RESUMO
The metal chelator PBT2 (5,7-dichloro-2-[(dimethylamino)methyl]-8-hydroxyquinoline) acts as a terdentate ligand capable of forming binary and ternary Cu2+ complexes. It was clinically trialed as an Alzheimer's disease (AD) therapy but failed to progress beyond phase II. The ß-amyloid (Aß) peptide associated with AD was recently concluded to form a unique Cu(Aß) complex that is inaccessible to PBT2. Herein, it is shown that the species ascribed to this binary Cu(Aß) complex in fact corresponds to ternary Cu(PBT2)NImAß complexes formed by the anchoring of Cu(PBT2) on imine nitrogen (NIm) donors of His side chains. The primary site of ternary complex formation is His6, with a conditional stepwise formation constant at pH 7.4 (Kc [M-1]) of logKc = 6.4 ± 0.1, and a second site is supplied by His13 or His14 (logKc = 4.4 ± 0.1). The stability of Cu(PBT2)NImH13/14 is comparable with that of the simplest Cu(PBT2)NIm complexes involving the NIm coordination of free imidazole (logKc = 4.22 ± 0.09) and histamine (logKc = 4.00 ± 0.05). The 100-fold larger formation constant for Cu(PBT2)NImH6 indicates that outer-sphere ligand-peptide interactions strongly stabilize its structure. Despite the relatively high stability of Cu(PBT2)NImH6, PBT2 is a promiscuous chelator capable of forming a ternary Cu(PBT2)NIm complex with any ligand containing an NIm donor. These ligands include histamine, L-His, and ubiquitous His side chains of peptides and proteins in the extracellular milieu, whose combined effect should outweigh that of a single Cu(PBT2)NImH6 complex regardless of its stability. We therefore conclude that PBT2 is capable of accessing Cu(Aß) complexes with high stability but low specificity. The results have implications for future AD therapeutic strategies and understanding the role of PBT2 in the bulk transport of transition metal ions. Given the repurposing of PBT2 as a drug for breaking antibiotic resistance, ternary Cu(PBT2)NIm and analogous Zn(PBT2)NIm complexes may be relevant to its antimicrobial properties.
Assuntos
Doença de Alzheimer , Peptídeos beta-Amiloides , Humanos , Peptídeos beta-Amiloides/metabolismo , Cobre/química , Quelantes/uso terapêutico , Histamina , Ligantes , Doença de Alzheimer/metabolismoRESUMO
Treatments for Alzheimer's disease (AD) directed against the prominent amyloid plaque neuropathology are yet to be proved effective despite many phase 3 clinical trials. There are several other neurochemical abnormalities that occur in the AD brain that warrant renewed emphasis as potential therapeutic targets for this disease. Among those are the elementomic signatures of iron, copper, zinc, and selenium. Here, we review these essential elements of AD for their broad potential to contribute to Alzheimer's pathophysiology, and we also highlight more recent attempts to translate these findings into therapeutics. A reinspection of large bodies of discovery in the AD field, such as this, may inspire new thinking about pathogenesis and therapeutic targets.
Assuntos
Doença de Alzheimer/metabolismo , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/patologia , Doença de Alzheimer/fisiopatologia , Animais , Encéfalo/metabolismo , Cobre/metabolismo , Ferroptose , Humanos , Ferro/metabolismo , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo , Placa Amiloide/patologia , Selênio/metabolismo , Zinco/metabolismoRESUMO
Multidrug-resistant (MDR) N. gonorrhoeae is a current public health threat. New therapies are urgently needed. PBT2 is an ionophore that disrupts metal homeostasis. PBT2 administered with zinc is shown to reverse resistance to antibiotics in several bacterial pathogens. Here we show that both N. meningitidis and MDR N. gonorrhoeae are sensitive to killing by PBT2 alone. PBT2 is, thus, a candidate therapeutic for MDR N. gonorrhoeae infections.
Assuntos
Gonorreia , Neisseria meningitidis , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Gonorreia/tratamento farmacológico , Gonorreia/microbiologia , Humanos , Ionóforos/farmacologia , Ionóforos/uso terapêutico , Testes de Sensibilidade Microbiana , Neisseria gonorrhoeae , ZincoRESUMO
Dyshomeostasis or abnormal accumulation of metal ions such as copper, zinc, and iron have been linked to the pathogenesis of multiple neurodegenerative disorders including Alzheimer's disease (AD) and Huntington's disease (HD). 5,7-Dichloro-2-((dimethylamino)methyl)quinolin-8-ol, PBT2, is a second generation metal protein-attenuating compound that has recently advanced in Phase II clinical trials for the treatment of AD and HD based on promising preclinical efficacy data. Herein, we report the first radiosynthesis and preclinical positron emission tomography (PET) neuroimaging evaluation of [11C]PBT2 in rodents and nonhuman primates. Carbon-11 labeled PBT2 was synthesized in 4.8 ± 0.5% (nondecay corrected) radiochemical yield (RCY) at end-of-synthesis, based upon [11C]CH3I (n = 6), with >99% radiochemical purity and 80-90 GBq/µmol molar activity (Am) from the corresponding normethyl precursor. In the nonhuman primate brain, [11C]PBT2 uptake was extensive with peak concentration SUVpeak of 3.2-5.2 within 2.5-4.5 min postinjection in all cortical and subcortical gray matter regions (putamen > caudate > cortex â« white matter) followed by rapid washout from normal brain tissues. Furthermore, it is shown that [11C]PBT2 binds specifically in AD human brain tissue in vitro. The results presented here, combined with the clinical data available for PBT2, warrant the evaluation of [11C]PBT2 as an exploratory PET radiotracer in humans.
Assuntos
Radioisótopos de Carbono , Clioquinol/análogos & derivados , Neuroimagem/métodos , Tomografia por Emissão de Pósitrons/métodos , Compostos Radiofarmacêuticos/administração & dosagem , Doença de Alzheimer/patologia , Animais , Autorradiografia , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Encéfalo/patologia , Clioquinol/administração & dosagem , Clioquinol/síntese química , Clioquinol/farmacocinética , Avaliação Pré-Clínica de Medicamentos , Feminino , Humanos , Masculino , Camundongos Endogâmicos BALB C , Papio anubis , Compostos Radiofarmacêuticos/síntese química , Compostos Radiofarmacêuticos/farmacocinéticaRESUMO
The extracellular accumulation of amyloid ß (Aß) peptides is characteristic of Alzheimer's disease (AD). However, formation of diffusible, oligomeric forms of Aß, both on and off pathways to amyloid fibrils, is thought to include neurotoxic species responsible for synaptic loss and neurodegeneration, rather than polymeric amyloid aggregates. The 8-hydroxyquinolines (8-HQ) clioquinol (CQ) and PBT2 were developed for their ability to inhibit metal-mediated generation of reactive oxygen species from Aß:Cu complexes and have both undergone preclinical and Phase II clinical development for the treatment of AD. Their respective modes of action are not fully understood and may include both inhibition of Aß fibrillar polymerization and direct depolymerization of existing Aß fibrils. In the present study, we find that CQ and PBT2 can interact directly with Aß and affect its propensity to aggregate. Using a combination of biophysical techniques, we demonstrate that, in the presence of these 8-HQs and in the absence of metal ions, Aß associates with two 8-HQ molecules and forms a dimer. Furthermore, 8-HQ bind Aß with an affinity of 1-10 µm and suppress the formation of large (>30 kDa) oligomers. The stabilized low molecular weight species are nontoxic. Treatment with 8-HQs also reduces the levels of in vivo soluble oligomers in a Caenorhabditis elegans model of Aß toxicity. We propose that 8-HQs possess an additional mechanism of action that neutralizes neurotoxic Aß oligomer formation through stabilization of small (dimeric) nontoxic Aß conformers.
Assuntos
Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Hidroxiquinolinas/metabolismo , Fragmentos de Peptídeos/metabolismo , Peptídeos beta-Amiloides/química , Peptídeos beta-Amiloides/ultraestrutura , Animais , Benzotiazóis , Biofísica , Caenorhabditis elegans , Células Cultivadas , Córtex Cerebral/citologia , Cromatografia em Gel , Clioquinol/análogos & derivados , Clioquinol/metabolismo , Ensaio de Imunoadsorção Enzimática , Humanos , Camundongos , Microscopia Eletrônica , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Fragmentos de Peptídeos/química , Fragmentos de Peptídeos/ultraestrutura , Ligação Proteica/efeitos dos fármacos , Espalhamento a Baixo Ângulo , Tiazóis/metabolismoRESUMO
Gram-positive bacteria do not produce lipopolysaccharide as a cell wall component. As such, the polymyxin class of antibiotics, which exert bactericidal activity against Gram-negative pathogens, are ineffective against Gram-positive bacteria. The safe-for-human-use hydroxyquinoline analog ionophore PBT2 has been previously shown to break polymyxin resistance in Gram-negative bacteria, independent of the lipopolysaccharide modification pathways that confer polymyxin resistance. Here, in combination with zinc, PBT2 was shown to break intrinsic polymyxin resistance in Streptococcus pyogenes (Group A Streptococcus; GAS), Staphylococcus aureus (including methicillin-resistant S. aureus), and vancomycin-resistant Enterococcus faecium. Using the globally disseminated M1T1 GAS strain 5448 as a proof of principle model, colistin in the presence of PBT2 + zinc was shown to be bactericidal in activity. Any resistance that did arise imposed a substantial fitness cost. PBT2 + zinc dysregulated GAS metal ion homeostasis, notably decreasing the cellular manganese content. Using a murine model of wound infection, PBT2 in combination with zinc and colistin proved an efficacious treatment against streptococcal skin infection. These findings provide a foundation from which to investigate the utility of PBT2 and next-generation polymyxin antibiotics for the treatment of Gram-positive bacterial infections.
RESUMO
Within intensive care units, multi-drug resistant Acinetobacter baumannii outbreaks are a frequent cause of ventilator-associated pneumonia. During the on-going COVID-19 pandemic, patients who receive ventilator support experience a 2-fold increased risk of mortality when they contract a secondary A. baumannii pulmonary infection. In our recent paper (De Oliveira et al. (2022), Mbio, doi: 10.1128/mbio.03517-21), we demonstrate that the 8-hydroxquinoline ionophore, PBT2 breaks the resistance of A. baumannii to tetracycline class antibiotics. In vitro, the combination of PBT2 and zinc with either tetracycline, doxycycline, or tigecycline was shown to be bactericidal against multi-drug-resistant A. baumannii, and any resistance that did arise imposed a fitness cost. Using a murine model of pulmonary infection, treatment with PBT2 in combination with tetracycline or tigecycline proved efficacious against multidrug-resistant A. baumannii. These findings suggest that PBT2 may find utility as a resistance breaker to rescue the efficacy of tetracycline-class antibiotics commonly employed to treat multi-drug resistant A. baumannii infections.
RESUMO
Although new-generation antimicrobials, in particular ß-lactam/ß-lactamase inhibitors, have largely replaced polymyxins in carbapenem-resistant Gram-negative bacterial infections, polymyxins are still needed for carbapanem-resistant Acinetobacter baumannii infections and in settings where novel agents are not readily available. Despite their potent in vitro activity, the clinical utility of polymyxins is significantly limited by their pharmacokinetic properties and nephrotoxicity risk. There is significant interest, therefore, in developing next-generation polymyxins with activity against colistin-resistant strains and lower toxicity than existing polymyxins. In this review, we aim to present the antibacterial activity mechanisms, in vitro and in vivo efficacy data, and toxicity profiles of new-generation polymyxins, including SPR206, MRX-8, and QPX9003, as well as the general characteristics of old polymyxins. Considering the emergence of colistin-resistant strains particularly in endemic regions, the restoration of the antimicrobial activity of polymyxins via PBT2 is also described in this review.
RESUMO
Streptococcus pneumoniae is the primary cause of community-acquired bacterial pneumonia with rates of penicillin and multidrug-resistance exceeding 80% and 40%, respectively. The innate immune response generates a variety of antimicrobial agents to control infection, including zinc stress. Here, we characterize the impact of zinc intoxication on S. pneumoniae, observing disruptions in central carbon metabolism, lipid biogenesis, and peptidoglycan biosynthesis. Characterization of the pivotal peptidoglycan biosynthetic enzyme GlmU indicates a sensitivity to zinc inhibition. Disruption of the sole zinc efflux pathway, czcD, renders S. pneumoniae highly susceptible to ß-lactam antibiotics. To dysregulate zinc homeostasis in the wild-type strain, we investigated the safe-for-human-use ionophore 5,7-dichloro-2-[(dimethylamino)methyl]quinolin-8-ol (PBT2). PBT2 rendered wild-type S. pneumoniae strains sensitive to a range of antibiotics. Using an invasive ampicillin-resistant strain, we demonstrate in a murine pneumonia infection model the efficacy of PBT2 + ampicillin treatment. These findings present a therapeutic modality to break antibiotic resistance in multidrug-resistant S. pneumoniae.
Assuntos
Resistência a Ampicilina/fisiologia , Streptococcus pneumoniae/metabolismo , Zinco/metabolismo , Ampicilina/farmacologia , Resistência a Ampicilina/genética , Animais , Antibacterianos/farmacologia , Clioquinol/análogos & derivados , Clioquinol/farmacologia , Modelos Animais de Doenças , Feminino , Homeostase , Camundongos , Camundongos Endogâmicos BALB C , Testes de Sensibilidade Microbiana , PneumoniaRESUMO
The Gram-negative anaerobe Fusobacterium nucleatum is an opportunistic human pathogen, most frequently associated with periodontal disease through dental biofilm formation and, increasingly, with colorectal cancer development and progression. F. nucleatum infections are routinely treated by broad-spectrum ß-lactam antibiotics and metronidazole. However, these antibiotics can negatively impact the normal microflora. Therefore, the development of novel narrow-spectrum antimicrobials active against anaerobic pathogens is of great interest. Here, we examined the antimicrobial Zn ionophore PBT2, an 8-hydroxyquinoline analogue with metal chelating properties, against a single type isolate F. nucleatum ATCC 25586. PBT2-Zn was a potent inhibitor of growth and exhibited synergistic bactericidal (>3-log10 killing) activity at 5× MIC in planktonic cells, and at the MIC in biofilms grown in vitro. Physiological and transcriptional analyses uncovered a strong cellular response relating to Zn and Fe homeostasis in PBT2-Zn treated cells across subinhibitory and inhibitory concentrations. At 1× MIC, PBT2 alone induced a 3.75-fold increase in intracellular Zn, whereas PBT2-Zn challenge induced a 19-fold accumulation of intracellular Zn after 2 h. A corresponding 2.1-fold loss of Fe was observed at 1× MIC. Transcriptional analyses after subinhibitory PBT2-Zn challenge (0.125 µg/mL and 200 µM ZnSO4) revealed significant differential expression of 15 genes at 0.5 h, and 12 genes at 1 h. Upregulated genes included those with roles in Zn homeostasis (e.g., a Zn-transporting ATPase and the Zn-sensing transcriptional regulator, smtB) and hemin transport (hmuTUV) to re-establish Fe homeostasis. A concentration-dependent protective effect was observed for cells pretreated with hemin (50 µg/mL) prior to PBT2-Zn challenge. The data presented here supports our proposal that targeting the disruption of metallostasis by Zn-translocating ionophores is a strategy worth investigating further for the treatment of Gram-negative anaerobic pathogens.
Assuntos
Fusobacterium nucleatum , Zinco , Anaerobiose , Biofilmes , Humanos , IonóforosRESUMO
Neisseria gonorrhoeae (N. gonorrhoeae) causes the sexually transmitted disease gonorrhea, which has a global incidence of 106 million cases per year. No vaccine is available to prevent the disease, and the emergence of multidrug resistant (MDR) strains makes N. gonorrhoeae an immediate public health threat. Here, we show that an ionophore, PBT2, can reverse the intrinsic resistance of N. gonorrhoeae to polymyxin B and colistin. These antibiotics administered in combination with PBT2 may be an effective path to treat MDR gonococcal infections.
Assuntos
Antibacterianos/farmacologia , Clioquinol/análogos & derivados , Colistina/farmacologia , Neisseria gonorrhoeae/efeitos dos fármacos , Polimixina B/farmacologia , Clioquinol/farmacologia , Sinergismo Farmacológico , Testes de Sensibilidade MicrobianaRESUMO
Globally, more antimicrobials are used in food-producing animals than in humans, and the extensive use of medically important human antimicrobials poses a significant public health threat in the face of rising antimicrobial resistance (AMR). The development of novel ionophores, a class of antimicrobials used exclusively in animals, holds promise as a strategy to replace or reduce essential human antimicrobials in veterinary practice. PBT2 is a zinc ionophore with recently demonstrated antibacterial activity against several Gram-positive pathogens, although the underlying mechanism of action is unknown. Here, we investigated the bactericidal mechanism of PBT2 in the bovine mastitis-causing pathogen, Streptococcus uberis In this work, we show that PBT2 functions as a Zn2+/H+ ionophore, exchanging extracellular zinc for intracellular protons in an electroneutral process that leads to cellular zinc accumulation. Zinc accumulation occurs concomitantly with manganese depletion and the production of reactive oxygen species (ROS). PBT2 inhibits the activity of the manganese-dependent superoxide dismutase, SodA, thereby impairing oxidative stress protection. We propose that PBT2-mediated intracellular zinc toxicity in S. uberis leads to lethality through multiple bactericidal mechanisms: the production of toxic ROS and the impairment of manganese-dependent antioxidant functions. Collectively, these data show that PBT2 represents a new class of antibacterial ionophores capable of targeting bacterial metal ion homeostasis and cellular redox balance. We propose that this novel and multitarget mechanism of PBT2 makes the development of cross-resistance to medically important antimicrobials unlikely.IMPORTANCE More antimicrobials are used in food-producing animals than in humans, and the extensive use of medically important human antimicrobials poses a significant public health threat in the face of rising antimicrobial resistance. Therefore, the elimination of antimicrobial crossover between human and veterinary medicine is of great interest. Unfortunately, the development of new antimicrobials is an expensive high-risk process fraught with difficulties. The repurposing of chemical agents provides a solution to this problem, and while many have not been originally developed as antimicrobials, they have been proven safe in clinical trials. PBT2, a zinc ionophore, is an experimental therapeutic that met safety criteria but failed efficacy checkpoints against both Alzheimer's and Huntington's diseases. It was recently found that PBT2 possessed potent antimicrobial activity, although the mechanism of bacterial cell death is unresolved. In this body of work, we show that PBT2 has multiple mechanisms of antimicrobial action, making the development of PBT2 resistance unlikely.
Assuntos
Antibacterianos/farmacologia , Clioquinol/análogos & derivados , Ionóforos/farmacologia , Streptococcus/efeitos dos fármacos , Zinco/metabolismo , Animais , Bovinos , Clioquinol/farmacologia , Feminino , Mastite Bovina/microbiologia , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Superóxido Dismutase/antagonistas & inibidoresRESUMO
BACKGROUND: Accumulating evidence suggests that multi-target directed ligands have great potential for the treatment of complex diseases such as Alzheimer's Disease (AD). OBJECTIVE: To evaluate novel chimeric 8-hydroxyquinoline ligands with merged pharmacophores as potential multifunctional ligands for AD. METHODS: Nitroxoline, PBT2 and compounds 2-4 were evaluated in-vitro for their inhibitory potencies on cathepsin B, cholinesterases, and monoamine oxidases. Furthermore, chelation, antioxidative properties and the permeability of Blood-Brain Barrier (BBB) were evaluated by spectroscopy-based assays and the inhibition of Amyloid ß (Aß) aggregation was determined in immunoassay. Cell-based assays were performed to determine cytotoxicity, neuroprotection against toxic Aß species, and the effects of compound 2 on apoptotic cascade. RESULTS: Compounds 2-4 competitively inhibited cathepsin B ß-secretase activity, chelated metal ions and were weak antioxidants. All of the compounds inhibited Aß aggregation, whereas only compound 2 had a good BBB permeability according to the parallel artificial membrane permeability assay. Tested ligands 2 and 3 were not cytotoxic to SH-SY5Y and HepG2 cells at 10 µM. Compound 2 exerted neuroprotective effects towards Aß toxicity, reduced the activation of caspase-3/7 and diminished the apoptosis of cells treated with Aß1-42. CONCLUSION: Taken together, our data suggest that compound 2 holds a promise to be used as a multifunctional ligand for AD.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Antioxidantes/farmacologia , Quelantes/farmacologia , Inibidores da Colinesterase/farmacologia , Hidroxiquinolinas/farmacologia , Fármacos Neuroprotetores/farmacologia , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Antioxidantes/química , Antioxidantes/farmacocinética , Apoptose/efeitos dos fármacos , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Permeabilidade Capilar , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Quelantes/química , Quelantes/farmacocinética , Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacocinética , Avaliação Pré-Clínica de Medicamentos , Humanos , Hidroxiquinolinas/química , Hidroxiquinolinas/farmacocinética , Ligantes , Fármacos Neuroprotetores/farmacocinética , Agregação Patológica de Proteínas/tratamento farmacológico , Agregação Patológica de Proteínas/metabolismoRESUMO
Copper(II) complexes with 8-hydroxyquinoline (8-HQ) and two 8-HQ derivatives, namely clioquinol (CQ) and 5,7-dichloro-2-[(dimethylamino)methyl]quinolin-8-ol (PBT2), were investigated in organic and, where feasible, in aqueous solutions. This class of compounds is of particular interest in neurological disorders since they may act as metal-protein attenuating compounds and may help redistributing metal ions and restoring intracellular metal reserves, which are often perturbed in neurological patients. Several techniques, like potentiometry, UV-Vis absorption, electron paramagnetic resonance (EPR), cyclic voltammetry and electrospray ionisation-mass spectrometry (ESI-MS), were used to obtain information on both the formation of copper(II) complexes in solution as well as on the structure of their species. Multi-wavelength treatment of UV-Vis data clearly indicated the formation of both [Cu(PBT2)]+ and [Cu(PBT2)2] species; the speciation was also supported by ESI-MS data. The EPR results showed that the mono- and bis-copper(II) complexes with PBT2 have square-based pyramidal structures while the bis-copper (II) complexes with CQ or 8-HQ have square-planar o pseudo-octahedral geometries. The formation of copper(II) ternary complexes with 8-HQ, CQ and PBT2 and some selected neurotransmitters (glycine, glutamate and histidine) is also reported. Except for the copper(II) ternary complex with PBT2 and His, almost all ternary complexes have molecular geometries, which are not different from those of the bis-complexes. Interestingly the ternary copper(II) complexes, containing CQ, 8-HQ and PBT2 and glycine, glutamate or histidine turned out to be more soluble in aqueous solution than their binary complexes with parent 8-HQ derivatives; the copper(II) complexes can also be reduced more easily than their parent bis-complexes.
Assuntos
Aminoácidos/química , Cobre/química , Oxiquinolina/química , Complexos de Coordenação/química , Complexos de Coordenação/metabolismo , Espectroscopia de Ressonância de Spin Eletrônica , Glutationa/química , Neurotransmissores/química , Neurotransmissores/metabolismo , Dobramento de Proteína , Soluções , Espectrometria de Massas por Ionização por Electrospray , Espectrofotometria Ultravioleta , Termogravimetria , Resposta a Proteínas não DobradasRESUMO
Alzheimer's disease (AD) is the most common form of adult neurode-generation and is characterised by progressive loss of cognitive function leading to death. The neuropathological hallmarks include extracellular amyloid plaque accumulation in affected regions of the brain, formation of intraneuronal neurofibrillary tangles, chronic neuroinflammation, oxidative stress, and abnormal biometal homeostasis. Of the latter, major changes in copper (Cu) levels and localisation have been identified in AD brain, with accumulation of Cu in amyloid deposits, together with deficiency of Cu in some brain regions. The amyloid precursor protein (APP) and the amyloid beta (Aß) peptide both have Cu binding sites, and interaction with Cu can lead to potentially neurotoxic outcomes through generation of reactive oxygen species. In addition, AD patients have systemic changes to Cu metabolism, and altered Cu may also affect neuroinflammatory outcomes in AD. Although we still have much to learn about Cu homeostasis in AD patients and its role in disease aetiopathology, therapeutic approaches for regulating Cu levels and interactions with Cu-binding proteins in the brain are currently being developed. This review will examine how Cu is associated with pathological changes in the AD brain and how these may be targeted for therapeutic intervention.
Assuntos
Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Encéfalo/metabolismo , Cobre/metabolismo , Placa Amiloide/metabolismo , Doença de Alzheimer/patologia , Encéfalo/patologia , Humanos , Inflamação , Estresse Oxidativo , Placa Amiloide/patologia , Espécies Reativas de Oxigênio/metabolismoRESUMO
8-Hydroxyquinolines are heterocyclic compounds characterized by a moderate metal-binding affinity. The interest in 8-hydroxyquinolines has grown exponentially in the last two decades as they are privileged structures for the design of new drug candidates that exert a host of biological effects on various targets. The study of biological activities such as neuroprotection, anticancer, antibacterial, antifungal activity has been further promoted by the synthetic versatility of 8-hydroxyquinoline, which allows the generation of a large number of derivatives. These include numerous multifunctional analogues having the metal-binding motif of 8-hydroxyquinoline. In this review, we have summarized 8-hydroxyquinolines, 8-hydroxyquinoline-like compounds, 8-hydroxyquinoline-loaded nanoparticle systems with respect to their biological activities, interaction with metal ions and mechanisms of action.
Assuntos
Química Farmacêutica/métodos , Hidroxiquinolinas/farmacologia , Complexos de Coordenação , Hidroxiquinolinas/química , Metais , Relação Estrutura-AtividadeRESUMO
Eight-hydroxyquinolines (8HQs) are a class of compounds that have been identified as potential therapeutics for a number of neurodegenerative diseases. Understanding the influence of structural modifications to the 8HQ scaffold on cellular behaviour will aid the identification of compounds that might be effective in treating dementias. In this study, we describe the action of 2-[(dimethylamino)methyl]-8-hydroxyquinoline (DMAMQ) on adult murine neural stem cells (NSCs) cultured in vitro. Treatment of NSCs with DMAMQ resulted in enhanced self-renewal and increased neurite outgrowth. Concurrent with the positive growth effects was an increase in intracellular reactive oxygen species, with the growth being inhibited by inactivation of the NADPH oxidase (Nox) enzyme family. Our results indicate that DMAMQ can stimulate neurogenesis via the Nox signalling pathway, which may provide therapeutic benefit in treating dementias of various types by replenishing neurones using the brain's own reserves. The narrow concentration range over which these effects were observed, however, suggests that there may exist only a small therapeutic window for neuro-regenerative applications.
Assuntos
Proliferação de Células/efeitos dos fármacos , Oxiquinolina/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Animais , Western Blotting , Células Cultivadas , Citometria de Fluxo , Antígeno Ki-67/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Microscopia de Fluorescência , NADPH Oxidases/metabolismo , Células-Tronco Neurais/citologia , Células-Tronco Neurais/metabolismo , Oxiquinolina/químicaRESUMO
The loss of cognitive function is a pervasive and often debilitating feature of the aging process for which there are no effective therapeutics. We hypothesized that a novel metal chaperone (PBT2; Prana Biotechnology, Parkville, Victoria, Australia) would enhance cognition in aged rodents. We show here that PBT2 rapidly improves the performance of aged C57Bl/6 mice in the Morris water maze, concomitant with increases in dendritic spine density, hippocampal neuron number and markers of neurogenesis. There were also increased levels of specific glutamate receptors (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid and N-methyl-D-aspartate), the glutamate transporter (VGLUT1) and glutamate itself. Markers of synaptic plasticity [calmodulin-dependent protein kinase II (CaMKII) and phosphorylated CaMKII, CREB, synaptophysin] were also increased following PBT2 treatment. We also demonstrate that PBT2 treatment results in a subregion-specific increase in hippocampal zinc, which is increasingly recognized as a potent neuromodulator. These data demonstrate that metal chaperones are a novel approach to the treatment of age-related cognitive decline.
Assuntos
Envelhecimento/patologia , Clioquinol/análogos & derivados , Transtornos Cognitivos/prevenção & controle , Aprendizagem em Labirinto/efeitos dos fármacos , Envelhecimento/efeitos dos fármacos , Animais , Comportamento Animal/efeitos dos fármacos , Biomarcadores/metabolismo , Contagem de Células , Clioquinol/farmacologia , Clioquinol/uso terapêutico , Transtornos Cognitivos/tratamento farmacológico , Espinhas Dendríticas/efeitos dos fármacos , Espinhas Dendríticas/patologia , Feminino , Ácido Glutâmico/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/patologia , Camundongos , Camundongos Endogâmicos C57BL , Neurogênese/efeitos dos fármacos , Plasticidade Neuronal/efeitos dos fármacos , Proteína Fosfatase 2/metabolismo , Receptores de Glutamato/metabolismo , Sinapses/efeitos dos fármacos , Sinapses/metabolismo , Proteína Vesicular 1 de Transporte de Glutamato/metabolismo , Zinco/metabolismoRESUMO
As evidence for the role of metal ion dysregulation in the pathogenesis of multiple CNS disorders grows, it has become important to more precisely identify and differentiate the biological effects of various pharmacological modulators of metal ion homeostasis. This is particularly evident in disorders such as Alzheimer's disease (AD), where the use of metal chaperones (that transport metals), as opposed to chelators (which exclude metals from biological interactions), may prove to be the first truly disease modifying approach for this condition. The purpose of this mini-review is to highlight the emerging notion that metal chaperones, such as PBT2 (Prana Biotechnology), modulate a variety of critical pathways affecting key aspects of the AD cascade to provide a more "holistic" approach to the treatment of this disease.
RESUMO
BACKGROUND: There is evidence that interaction with biologically important metals, particularly copper and iron, contributes to the pathological aggregation and toxicity of the mutant huntingtin protein in HD. PBT2 is a novel 8-hydroxyquinoline drug in clinical trials for AD and HD which restores metal homeostasis and has demonstrated neuroprotective and cognitive benefits in animal models of AD and in a Phase IIa clinical trial in AD patients. OBJECTIVES: We assessed efficacy of PBT2 to improve function in nematode and mouse models of HD. METHODS: We assessed the effects of PBT2 on motility in a strain of C. elegans engineered to overexpress an extended polyglutamine tract. We then assessed the effects of daily oral administration of PBT2 on the R6/2 mouse a vertebrate model of HD. Behavioural measures (Rotarod performance, clasping latency and duration) and measures of overall health (body weight, lifespan) were assessed throughout the study. At conclusion brains were evaluated for weight and lateral ventricle area. RESULTS: PBT2 significantly decreased paralysis caused by overexpression of an extended polyglutamine tract in a C. elegans. R6/2 mice treated with PBT2 showed significantly better performance in the Rotarod task and significantly decreased duration of clasping than control animals. Mean body weight and brain weight in the PBT2 treatment group were significantly higher than the control cohort and median lifespan was prolonged by 26%. Mean lateral ventricle area in the PBT2-treated group was 46% smaller than in the control group. CONCLUSIONS: Treatment with PBT2 may be beneficial as a disease modifying therapy for HD.