activated MAO was associated with the formation of NFTs. involved in neurodegeneration via oxidative stress, which has a Pharmacological studies have demonstrated that central role in neurodegenerative diseases (22). Other mecha- MAO inhibitors exert neuroprotective effects in patients nisms have been identified, including neuroinflammation (23), with AD (21,52,53) through the following mechanisms: triggering of apoptosis (18,24), failure of aggregated-protein Improvement of cognitive impairment (50,54,55); antioxidant clearance (25-27) and glial activation (28) by MAO. and enhancement of iron chelating activities (56-59); regula- PD is the second most common age-related neurodegenera- tion of APP and Aβ expression processing (56,60), involving tive disease after AD, and is characterized by progressive loss the activation of certain signaling pathways, including the of dopaminergic neurons in the substantia nigra, depletion of p42/44 mitogen-activated protein kinase (MAPK) and protein DA in the striatum, abnormal mitochondrial and proteasomal kinase C (PKC) signaling pathways (61); and inhibition of functions and accumulation of α-synuclein (29,30). It has been cholinesterase (ChE) activity (62-64). suggested that the increased turnover of DA and dopami- nergic neurodegeneration are associated with oxidative stress 4. Increased MAO activity in the platelets of patients with derived from an increased production of hydrogen peroxide, AD? which is formed during the oxidative deamination of DA by MAO (29,31). A recent study showed that activated MAO MAO activity has previously been found to be high in the induces α-synuclein aggregation, which may be associated with brain and in platelets in patients with AD, while the activity early Parkinsonism and dopaminergic neurodegeneration in of MAO-B in the brain increases with age due to an increased the substantia nigra in SMAD family member 3-null mice (32). concentration of MAO-B (35). Compared with age- and The evidence that either inhibition or iron chelation of MAO gender-matched controls, MAO activity in platelets was signif- exerts neuroprotective effects strongly indicates that MAO is icantly higher in patients with dementia of the Alzheimer type, a major component in the process of PD neurodegeneration and the
Load more

Recommended publications
  • Novel Neuroprotective Compunds for Use in Parkinson's Disease
    Novel neuroprotective compounds for use in Parkinson’s disease A thesis submitted to Kent State University in partial Fulfillment of the requirements for the Degree of Master of Science By Ahmed Shubbar December, 2013 Thesis written by Ahmed Shubbar B.S., University of Kufa, 2009 M.S., Kent State University, 2013 Approved by ______________________Werner Geldenhuys ____, Chair, Master’s Thesis Committee __________________________,Altaf Darvesh Member, Master’s Thesis Committee __________________________,Richard Carroll Member, Master’s Thesis Committee ___Eric_______________________ Mintz , Director, School of Biomedical Sciences ___Janis_______________________ Crowther , Dean, College of Arts and Sciences ii Table of Contents List of figures…………………………………………………………………………………..v List of tables……………………………………………………………………………………vi Acknowledgments.…………………………………………………………………………….vii Chapter 1: Introduction ..................................................................................... 1 1.1 Parkinson’s disease .............................................................................................. 1 1.2 Monoamine Oxidases ........................................................................................... 3 1.3 Monoamine Oxidase-B structure ........................................................................... 8 1.4 Structural differences between MAO-B and MAO-A .............................................13 1.5 Mechanism of oxidative deamination catalyzed by Monoamine Oxidases ............15 1 .6 Neuroprotective effects
    [Show full text]
  • Trace Amine-Associated Receptor 1 Activation Regulates Glucose-Dependent
    Trace amine-associated receptor 1 activation regulates glucose-dependent insulin secretion in pancreatic beta cells in vitro by ©Arun Kumar A thesis submitted to the School of Graduate Studies in partial fulfillment of the requirements for the degree of Master of Science Department of Biochemistry, Faculty of Science Memorial University of Newfoundland FEBRUARY 2021 St. John’s, Newfoundland and Labrador i Abstract Trace amines are a group of endogenous monoamines which exert their action through a family of G protein-coupled receptors known as trace amine-associated receptors (TAARs). TAAR1 has been reported to regulate insulin secretion from pancreatic beta cells in vitro and in vivo. This study investigates the mechanism(s) by which TAAR1 regulates insulin secretion. The insulin secreting rat INS-1E -cell line was used for the study. Cells were pre-starved (30 minutes) and then incubated with varying concentrations of glucose (2.5 – 20 mM) or KCl (3.6 – 60 mM) for 2 hours in the absence or presence of various concentrations of the selective TAAR1 agonist RO5256390. Secreted insulin per well was quantified using ELISA and normalized to the total protein content of individual cultures. RO5256390 significantly (P < 0.0001) increased glucose- stimulated insulin secretion in a dose-dependent manner, with no effect on KCl-stimulated insulin secretion. Affymetrix-microarray data analysis identified genes (Gnas, Gng7, Gngt1, Gria2, Cacna1e, Kcnj8, and Kcnj11) whose expression was associated with changes in TAAR1 in response to changes in insulin secretion in pancreatic beta cell function. The identified potential links to TAAR1 supports the regulation of glucose-stimulated insulin secretion through KATP ion channels.
    [Show full text]
  • S41598-021-90243-1.Pdf
    www.nature.com/scientificreports OPEN Metabolomics and computational analysis of the role of monoamine oxidase activity in delirium and SARS‑COV‑2 infection Miroslava Cuperlovic‑Culf1,2*, Emma L. Cunningham3, Hossen Teimoorinia4, Anuradha Surendra1, Xiaobei Pan5, Stefany A. L. Bennett2,6, Mijin Jung5, Bernadette McGuiness3, Anthony Peter Passmore3, David Beverland7 & Brian D. Green5* Delirium is an acute change in attention and cognition occurring in ~ 65% of severe SARS‑CoV‑2 cases. It is also common following surgery and an indicator of brain vulnerability and risk for the development of dementia. In this work we analyzed the underlying role of metabolism in delirium‑ susceptibility in the postoperative setting using metabolomic profling of cerebrospinal fuid and blood taken from the same patients prior to planned orthopaedic surgery. Distance correlation analysis and Random Forest (RF) feature selection were used to determine changes in metabolic networks. We found signifcant concentration diferences in several amino acids, acylcarnitines and polyamines linking delirium‑prone patients to known factors in Alzheimer’s disease such as monoamine oxidase B (MAOB) protein. Subsequent computational structural comparison between MAOB and angiotensin converting enzyme 2 as well as protein–protein docking analysis showed that there potentially is strong binding of SARS‑CoV‑2 spike protein to MAOB. The possibility that SARS‑CoV‑2 infuences MAOB activity leading to the observed neurological and platelet‑based complications of SARS‑CoV‑2 infection requires further investigation. COVID-19 is an ongoing major global health emergency caused by severe acute respiratory syndrome coro- navirus SARS-CoV-2. Patients admitted to hospital with COVID-19 show a range of features including fever, anosmia, acute respiratory failure, kidney failure and gastrointestinal issues and the death rate of infected patients is estimated at 2.2%1.
    [Show full text]
  • Acetylcholinesterase and Monoamine Oxidase-B Inhibitory Activities By
    www.nature.com/scientificreports OPEN Acetylcholinesterase and monoamine oxidase‑B inhibitory activities by ellagic acid derivatives isolated from Castanopsis cuspidata var. sieboldii Jong Min Oh1, Hyun‑Jae Jang2, Myung‑Gyun Kang3, Soobin Song2, Doo‑Young Kim2, Jung‑Hee Kim2, Ji‑In Noh1, Jong Eun Park1, Daeui Park3, Sung‑Tae Yee1 & Hoon Kim1* Among 276 herbal extracts, a methanol extract of Castanopsis cuspidata var. sieboldii stems was selected as an experimental source for novel acetylcholinesterase (AChE) inhibitors. Five compounds were isolated from the extract by activity‑guided screening, and their inhibitory activities against butyrylcholinesterase (BChE), monoamine oxidases (MAOs), and β‑site amyloid precursor protein cleaving enzyme 1 (BACE‑1) were also evaluated. Of these compounds, 4′‑O‑(α‑l‑rhamnopyranosyl)‑ 3,3′,4‑tri‑O‑methylellagic acid (3) and 3,3′,4‑tri‑O‑methylellagic acid (4) efectively inhibited AChE with IC50 values of 10.1 and 10.7 µM, respectively. Ellagic acid (5) inhibited AChE (IC50 = 41.7 µM) less than 3 and 4. In addition, 3 efectively inhibited MAO‑B (IC50 = 7.27 µM) followed by 5 (IC50 = 9.21 µM). All fve compounds weakly inhibited BChE and BACE‑1. Compounds 3, 4, and 5 reversibly and competitively inhibited AChE, and were slightly or non‑toxic to MDCK cells. The binding energies of 3 and 4 (− 8.5 and − 9.2 kcal/mol, respectively) for AChE were greater than that of 5 (− 8.3 kcal/mol), and 3 and 4 formed a hydrogen bond with Tyr124 in AChE. These results suggest 3 is a dual‑targeting inhibitor of AChE and MAO‑B, and that these compounds should be viewed as potential therapeutics for the treatment of Alzheimer’s disease.
    [Show full text]
  • Effects of an Anti-Inflammatory VAP-1/SSAO Inhibitor, PXS-4728A
    Schilter et al. Respiratory Research (2015) 16:42 DOI 10.1186/s12931-015-0200-z RESEARCH Open Access Effects of an anti-inflammatory VAP-1/SSAO inhibitor, PXS-4728A, on pulmonary neutrophil migration Heidi C Schilter1*†, Adam Collison2†, Remo C Russo3,4†, Jonathan S Foot1, Tin T Yow1, Angelica T Vieira4, Livia D Tavares4, Joerg Mattes2, Mauro M Teixeira4 and Wolfgang Jarolimek1,5 Abstract Background and purpose: The persistent influx of neutrophils into the lung and subsequent tissue damage are characteristics of COPD, cystic fibrosis and acute lung inflammation. VAP-1/SSAO is an endothelial bound adhesion molecule with amine oxidase activity that is reported to be involved in neutrophil egress from the microvasculature during inflammation. This study explored the role of VAP-1/SSAO in neutrophilic lung mediated diseases and examined the therapeutic potential of the selective inhibitor PXS-4728A. Methods: Mice treated with PXS-4728A underwent intra-vital microscopy visualization of the cremaster muscle upon CXCL1/KC stimulation. LPS inflammation, Klebsiella pneumoniae infection, cecal ligation and puncture as well as rhinovirus exacerbated asthma models were also assessed using PXS-4728A. Results: Selective VAP-1/SSAO inhibition by PXS-4728A diminished leukocyte rolling and adherence induced by CXCL1/KC. Inhibition of VAP-1/SSAO also dampened the migration of neutrophils to the lungs in response to LPS, Klebsiella pneumoniae lung infection and CLP induced sepsis; whilst still allowing for normal neutrophil defense function, resulting in increased survival. The functional effects of this inhibition were demonstrated in the RV exacerbated asthma model, with a reduction in cellular infiltrate correlating with a reduction in airways hyperractivity.
    [Show full text]
  • Association of Monoamine Oxidase B and Catechol-O-Methyltransferase Polymorphisms with Sporadic Parkinson's Disease in an Iranian Population
    Original article Association of monoamine oxidase B and catechol-O-methyltransferase polymorphisms with sporadic Parkinson’s disease in an Iranian population Anahita Torkaman-Boutorabi1, Gholam Ali Shahidi2, Samira Choopani3, Mohammad Reza Zarrindast1 1Department of Neuroscience, School of Advanced Technologies in Medicine , Tehran University of Medical Sciences, Tehran, Iran, 2Department of Neurology, Hazrat Rasool Hospital, Tehran University of Medical Sciences, Tehran, Iran, 3Department of Physiology and Pharmacology, Pasteur Institute of Iran, Tehran, Iran Folia Neuropathol 2012; 50 (4): 382-389 DOI: 10.5114/fn.2012.32368 Abstract 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.
    [Show full text]
  • The Role of Serotonin in Memory: Interactions with Neurotransmitters and Downstream Signaling
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Bushehr University of Medical Sciences Repository Exp Brain Res (2014) 232:723–738 DOI 10.1007/s00221-013-3818-4 REVIEW The role of serotonin in memory: interactions with neurotransmitters and downstream signaling Mohammad Seyedabadi · Gohar Fakhfouri · Vahid Ramezani · Shahram Ejtemaei Mehr · Reza Rahimian Received: 28 April 2013 / Accepted: 20 December 2013 / Published online: 16 January 2014 © Springer-Verlag Berlin Heidelberg 2014 Abstract Serotonin, or 5-hydroxytryptamine (5-HT), is there has been an alteration in the density of serotonergic found to be involved in many physiological or pathophysi- receptors in aging and Alzheimer’s disease, and serotonin ological processes including cognitive function. Seven dis- modulators are found to alter the process of amyloidogen- tinct receptors (5-HT1–7), each with several subpopulations, esis and exert cognitive-enhancing properties. Here, we dis- have been identified for serotonin, which are different in cuss the serotonin-induced modulation of various systems terms of localization and downstream signaling. Because involved in mnesic function including cholinergic, dopa- of the development of selective agonists and antagonists minergic, GABAergic, glutamatergic transmissions as well for these receptors as well as transgenic animal models as amyloidogenesis and intracellular pathways. of cognitive disorders, our understanding of the role of serotonergic transmission in learning and memory has Keywords Serotonin · Memory · Signaling pathways improved in recent years. A large body of evidence indi- cates the interplay between serotonergic transmission and Abbreviations other neurotransmitters including acetylcholine, dopamine, 2PSDT Two-platform spatial discrimination task γ-aminobutyric acid (GABA) and glutamate, in the neu- 3xTg-AD Triple-transgenic mouse model of Alzheimer’s robiological control of learning and memory.
    [Show full text]
  • Characterization of Dopaminergic System in the Striatum of Young Adult Park2-/- Knockout Rats
    www.nature.com/scientificreports OPEN Characterization of Dopaminergic System in the Striatum of Young Adult Park2−/− Knockout Rats Received: 27 June 2016 Jickssa M. Gemechu1,2, Akhil Sharma1, Dongyue Yu1,3, Yuran Xie1,4, Olivia M. Merkel 1,5 & Accepted: 20 November 2017 Anna Moszczynska 1 Published: xx xx xxxx Mutations in parkin gene (Park2) are linked to early-onset autosomal recessive Parkinson’s disease (PD) and young-onset sporadic PD. Park2 knockout (PKO) rodents; however, do not display neurodegeneration of the nigrostriatal pathway, suggesting age-dependent compensatory changes. Our goal was to examine dopaminergic (DAergic) system in the striatum of 2 month-old PKO rats in order to characterize compensatory mechanisms that may have occurred within the system. The striata form wild type (WT) and PKO Long Evans male rats were assessed for the levels of DAergic markers, for monoamine oxidase (MAO) A and B activities and levels, and for the levels of their respective preferred substrates, serotonin (5-HT) and ß-phenylethylamine (ß-PEA). The PKO rats displayed lower activities of MAOs and higher levels of ß-PEA in the striatum than their WT counterparts. Decreased levels of ß-PEA receptor, trace amine-associated receptor 1 (TAAR-1), and postsynaptic DA D2 (D2L) receptor accompanied these alterations. Drug-naive PKO rats displayed normal locomotor activity; however, they displayed decreased locomotor response to a low dose of psychostimulant methamphetamine, suggesting altered DAergic neurotransmission in the striatum when challenged with an indirect agonist. Altogether, our fndings suggest that 2 month-old PKO male rats have altered DAergic and trace aminergic signaling.
    [Show full text]
  • The Up-Regulation of Oxidative Stress As a Potential Mechanism of Novel MAO-B Inhibitors for Glioblastoma Treatment
    molecules Article The Up-Regulation of Oxidative Stress as a Potential Mechanism of Novel MAO-B Inhibitors for Glioblastoma Treatment Guya Diletta Marconi 1, Marialucia Gallorini 1 , Simone Carradori 1,* , Paolo Guglielmi 2, Amelia Cataldi 1 and Susi Zara 1 1 Department of Pharmacy, University “G. d’Annunzio” of Chieti-Pescara, Via dei Vestini 31, 66100 Chieti, Italy; [email protected] (G.D.M.); [email protected] (M.G.); [email protected] (A.C.); [email protected] (S.Z.) 2 Department of Drug Chemistry and Technologies, Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy; [email protected] * Correspondence: [email protected], Tel.: +39-0871-355-4583 Academic Editor: Simona Collina Received: 24 April 2019; Accepted: 23 May 2019; Published: 25 May 2019 Abstract: Gliomas are malignant brain tumors characterized by rapid spread and growth into neighboring tissues and graded I–IV by the World Health Organization. Glioblastoma is the fastest growing and most devastating IV glioma. The aim of this paper is to evaluate the biological effects of two potent and selective Monoamine Oxidase B (MAO-B) inhibitors, Cmp3 and Cmp5, in C6 glioma cells and in CTX/TNA2 astrocytes in terms of cell proliferation, apoptosis occurrence, inflammatory events and cell migration. These compounds decrease C6 glioma cells viability sparing normal astrocytes. Cell cycle analysis, the Mitochondrial Membrane Potential (MMP) and Reactive Oxygen Species (ROS) production were detected, revealing that Cmp3 and Cmp5 induce a G1 or G2/M cell cycle arrest, as well as a MMP depolarization and an overproduction of ROS; moreover, they inhibit the expression level of inducible nitric oxide synthase 2, thus contributing to fatal drug-induced oxidative stress.
    [Show full text]
  • Neuronal Nicotinic Receptors
    NEURONAL NICOTINIC RECEPTORS Dr Christopher G V Sharples and preparations lend themselves to physiological and pharmacological investigations, and there followed a Professor Susan Wonnacott period of intense study of the properties of nAChR- mediating transmission at these sites. nAChRs at the Department of Biology and Biochemistry, muscle endplate and in sympathetic ganglia could be University of Bath, Bath BA2 7AY, UK distinguished by their respective preferences for C10 and C6 polymethylene bistrimethylammonium Susan Wonnacott is Professor of compounds, notably decamethonium and Neuroscience and Christopher Sharples is a hexamethonium,5 providing the first hint of diversity post-doctoral research officer within the among nAChRs. Department of Biology and Biochemistry at Biochemical approaches to elucidate the structure the University of Bath. Their research and function of the nAChR protein in the 1970’s were focuses on understanding the molecular and facilitated by the abundance of nicotinic synapses cellular events underlying the effects of akin to the muscle endplate, in electric organs of the acute and chronic nicotinic receptor electric ray,Torpedo , and eel, Electrophorus . High stimulation. This is with the goal of affinity snakea -toxins, principallyaa -bungarotoxin ( - Bgt), enabled the nAChR protein to be purified, and elucidating the structure, function and subsequently resolved into 4 different subunits regulation of neuronal nicotinic receptors. designateda ,bg , and d .6 An additional subunit, e , was subsequently identified in adult muscle. In the early 1980’s, these subunits were cloned and sequenced, The nicotinic acetylcholine receptor (nAChR) arguably and the era of the molecular analysis of the nAChR has the longest history of experimental study of any commenced.
    [Show full text]
  • Amino Acid Catabolism: Urea Cycle the Urea Bi-Cycle Two Issues
    BI/CH 422/622 OUTLINE: OUTLINE: Protein Degradation (Catabolism) Digestion Amino-Acid Degradation Inside of cells Urea Cycle – dealing with the nitrogen Protein turnover Ubiquitin Feeding the Urea Cycle Activation-E1 Glucose-Alanine Cycle Conjugation-E2 Free Ammonia Ligation-E3 Proteosome Glutamine Amino-Acid Degradation Glutamate dehydrogenase Ammonia Overall energetics free Dealing with the carbon transamination-mechanism to know Seven Families Urea Cycle – dealing with the nitrogen 1. ADENQ 5 Steps 2. RPH Carbamoyl-phosphate synthetase oxidase Ornithine transcarbamylase one-carbon metabolism Arginino-succinate synthetase THF Arginino-succinase SAM Arginase 3. GSC Energetics PLP uses Urea Bi-cycle 4. MT – one carbon metabolism 5. FY – oxidases Amino Acid Catabolism: Urea Cycle The Urea Bi-Cycle Two issues: 1) What to do with the fumarate? 2) What are the sources of the free ammonia? a-ketoglutarate a-amino acid Aspartate transaminase transaminase a-keto acid Glutamate 1 Amino Acid Catabolism: Urea Cycle The Glucose-Alanine Cycle • Vigorously working muscles operate nearly anaerobically and rely on glycolysis for energy. a-Keto acids • Glycolysis yields pyruvate. – If not eliminated (converted to acetyl- CoA), lactic acid will build up. • If amino acids have become a fuel source, this lactate is converted back to pyruvate, then converted to alanine for transport into the liver. Excess Glutamate is Metabolized in the Mitochondria of Hepatocytes Amino Acid Catabolism: Urea Cycle Excess glutamine is processed in the intestines, kidneys, and liver. (deaminating) (N,Q,H,S,T,G,M,W) OAA à Asp Glutamine Synthetase This costs another ATP, bringing it closer to 5 (N,Q,H,S,T,G,M,W) 29 N 2 Amino Acid Catabolism: Urea Cycle Excess glutamine is processed in the intestines, kidneys, and liver.
    [Show full text]
  • Amino&Acid&Metabolism& (Chapter&21)&
    BIOCH 765: Biochemistry II Spring 2014 Amino&Acid&Metabolism& (Chapter&21)& Jianhan&Chen& Office&Hour:&MF&1:30A2:30PM,&Chalmers&034& Email:&[email protected]& Office:&785A2518& Overview& • IntroducPon&to&amino&acids&and&proteins&(1)& • Protein&degradaPon&(1)& • Amino&acid&deaminaPon&(1)& • The&urea&cycle&(1)& • Breakdown&of&amino&acids&(2)& • Amino&acid&synthesis&(1)& • Nitrogen&fiXaPon&(1)& • Key&reference:&Chapter&21&& &&&&&of&Voet,&Voet&&&Pra\&(and& &&&&&this&lecture&note/google)& (c)&Jianhan&Chen& 2& Overview&of&Metabolism& • Metabolism is the sum/total of all the biochemical reactions that take place in a living organism. • Catabolism is all metabolic reactions in which large biochemical molecules are broken down to smaller ones, thus generating energy. • Anabolism is all metabolic reactions in which small biochemical molecules are joined to form larger ones through consumption of energy. catabolism + energy anabolism 3 Major&Stages&of&Catabolism& 4 Insert: macromolecule anabolism Plants start with Biosynthetic pathways always differ from catabolic pathways. 5 Summary of Protein/Amino Acid Body Proteins (protein turnover) Metabolism Amino alcohols Hormones Heme Dietary Proteins Amino Acids Purines (digestion) Pyrimidines degradation Neurotransmitters Nucleotides Glucose + Pyruvate Carbon skeletons NH4 Urea Acetyl Citric Acid cholesterol ATP CoA cycle Fatty acids Ketone bodies 6 Chapter&21&A&1& 1.#PROTEIN#DEGRADATION# Key#Concepts#21.1## •&EXtracellular&and&intracellular&proteins&may&be&digested&by&lysosomal&proteases.& •&Other&proteins&to&be&degraded&are&first&conjugated&to&the&protein&ubiquiPn.&
    [Show full text]