RESUMO
Extracellular nucleotides can regulate the production/drainage of the aqueous humor via activation of P2 receptors, thus affecting the intraocular pressure (IOP). We evaluated 5-OMe-UDP(α-B), 1A, a potent P2Y6-receptor agonist, for reducing IOP and treating glaucoma. Cell viability in the presence of 1A was measured using [3-(4, 5-dimethyl-thiazol-2-yl) 2, 5-diphenyl-tetrazolium bromide] (MTT) assay in rabbit NPE ciliary non-pigmented and corneal epithelial cells, human retinoblastoma, and liver Huh7 cells. The effect of 1A on IOP was determined in acute glaucomatous rabbit hyaluronate model and phenol-induced chronic glaucomatous rabbit model. The origin of activity of 1A was investigated by generation of a homology model of hP2Y6-R and docking studies. 1A did not exert cytotoxic effects up to 100 mM vs. trusopt and timolol in MTT assay in ocular and liver cells. In normotensive rabbits, 100 µM 1A vs. xalatan, trusopt, and pilocarpine reduced IOP by 45 vs. 20-30%, respectively. In the phenol animal model, 1A (100 µM) showed reduction of IOP by 40 and 20%, following early and late administration, respectively. Docking results suggest that the high activity and selectivity of 1A is due to intramolecular interaction between Pα-BH3 and C5-OMe which positions 1A in a most favorable site inside the receptor. P2Y6-receptor agonist 1A effectively and safely reduces IOP in normotense, acute, and chronic glaucomatous rabbits, and hence may be suggested as a novel approach for the treatment of glaucoma.
Assuntos
Glaucoma , Pressão Intraocular/efeitos dos fármacos , Agonistas do Receptor Purinérgico P2Y/farmacologia , Receptores Purinérgicos P2/efeitos dos fármacos , Animais , Humanos , Coelhos , Difosfato de Uridina/química , Difosfato de Uridina/farmacologiaRESUMO
Purpose: Retinitis pigmentosa (RP) is a group of hereditary retinal degeneration in which mutations commonly result in the initial phase of rod cell death followed by gradual cone cell death. The mechanisms by which the mutations lead to photoreceptor cell death in RP have not been clearly elucidated. There is currently no effective treatment for RP. The purpose of this work was to explore iron chelation therapy for improving cone survival and function in the rd10 mouse model of RP. Methods: Two iron-chelating drugs, 5-(4-(2-hydroxyethyl) piperazin-1-yl (methyl)-8-hydroxyquinoline (VK28) and its chimeric derivative 5-(N-methyl-N-propargyaminomethyl)-quinoline-8-oldihydrochloride (VAR10303), were injected intraperitoneally to rd10 mice every other day starting from postnatal day 14. We investigate the effects of the two compounds on cone rescue at three time points, using a combination of immunocytochemistry, RT-PCR, Western blot analysis, and a series of visual function tests. Results: VK28 and VAR10303 treatments partially rescued cones, and significantly improved visual function in rd10 mice. Moreover, we showed that the neuroprotective effects of VK28 and VAR10303 were correlated to inhibition of neuroinflammation, oxidative stress, and apoptosis. Furthermore, we demonstrated that downregulation of NF-kB and p53 is likely to be the mechanisms by which proinflammatory mediators and apoptosis are reduced in the rd10 retina, respectively. Conclusions: VK28 and VAR10303 provided partial histologic and functional rescue of cones in RD10 mice. Our study demonstrated that iron chelation therapy might represent an effective therapeutic strategy for RP patients.
Assuntos
Modelos Animais de Doenças , Quelantes de Ferro/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Células Fotorreceptoras Retinianas Cones/fisiologia , Retinose Pigmentar/tratamento farmacológico , Animais , Apoptose/efeitos dos fármacos , Western Blotting , Sobrevivência Celular/fisiologia , Eletrorretinografia , Hidroxiquinolinas/uso terapêutico , Imuno-Histoquímica , Injeções Intraperitoneais , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Piperazinas/uso terapêutico , Quinolinas/uso terapêutico , Reação em Cadeia da Polimerase em Tempo Real , Retinose Pigmentar/metabolismo , Retinose Pigmentar/patologia , Proteína Supressora de Tumor p53/metabolismoRESUMO
In many of the neurodegenerative diseases, such as Alzheimer's disease (AD) and AD-related disorders, as well as in the regular ageing process, excessive generation of oxidative stress (OS) and accumulation of iron levels and deposition have been observed in specific affected-brain regions and thus, regarded as contributing factors to the pathogenesis of the diseases. In AD, iron promotes amyloid ß (Aß) neurotoxicity by producing free radical damage and OS in brain areas affected by neurodegeneration, presumably by facilitating the aggregation of Aß. In addition, it was shown that iron modulates intracellular levels of the holo amyloid precursor protein (APP) by iron-responsive elements (IRE) RNA stem loops in the 5' untranslated region (5'UTR) of the APP transcript. As a consequence of these observations, iron chelation is one of the major new therapeutic strategies for the treatment of AD. This review describes the benefits and importance of the multimodal brain permeable chimeric iron-chelating/propargylamine drug M30, concerning its neuroprotective/neurorestorative inter-related activities relevant of the pathological features ascribed to AD, with a special focus on the effect of the drug on APP regulation and processing.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Hidroxiquinolinas/farmacologia , Quelantes de Ferro/farmacologia , Fármacos Neuroprotetores/farmacologia , Animais , HumanosRESUMO
Previous studies into the mechanism of SSRI-antipsychotic synergism in our laboratory identified unique changes in the brain, particularly in the γ-aminobutyric acid (GABA)-A receptor and its modulators. This study examined the role of brain derived neurotrophic factor (BDNF)-cAMP response element binding (CREB) protein signaling pathways, including protein kinase B (AKT), glycogen synthase kinase (GSK)-3ß and related molecules in the molecular response to haloperidol, fluvoxamine, combined haloperidol+fluvoxamine and clozapine treatments in rat frontal cortex, hippocampus and primary cortical neuronal cultures. The effect of fluvoxamine augmentation on BDNF-CREB pathways in peripheral mononuclear cells (PMC׳s) of medicated schizophrenia patients was also studied. Chronic haloperidol (1mg/kg) +fluvoxamine (10mg/kg) treatment increased TrkB receptor and BDNF expression levels, and the phosphorylation of AKT/CREB/GSK-3ß, compared to the individual drugs in rat brain. In addition, haloperidol+fluvoxamine treatment improved cognitive functions in rats, indicating that the molecular changes may have a role in behavioral improvement. In primary neuronal cell cultures, pretreatment with a selective PI3K inhibitor abolished the haloperidol+fluvoxamine-induced phosphorylation of AKT and GSK-3ß, but did not affect the upregulation of CREB phosphorylation. In the clinic, PMC׳s of treated patients showed upregulation of mRNA expression and protein levels of BDNF, CREB and AKT after addition of fluvoxamine. Analyses of PMC genes and proteins showed significant inter-correlations and some gene changes correlated with improvement in negative and cognitive symptoms. Our study provides new knowledge of the molecular mechanisms of symptom amelioration in schizophrenia and may advance development of new drugs for this disease and other neuropsychiatric disorders.
Assuntos
Antipsicóticos/farmacologia , Antipsicóticos/uso terapêutico , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Proteína de Ligação a CREB/metabolismo , Esquizofrenia , Inibidores Seletivos de Recaptação de Serotonina/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Adulto , Animais , Fator Neurotrófico Derivado do Encéfalo/genética , Proteína de Ligação a CREB/genética , Combinação de Medicamentos , Embrião de Mamíferos , Feminino , Fluvoxamina/farmacologia , Fluvoxamina/uso terapêutico , Haloperidol/farmacologia , Haloperidol/uso terapêutico , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Humanos , Técnicas In Vitro , Masculino , Pessoa de Meia-Idade , Ratos , Ratos Sprague-Dawley , Esquizofrenia/tratamento farmacológico , Esquizofrenia/metabolismo , Esquizofrenia/patologia , Inibidores Seletivos de Recaptação de Serotonina/farmacologiaRESUMO
Previous study demonstrated that the novel multitarget compound, MT-031 preserved in one molecule entity the beneficial properties of its parent drugs, rasagiline and rivastigmine, and exerted high dual potencies of monoamine oxidase-A (MAO-A) and cholinesterase (ChE) inhibition in acute-treated mice and neuroprotective effects against H2O2-induced neurotoxicity in human neuroblastoma SH-SY5Y cells. The present study aimed to further investigate the anti-inflammatory and protective effects of MT-031 in scopolamine mouse model and inflammatory cell cultures. Our findings demonstrated that once daily chronic administration of MT-031 (5-10 mg/kg) to mice antagonized scopolamine-induced memory and cognitive impairments, displayed brain selective MAO-A and AChE/BuChE inhibition, increased the levels of striatal dopamine (DA), serotonin (5-HT) and norepinephrine and prevented the metabolism of DA and 5-HT. In addition, MT-031 upregulated mRNA expression levels of Bcl-2, the neurotrophic factors, (e.g., brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF) and nerve growth factor (NGF)), the antioxidant enzyme catalase and the anti-inflammatory cytokine, neurotrophic tyrosine kinase receptor (Ntrk), and down-regulated the mRNA expression levels of the pro-inflammatory interleukin (IL)-6 in scopolamine-induced mice. In accordance, MT-031 was shown to reduce reactive oxygen species accumulation, increase the levels of anti-inflammatory cytokines, IL-10 and decrease the levels of the pro-inflammatory cytokines, IL-1ß, IL-6, IL-17 and interferon-gamma (IFN-γ) in activated mouse splenocytes and microglial cells. Taken together, these pharmacological properties of MT-031 can be of clinical importance for developing this novel multitarget compound as a novel drug candidate for the treatment of Alzheimer's disease.
Assuntos
Anti-Inflamatórios/administração & dosagem , Butirilcolinesterase , Inibidores da Colinesterase/administração & dosagem , Inibidores da Monoaminoxidase/administração & dosagem , Fármacos Neuroprotetores/administração & dosagem , Escopolamina/toxicidade , Acetilcolinesterase/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Butirilcolinesterase/metabolismo , Células Cultivadas , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Sistemas de Liberação de Medicamentos/métodos , Mediadores da Inflamação/antagonistas & inibidores , Mediadores da Inflamação/metabolismo , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Monoaminoxidase/metabolismoRESUMO
The aim of the present study was to evaluate the therapeutic effect of the novel neuroprotective multitarget brain permeable monoamine oxidase inhibitor/iron chelating-radical scavenging drug, VAR10303 (VAR), co-administered with high-calorie/energy-supplemented diet (ced) in SOD1G93A transgenic amyotrophic lateral sclerosis (ALS) mice. Administration of VAR-ced was initiated after the appearance of disease symptoms (at day 88), as this regimen is comparable with the earliest time at which drug therapy could start in ALS patients. Using this rescue protocol, we demonstrated in the current study that VAR-ced treatment provided several beneficial effects in SOD1G93A mice, including improvement in motor performance, elevation of survival time, and attenuation of iron accumulation and motoneuron loss in the spinal cord. Moreover, VAR-ced treatment attenuated neuromuscular junction denervation and exerted a significant preservation of myofibril regular morphology, associated with a reduction in the expression levels of genes related to denervation and atrophy in the gastrocnemius (GNS) muscle in SOD1G93A mice. These effects were accompanied by upregulation of mitochondrial DNA and elevated activities of complexes I and II in the GNS muscle. We have also demonstrated that VAR-ced treatment upregulated the mitochondrial biogenesis master regulator, peroxisome proliferator-activated receptor-γ co-activator 1α (PGC-1α) and increased PGC-1α-targeted metabolic genes and proteins, such as, PPARγ, UCP1/3, NRF1/2, Tfam, and ERRα in GNS muscle. These results provide evidence of therapeutic potential of VAR-ced in SOD1G93A mice with underlying molecular mechanisms, further supporting the importance role of multitarget iron chelators in ALS treatment.
Assuntos
Esclerose Lateral Amiotrófica/tratamento farmacológico , DNA Mitocondrial/metabolismo , Hidroxiquinolinas/farmacologia , Hidroxiquinolinas/uso terapêutico , Destreza Motora/efeitos dos fármacos , Taxa de Sobrevida , Esclerose Lateral Amiotrófica/dietoterapia , Animais , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Terapia Combinada , Denervação , Complexo I de Transporte de Elétrons/metabolismo , Complexo II de Transporte de Elétrons/metabolismo , Feminino , Expressão Gênica/efeitos dos fármacos , Ferro/metabolismo , Camundongos , Camundongos Transgênicos , Neurônios Motores/efeitos dos fármacos , Músculo Esquelético/metabolismo , Miofibrilas/efeitos dos fármacos , Junção Neuromuscular/patologia , Estresse Oxidativo/efeitos dos fármacos , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Medula Espinal/metabolismo , Medula Espinal/fisiologia , Superóxido Dismutase-1/genética , Regulação para Cima/efeitos dos fármacosRESUMO
Current novel therapeutic approach suggests that multifunctional compounds with diverse biological properties and a single bioavailability and pharmacokinetic metabolism, will produce higher significant advantages in treatment of neurodegenerative diseases, such as Alzheimer's disease (AD). Based on this rational, a new class of cholinesterase (ChE)-monoamine oxidase (MAO) inhibitors were designed and synthesized by amalgamating the propargyl moiety of the irreversible selective MAO-B inhibitor, neuroprotective/neurorestorative anti-Parkinsonian drug, rasagiline, into the "N-methyl" position of the ChE inhibitor, anti-AD drug rivastigmine. Initially, we examined the MAO and ChE inhibitory effect of these novel compounds, MT series in vitro and in vivo. Among MT series, MT-031 exhibited higher potency as a dual MAO-A and ChE inhibitor compared to other compounds in acute-treated mice. Additionally, MT-031 was found to increase the striatal levels of dopamine (DA), serotonin (5-HT) and norepinephrine (NE), and prevent the metabolism of DA and 5-HT. Finally, we have demonstrated that MT-031 exerted neuroprotective effect against H2O2-induced neurotoxicity and reactive oxygen species generation in human neuroblastoma SH-SY5Y cells. These findings provide evidence that MT-031 is a potent brain permeable novel multifunctional, neuroprotective and MAO-A/ChE inhibitor, preserves in one molecule entity some of the beneficial properties of its parent drugs, rasagiline and rivastigmine, and thus may be indicated as novel therapeutic approach for AD.
Assuntos
Doença de Alzheimer , Inibidores da Colinesterase/administração & dosagem , Inibidores da Colinesterase/síntese química , Desenho de Fármacos , Inibidores da Monoaminoxidase/administração & dosagem , Inibidores da Monoaminoxidase/síntese química , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Combinação de Medicamentos , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Ratos , Ratos Sprague-Dawley , Resultado do TratamentoRESUMO
Accumulation of evidence has demonstrated high levels of iron in the central nervous system of both sporadic and familial amyotrophic lateral sclerosis (ALS) patients and in ALS mouse models. In accordance, iron chelation therapy was found to exert beneficial effects on ALS mice. Our group has designed and synthesized series of multifunctional non-toxic, brain permeable iron-chelating compounds for neurodegenerative diseases. Recent study has shown that co-administration of one of these drugs, VAR10303 with high calorie/energy-supplemented diet (VAR-ced), initiated after the appearance of disease symptoms improved motor performance, extended survival, and attenuated iron accumulation and motoneuron loss in SOD1(G93A) mice. Since VAR was found to exert diverse pharmacological properties associated with mitochondrial biogenesis in the gastrocnemius (GNS) muscle, we further assessed in the current study the impact of VAR-ced on additional neurorescue-associated molecular targets in the GNS and frontal cortex in SOD1(G93A) mice. The results show that VAR-ced treatment upregulated the expression of various HIF-1α-target glycolytic genes and elevated the levels of Bcl-2, neurotrophic factors, and AKT/GSK3ß signaling in the GNS and frontal cortex of SOD1(G93A) mice, suggesting that these protective regulatory parameters regulated by VAR-ced treatment may be associated with the beneficial effects of the drug observed on ALS mice.
Assuntos
Esclerose Lateral Amiotrófica/metabolismo , Lobo Frontal/metabolismo , Hidroxiquinolinas/farmacologia , Quelantes de Ferro/farmacologia , Músculo Esquelético/metabolismo , Fármacos Neuroprotetores/farmacologia , Esclerose Lateral Amiotrófica/genética , Animais , Apoptose , Feminino , Lobo Frontal/efeitos dos fármacos , Glicogênio Sintase Quinase 3 beta/genética , Glicogênio Sintase Quinase 3 beta/metabolismo , Glicólise , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Camundongos , Músculo Esquelético/efeitos dos fármacos , Fatores de Crescimento Neural/genética , Fatores de Crescimento Neural/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Superóxido Dismutase-1/genéticaRESUMO
The mitochondrial theory of ageing proposes that accumulation of damage to mitochondrial function and DNA mutation lead to ageing of humans and animals. It has been suggested that mitochondria play dynamic roles in regulating synaptogenesis and morphological/functional responses of synaptic activity, and thus, deteriorating of mitochondrial function (e.g., deficits of the mitochondrial respiratory enzymes, reduced calcium influx, increased accumulation of mitochondrial DNA defects/apoptotic proteins and impairment of mitochondrial membrane potential) can lead to severe neuronal energy deficit, and in the long run, to modifications in neuronal synapses and neurodegeneration in the ageing brain. Hence, considering the mechanisms by which mitochondrial impairment can lead to neuronal death, the development of neuroprotective molecules that target various mitochondrial pathogenic processes can be effective in the treatment of ageing and age-related neurodegenerative diseases. This review addresses several aspects of the neuroprotective effects of propargylamine derivatives (e.g., the monoamine oxidase-B inhibitors, selegiline and rasagiline and the multifunctional drugs, ladostigil, M30 and VAR10303) in ageing with a special focus on mitochondrial molecular protective mechanisms.
Assuntos
Envelhecimento/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Pargilina/análogos & derivados , Propilaminas/farmacologia , Envelhecimento/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Humanos , Mitocôndrias/metabolismo , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/uso terapêutico , Pargilina/química , Pargilina/farmacologia , Pargilina/uso terapêutico , Propilaminas/química , Propilaminas/uso terapêuticoRESUMO
UNLABELLED: Alzheimer's disease (AD) is accepted nowadays as a complex neurodegenerative disorder with multifaceted cerebral pathologies, including extracellular deposition of amyloid ß peptide-containing plaques, intracellular neurofibrillary tangles, progressive loss of cholinergic neurons, metal dyshomeostasis, mitochondrial dysfunction, neuroinflammation, glutamate excitoxicity, oxidative stress and increased MAO enzyme activity. This may explain why it is currently widely accepted that a more effective therapy for AD would result from the use of multifunctional drugs, which may affect more than one brain target involved in the disease pathology. The current review will discuss the potential benefits of novel multimodal neuroprotective, brain permeable drugs, recently developed by Youdim and collaborators, as a valuable therapeutic approach for AD treatment. The pharmacological and neuroprotective properties of these multitarget-directed ligands, which target MAO enzymes, the cholinergic system, iron accumulation and amyloid ß peptide generation/aggregation are described, with a special emphasis on their potential therapeutic value for ageing and AD-associated cognitive functions. This review is conceived as a tribute to the broad neuropharmacology work of Professor Moussa Youdim, Professor Emeritus in the Faculty of Medicine and Director of Eve Topf Center of Excellence in Technion-Israel Institute of Technology, and Chief Scientific Officer of ABITAL Pharma Pipeline Ltd., at the occasion of his 75th birthday. LINKED ARTICLES: This article is part of a themed section on Updating Neuropathology and Neuropharmacology of Monoaminergic Systems. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v173.13/issuetoc.
Assuntos
Envelhecimento/efeitos dos fármacos , Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/antagonistas & inibidores , Inibidores da Colinesterase/farmacologia , Ferro/metabolismo , Inibidores da Monoaminoxidase/farmacologia , Fármacos Neuroprotetores/farmacologia , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Animais , Inibidores da Colinesterase/química , Colinesterases/metabolismo , Humanos , Monoaminoxidase/metabolismo , Inibidores da Monoaminoxidase/química , Fármacos Neuroprotetores/químicaRESUMO
Amyotrophic lateral sclerosis (ALS) is the most common degenerative disease of the motoneuron system, involving various abnormalities, such as mitochondrial dysfunction, oxidative stress, transitional metal accumulation, neuroinflammation, glutamate excitotoxicity, apoptosis, decreased supply of trophic factors, cytoskeletal abnormalities, and extracellular superoxide dismutase (SOD)-1 toxicity. These multiple disease etiologies implicated in ALS gave rise to the perception that future therapeutic approaches for the disease should be aimed at targeting multiple pathological pathways. In line with this view, we have evaluated in the current study the therapeutic effects of low doses of the novel multifunctional monoamine oxidase (MAO) inhibitor/iron-chelating compound, M30 in combination with high Calorie Energy supplemented Diet (CED) in the SOD1-G93A transgenic mouse model of ALS. Our results demonstrated that the combined administration of M30 with CED produced additive neuroprotective effects on motor performance and increased survival of SOD1-G93A mice. We also found that both M30 and M30/CED regimens caused a significant inhibition of MAO-A and -B activities and decreased the turnover of dopamine in the brain of SOD1-G93A mice. In addition, M30/CED combined treatment resulted in a significant increase in mRNA expression levels of various mitochondrial biogenesis and metabolism regulators, such as peroxisome proliferator-activated receptor-γ (PPARγ)-co activator 1 alpha (PGC-1α), PPARγ, uncoupling protein 1, and insulin receptor in the gastrocnemius muscle of SOD1-G93A mice. These results suggest that a combination of drug/agents with different, but complementary mechanisms may be beneficial in the treatment of ALS.
Assuntos
Esclerose Lateral Amiotrófica/prevenção & controle , Dieta , Hidroxiquinolinas/administração & dosagem , Quelantes de Ferro/administração & dosagem , Inibidores da Monoaminoxidase/administração & dosagem , Fármacos Neuroprotetores/administração & dosagem , Ácido 3,4-Di-Hidroxifenilacético/metabolismo , Esclerose Lateral Amiotrófica/genética , Esclerose Lateral Amiotrófica/metabolismo , Esclerose Lateral Amiotrófica/fisiopatologia , Animais , Monoaminas Biogênicas/metabolismo , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/metabolismo , Modelos Animais de Doenças , Masculino , Camundongos , Camundongos Transgênicos , Monoaminoxidase/metabolismo , Atividade Motora/efeitos dos fármacos , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo , Fenilacetatos/metabolismo , Superóxido Dismutase/genética , Superóxido Dismutase-1 , Análise de Sobrevida , Fatores de Transcrição/metabolismoRESUMO
Current therapies for Alzheimer's disease (AD) offer partial symptomatic relief and do not modify disease progression. There is substantial evidence indicating a disease onset years before clinical diagnosis, at which point no effective therapy has been found. In this study, we investigated the efficacy of a new multi-target drug, M30, at relatively early stages of the AD-like amyloid pathology in a robust rat transgenic model. McGill-R-Thy1-APP transgenic rats develop the full AD-like amyloid pathology in a progressive fashion, and have a minimal genetic burden. McGill rats were given 5âmg/kg M30 or vehicle per os, every 2 days for 4 months, starting at a stage where the transgenic animals suffer detectable cognitive impairments. At the completion of the treatment, cognitive functions were assessed with Novel Object Location and Novel Object Recognition tests. The brains were then analyzed to assess amyloid-ß (Aß) burden and the levels of key inflammatory markers. Long-term treatment with M30 was associated with both the prevention and the reversal of transgene-related cognitive decline. The effects on cognition were accompanied by a shift of the Aß-immunoreactive material toward an amyloid plaque aggregated molecular form, diminished molecular signs of CNS inflammation and a change in microglia morphology toward a surveying phenotype. This study is the first to demonstrate the therapeutic potential of M30 in a rat model of the AD amyloid pathology. It provides a rationale for further investigations with M30 and with potential multi-target approaches to delay, prevent or reverse the progression the AD pathology at early disease-stages.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Anti-Inflamatórios/farmacologia , Encéfalo/efeitos dos fármacos , Cognição/efeitos dos fármacos , Hidroxiquinolinas/farmacologia , Nootrópicos/farmacologia , Doença de Alzheimer/imunologia , Peptídeos beta-Amiloides/metabolismo , Animais , Encéfalo/imunologia , Cognição/fisiologia , Modelos Animais de Doenças , Feminino , Peroxidação de Lipídeos/efeitos dos fármacos , Peroxidação de Lipídeos/fisiologia , Masculino , Microglia/efeitos dos fármacos , Microglia/metabolismo , Microglia/patologia , Fármacos Neuroprotetores/farmacologia , Ratos Transgênicos , Reconhecimento Psicológico/efeitos dos fármacosRESUMO
The present study aimed to investigate the protective effects of prolonged treatment with the selective, irreversible monoamine oxidase-B inhibitor, novel anti-parkinsonian drug, rasagiline (Azilect) in aged animals. Our findings from behavioral experiments demonstrated that long-term treatment of aged mice with rasagiline (0.2 mg/kg) exerted significant beneficial effects on mood-related dysfunction and spatial learning and memory functions. At this dose of rasagiline, chronic drug administration significantly inhibited monoamine oxidase-B activity and caused an increase in striatal dopamine and serotonin levels, while decreasing their metabolism. In addition, rasagiline treatment elevated striatal mRNA expression levels of dopamine receptors D1 and D2. Furthermore, we found that rasagiline upregulated expression levels of the synaptic plasticity markers brain-derived neurotrophic factor, tyrosine kinase-B receptor, and synapsin-1, increased Bcl-2 to Bax antiapoptotic ratio and the activity of the antioxidant enzyme, catalase in brain of aged mice. The present study demonstrated that long-term treatment with rasagiline could affect behavioral deficits in aged mice and upregulate various neuroprotective parameters in the aging brain, indicating that the drug may have therapeutic potential for treatment of age-associated neurodegenerative disorders.
Assuntos
Envelhecimento/efeitos dos fármacos , Transtornos Cognitivos/tratamento farmacológico , Regulação da Expressão Gênica/efeitos dos fármacos , Indanos/uso terapêutico , Monoaminoxidase/metabolismo , Fármacos Neuroprotetores/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Animais , Catecolaminas/metabolismo , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/metabolismo , Modelos Animais de Doenças , Comportamento Exploratório/efeitos dos fármacos , Estudos Longitudinais , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Receptores de Dopamina D1/genética , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/genética , Receptores de Dopamina D2/metabolismo , Natação/psicologiaRESUMO
Previous neuroprotective studies demonstrated that 1-(R)-aminoindan (AI), which is the major metabolite of the anti-Parkinsonian drug rasagiline, possesses beneficial pharmacological effects in various cell culture and animal models of neurodegeneration. The present study was aimed at investigating the possible neuroprotective effects of AI on cognitive impairments and neurochemical alterations in aged mice. Our findings provide evidence that following chronic systemic treatment with AI (5 mg/kg; daily; 3 months) of aged mice (24 months old), the compound exerted a significant positive impact on neuropsychiatric functions and cognitive behavior deficits, assessed in a variety of tasks (spatial learning and memory retention, working memory, learning abilities and nest building behavior) and produced an antidepressant-like effect. In addition, chronic AI treatment significantly enhanced expression levels of neurotrophins, including brain derived neurotrophic factor (BDNF) and nerve growth factor (NGF), tyrosine kinase- B (Trk-B) receptor and synaptic plasticity markers, such as synapsin-1 and growth-associated protein-43 (GAP-43) in the striatum and hippocampus in aged mice. Our results also indicate that AI treatment up-regulated the expression levels of the pro-survival Bcl-2 mRNA, increased the anti-apoptotic index Bcl-2/Bax and enhanced the activity of the antioxidant enzyme catalase in the brain of aged mice. These effects of AI were also confirmed in aged rats (24 months old). Altogether, the present findings indicate that AI can induce neuroprotective effects on age-related alterations in neurobehavioral functions and exerts neurotrophic up-regulatory and anti-apoptotic properties in aged animals.
Assuntos
Envelhecimento/efeitos dos fármacos , Envelhecimento/psicologia , Antidepressivos/farmacologia , Encéfalo/efeitos dos fármacos , Indanos/farmacologia , Nootrópicos/farmacologia , Envelhecimento/metabolismo , Animais , Encéfalo/metabolismo , Transtornos Cognitivos/tratamento farmacológico , Transtornos Cognitivos/metabolismo , Transtorno Depressivo/tratamento farmacológico , Transtorno Depressivo/metabolismo , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Comportamento de Nidação/efeitos dos fármacos , Ratos Sprague-Dawley , Reconhecimento Psicológico/efeitos dos fármacos , Memória Espacial/efeitos dos fármacosRESUMO
Verbal memory impairment in schizophrenia is associated with abnormalities in gamma-aminobutyric acid (GABA)-ergic and brain-derived neurotrophic factor (BDNF) systems. Recent evidence from animal and clinical studies that adding fluvoxamine to antipsychotics alters the expression of transcripts encoding for the GABA-A receptor and BDNF led us to postulate that fluvoxamine augmentation may improve memory in schizophrenia. To test this, we examined the effect of add-on fluvoxamine on verbal memory and other cognitive functions and related it to the expression of mRNA coding for the GABA-A receptor and BDNF in peripheral mononuclear cells (PMC) of schizophrenic patients. Twenty-nine patients completed a 6-week study in which fluvoxamine (100 mg/day) was added to ongoing antipsychotic treatment. Verbal memory, abstraction working memory, object and face recognition, and psychomotor speed and clinical symptoms were assessed at baseline and after 3 and 6 weeks of treatment. Blood samples were taken at baseline and weeks 1, 3, and 6 and PMC was assayed for the GABA-A beta3 receptor and BDNF mRNA by quantitative real-time reverse transcription-PCR. Associative and logical verbal memory improved significantly and showed a significant correlation with changes in PMC BDNF and GABA-A beta3 receptor mRNA, which increased during treatment. Abstraction and object recognition improved, but this did not correlate with PMC measures. Negative and positive symptoms improved significantly; the latter showed significant correlations with changes in PMC measures. Addition of fluvoxamine to antipsychotics improves verbal memory. It is postulated that the mechanism involves enhanced GABA-A receptor/BDNF-dependent synaptic plasticity in the hippocampus.
Assuntos
Antipsicóticos/administração & dosagem , Fator Neurotrófico Derivado do Encéfalo/biossíntese , Leucócitos Mononucleares/metabolismo , Memória/efeitos dos fármacos , Receptores de GABA-A/biossíntese , Esquizofrenia/sangue , Inibidores Seletivos de Recaptação de Serotonina/administração & dosagem , Adulto , Quimioterapia Combinada , Feminino , Fluvoxamina/administração & dosagem , Regulação da Expressão Gênica , Humanos , Leucócitos Mononucleares/efeitos dos fármacos , Masculino , Memória/fisiologia , RNA Mensageiro/biossíntese , Esquizofrenia/tratamento farmacológico , Resultado do Tratamento , Aprendizagem Verbal/efeitos dos fármacos , Aprendizagem Verbal/fisiologia , Adulto JovemRESUMO
Recently, we have designed and synthesized a novel multipotent, brain-permeable iron-chelating drug, VAR10303 (VAR), possessing both propargyl and monoamine oxidase (MAO) inhibitory moieties. The present study was undertaken to determine the multiple pharmacological activities of VAR in neurodegenerative preclinical models. We demonstrate that VAR affords iron chelating/iron-induced lipid-peroxidation inhibitory potency and brain selective MAO-A and MAO-B inhibitory effects, with only limited tyramine-cardiovascular potentiation of blood pressure. The results show that in 6-hydroxydopamine rat (neuroprotection) and in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse (neurorescue) Parkinson's disease models, VAR significantly attenuated the loss of striatal dopamine levels, markedly reduced dopamine turnover, and increased tyrosine-hydroxylase levels. Furthermore, chronic systemic treatment of aged rats with VAR improved cognitive behavior deficits and enhanced the expression levels of neurotrophic factors (e.g., brain-derived neurotrophic factor, glial cell-derived neurotrophic factor, and nerve growth factor), Bcl-2 family members and synaptic plasticity in the hippocampus. Our study indicates that the multitarget compound VAR exerted neuroprotective and neurorestorative effects in animal models of Parkinson's disease and aging, further suggesting that a drug that can regulate multiple brain targets could be an ideal treatment-strategy for age-associated neurodegenerative disorders.
Assuntos
Hidroxiquinolinas/farmacologia , Hidroxiquinolinas/uso terapêutico , Quelantes de Ferro/farmacologia , Quelantes de Ferro/uso terapêutico , Inibidores da Monoaminoxidase/farmacologia , Inibidores da Monoaminoxidase/uso terapêutico , Fármacos Neuroprotetores , Doença de Parkinson/tratamento farmacológico , Envelhecimento , Animais , Cognição , Modelos Animais de Doenças , Dopamina/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Terapia de Alvo Molecular , Monoaminoxidase , Fatores de Crescimento Neural/metabolismo , Plasticidade Neuronal/efeitos dos fármacos , Doença de Parkinson/genética , Doença de Parkinson/metabolismo , Doença de Parkinson/psicologia , Ratos Sprague-DawleyRESUMO
BACKGROUND AND PURPOSE: Neurodegenerative diseases are now recognized to be multifunctional, whereby a heterogeneous set of reactions acts independently or cooperatively, leading eventually to the demise of neurons. This has led our group to design and synthesize the multifunctional, nontoxic, brain-permeable, iron chelator compound M30 with a range of pharmacological properties. Here, we have characterized the molecular targets of M30 in the brains of animal models of type 2 diabetes mellitus (T2DM). EXPERIMENTAL APPROACH: Effects of M30 on molecular mechanisms associated with neuroprotection in the CNS were investigated-in the high-fat diet (HFD) and ob/ob transgenic mouse models of T2DM, using real-time PCR and Western blotting analyses. Brain monoamine oxidase (MAO) activity and catecholamine levels, and peripheral glucose tolerance were assayed after treatment in vivo. KEY RESULTS: M30 increased cerebral levels of insulin and insulin receptor and phosphorylated-GSK-3ß in HFD mice, compared with vehicle-treated HFD mice. In both T2DM mice models, M30 treatment significantly up-regulated cerebral hypoxia-inducible factor (HIF)-1α protein levels and induced the expression of several HIF-1 target genes involved in neuroprotection, glycolysis, neurogenesis, oxidative stress and anti-inflammation. Additionally, M30 inhibited MAO-A and -B activities in the cerebellum. Accordingly, M30 administration significantly reduced brain levels of dopamine metabolites and increased levels of 5-HT and noradrenaline. Glucose tolerance was also improved after M30 treatment in both models of T2DM. CONCLUSIONS AND IMPLICATIONS: In the brain of HFD and ob/ob transgenic mice, M30 exerted a variety of beneficial neuroprotective regulatory effects that may act synergistically to delay or prevent neurodegenerative processes associated with T2DM.
Assuntos
Encéfalo/efeitos dos fármacos , Diabetes Mellitus Tipo 2/metabolismo , Hidroxiquinolinas/farmacologia , Quelantes de Ferro/farmacologia , Animais , Glicemia/metabolismo , Western Blotting , Encéfalo/metabolismo , Dieta Hiperlipídica , Modelos Animais de Doenças , Dopamina/metabolismo , Quinase 3 da Glicogênio Sintase/efeitos dos fármacos , Quinase 3 da Glicogênio Sintase/metabolismo , Glicogênio Sintase Quinase 3 beta , Subunidade alfa do Fator 1 Induzível por Hipóxia/efeitos dos fármacos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Insulina/metabolismo , Camundongos , Camundongos Transgênicos , Monoaminoxidase/efeitos dos fármacos , Monoaminoxidase/metabolismo , Norepinefrina/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Receptor de Insulina/efeitos dos fármacos , Receptor de Insulina/metabolismo , Serotonina/metabolismoRESUMO
Increasing evidence suggests that dysregulation of brain insulin/insulin receptor (InsR) and insulin signaling cascade are associated with the pathogenesis of Alzheimer's disease (AD). Our group has designed and synthesized a series of multi-target iron chelating, brain permeable compounds for AD. One leading multi-target compound, M30 possesses the neuroprotective N-propargyl moiety of the anti-Parkinsonian, monoamine oxidase (MAO)-B inhibitor, rasagiline (Azilect®) and the antioxidant-iron chelating moiety of an 8-hydroxyquinoline derivative of the iron chelator, VK28. Positive outcomes for the behavioral/cognitive and neuroprotective effects of M30 were recently obtained in preclinical experimental studies, regarding pathological aspects relevant to ageing and AD. We report that chronic treatment with M30 (1 and 5 mg/kg p.o; three times a week for 9 months) significantly elevated cortical insulin and InsR transcript and protein expression, respectively and increased the phosphorylated form of glycogen synthase kinase-3ß in the frontal cortex of amyloid precursor protein (APP) and presenilin 1 (PS1) double transgenic mice. In addition, M30 treatment upregulated the levels of hypoxia-inducible factor (HIF)-1α and expression of its target genes involved in glycolysis including, aldolase A, enolase-1 and glucose transporter-1 (Glut-1), in the frontal cortex of APP/PS1 mice. Treatment with M30 also lead to an increase in the hepatic protein expression levels of InsR and Glut-1 and lowered the increase in blood glucose levels following glucose tolerance test. The present findings indicate that the multifunctional iron chelating drug, M30 regulates major brain glucose metabolism parameters and thus, might be beneficial for AD, in which impaired neuronal insulin signaling and Glut expression have been implicated.
Assuntos
Doença de Alzheimer/metabolismo , Transportador de Glucose Tipo 1/biossíntese , Hidroxiquinolinas/administração & dosagem , Subunidade alfa do Fator 1 Induzível por Hipóxia/biossíntese , Insulina/biossíntese , Quelantes de Ferro/administração & dosagem , Doença de Alzheimer/tratamento farmacológico , Precursor de Proteína beta-Amiloide/genética , Animais , Sistemas de Liberação de Medicamentos/métodos , Lobo Frontal/efeitos dos fármacos , Lobo Frontal/metabolismo , Glicólise/efeitos dos fármacos , Glicólise/fisiologia , Masculino , Camundongos , Presenilina-1/genética , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologiaRESUMO
DJ-1 is an oxidative stress sensor that localizes to the mitochondria when the cell is exposed to oxidative stress. DJ-1 mutations that result in gene deficiency are linked to increased risk of Parkinson's disease (PD). Activation of microglial stress conditions that are linked to PD may result in neuronal death. We postulated that DJ-1 deficiency may increase microglial neurotoxicity. We found that down-regulation of DJ-1 in microglia using an shRNA approach increased cell sensitivity to dopamine as measured by secreted pro-inflammatory cytokines such as IL-1ß and IL-6. Furthermore, we discovered that DJ-1-deficient microglia had increased monoamine oxidase activity that resulted in elevation of intracellular reactive oxygen species and nitric oxide leading to increased dopaminergic neurotoxicity. Rasagaline, a monoamine oxidase inhibitor approved for treatment of PD, reduced the microglial pro-inflammatory phenotype and significantly reduced neurotoxicity. Moreover, we discovered that DJ-1-deficient microglia have reduced expression of triggering receptor expressed on myeloid cells 2 (TREM2), previously suggested as a risk factor for pro-inflammation in neurodegenerative diseases. Further studies of DJ-1-mediated cellular pathways in microglia may contribute useful insights into the development of PD providing future avenues for therapeutic intervention