RESUMO
The interaction of the activating transcription factor 6 (ATF6), a key effector of the unfolded protein response (UPR) in the endoplasmic reticulum, with the neuronal calcium sensor Downstream Regulatory Element Antagonist Modulator (DREAM) is a potential therapeutic target in neurodegeneration. Modulation of the ATF6-DREAM interaction with repaglinide (RP) induced neuroprotection in a model of Huntington's disease. Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder with no cure, characterized by the progressive loss of motoneurons resulting in muscle denervation, atrophy, paralysis, and death. The aim of this work was to investigate the potential therapeutic significance of DREAM as a target for intervention in ALS. We found that the expression of the DREAM protein was reduced in the spinal cord of SOD1G93A mice compared to wild-type littermates. RP treatment improved motor strength and reduced the expression of the ALS progression marker collagen type XIXα1 (Col19α1 mRNA) in the quadriceps muscle in SOD1G93A mice. Moreover, treated SOD1G93A mice showed reduced motoneuron loss and glial activation and increased ATF6 processing in the spinal cord. These results indicate that the modulation of the DREAM-ATF6 interaction ameliorates ALS symptoms in SOD1G93A mice.
Assuntos
Esclerose Lateral Amiotrófica , Camundongos , Animais , Camundongos Transgênicos , Esclerose Lateral Amiotrófica/tratamento farmacológico , Esclerose Lateral Amiotrófica/genética , Esclerose Lateral Amiotrófica/metabolismo , Fator 6 Ativador da Transcrição/genética , Fator 6 Ativador da Transcrição/metabolismo , Neuroproteção , Neurônios Motores/metabolismo , Proteínas Interatuantes com Canais de Kv/metabolismo , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismo , Modelos Animais de DoençasRESUMO
Neuroinflammation is involved in the pathogenesis of neurodegenerative diseases such as Alzheimer's disease (AD), and is notably dependent on age. One important inflammatory pathway exerted by innate immune cells of the nervous system in response to danger signals is mediated by inflammasomes (IF) and leads to the generation of potent pro-inflammatory cytokines. The protein "apoptosis-associated speck-like protein containing a caspase recruitment domain" (ASC) modulates IF activation but has also other functions which are crucial in AD. We intended to characterize immunohistochemically ASC and pattern recognition receptors (PRR) of IF in the hippocampus (HP) of the transgenic mouse model Tg2576 (APP), in which amyloid-beta (Aß) pathology is directly dependent on age. We show in old-aged APP a significant amount of ASC in microglia and astrocytes associated withAß plaques, in the absence of PRR described by others in glial cells. In addition, APP developed foci with clusters of extracellular ASC granules not spatiallyrelated to Aß plaques, which density correlated with the advanced age of mice and AD development. Clusters were associated withspecific astrocytes characterized by their enlarged ring-shaped process terminals, ASC content, and frequent perivascular location. Their possible implication in ASC clearance and propagation of inflammation is discussed.
Assuntos
Doença de Alzheimer/metabolismo , Precursor de Proteína beta-Amiloide/genética , Proteínas Adaptadoras de Sinalização CARD/metabolismo , Hipocampo/metabolismo , Doença de Alzheimer/genética , Animais , Grânulos Citoplasmáticos/metabolismo , Modelos Animais de Doenças , Humanos , Masculino , Camundongos , Camundongos TransgênicosRESUMO
Alzheimer's disease (AD) is a progressive degenerative disorder and the most common cause of dementia in aging populations. Although the pathological hallmarks of AD are well defined, currently no effective therapy exists. Liver growth factor (LGF) is a hepatic albumin-bilirubin complex with activity as a tissue regenerating factor in several neurodegenerative disorders such as Parkinson's disease and Friedreich's ataxia. Our aim here was to analyze the potential therapeutic effect of LGF on the APPswe mouse model of AD. Twenty-month-old mice received intraperitoneal (i.p.) injections of 1.6 µg LGF or saline, twice a week during three weeks. Mice were sacrificed one week later, and the hippocampus and dorsal cortex were prepared for immunohistochemical and biochemical studies. LGF treatment reduced amyloid-ß (Aß) content, phospho-Tau/Tau ratio and the number of Aß plaques with diameter larger than 25 µm. LGF administration also modulated protein ubiquitination and HSP70 protein levels, reduced glial reactivity and inflammation, and the expression of the pro-apoptotic protein Bax. Because the administration of this factor also restored cognitive damage in APPswe mice, we propose LGF as a novel therapeutic tool that may be useful for the treatment of AD.
Assuntos
Doença de Alzheimer/etiologia , Doença de Alzheimer/metabolismo , Bilirrubina/genética , Bilirrubina/metabolismo , Suscetibilidade a Doenças , Albumina Sérica Humana/genética , Albumina Sérica Humana/metabolismo , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/genética , Peptídeos beta-Amiloides/metabolismo , Animais , Comportamento Animal , Córtex Cerebral/metabolismo , Córtex Cerebral/patologia , Modelos Animais de Doenças , Expressão Gênica , Hipocampo/metabolismo , Hipocampo/patologia , Humanos , Memória de Curto Prazo , Camundongos , Camundongos Transgênicos , Microglia/metabolismo , Fosforilação , Placa Amiloide/etiologia , Placa Amiloide/metabolismo , Placa Amiloide/patologia , Ubiquitinação , Proteínas tau/metabolismoRESUMO
Since Toll-like receptor 4 (TLR4) mediates brain damage after stroke, development of TLR4 antagonists is a promising therapeutic strategy for this disease. Our aim was to generate TLR4-blocking DNA aptamers to be used for stroke treatment. From a random oligonucleotide pool, we identified two aptamers (ApTLR#1R, ApTLR#4F) with high affinity for human TLR4 by systematic evolution of ligands by exponential enrichment (SELEX). Optimized truncated forms (ApTLR#1RT, ApTLR#4FT) were obtained. Our data demonstrate specific binding of both aptamers to human TLR4 as well as a TLR4 antagonistic effect. ApTLR#4F and ApTLR#4FT showed a long-lasting protective effect against brain injury induced by middle cerebral artery occlusion (MCAO), an effect that was absent in TLR4-deficient mice. Similar effects were obtained in other MCAO models, including in rat. Additionally, efficacy of ApTLR#4FT in a model of brain ischemia-reperfusion in rat supports the use of this aptamer in patients undergoing artery recanalization induced by pharmacological or mechanical interventions. The absence of major toxicology aspects and the good safety profile of the aptamers further encourage their future clinical positioning for stroke therapy and possibly other diseases in which TLR4 plays a deleterious role.
Assuntos
Aptâmeros de Nucleotídeos/administração & dosagem , Infarto da Artéria Cerebral Média/tratamento farmacológico , Acidente Vascular Cerebral/prevenção & controle , Receptor 4 Toll-Like/metabolismo , Animais , Aptâmeros de Nucleotídeos/farmacologia , Modelos Animais de Doenças , Humanos , Infarto da Artéria Cerebral Média/complicações , Infarto da Artéria Cerebral Média/etiologia , Camundongos , Ratos , Técnica de Seleção de Aptâmeros , Transdução de Sinais , Acidente Vascular Cerebral/genética , Acidente Vascular Cerebral/metabolismoRESUMO
Friedreich's ataxia (FA) is a severe disorder with autosomal recessive inheritance that is caused by the abnormal expansion of GAA repeat in intron 1 of FRDA gen. This alteration leads to a partial silencing of frataxin transcription, causing a multisystem disorder disease that includes neurological and non-neurological damage. Recent studies have proven the effectiveness of neurotrophic factors in a number of neurodegenerative diseases. Therefore, we intend to determine if liver growth factor (LGF), which has a demonstrated antioxidant and neuroprotective capability, could be a useful therapy for FA. To investigate the potential therapeutic activity of LGF we used transgenic mice of the FXNtm1MknTg (FXN)YG8Pook strain. In these mice, intraperitoneal administration of LGF (1.6 µg/mouse) exerted a neuroprotective effect on neurons of the lumbar spinal cord and improved cardiac hypertrophy. Both events could be the consequence of the increment in frataxin expression induced by LGF in spinal cord (1.34-fold) and heart (1.2-fold). LGF also upregulated by 2.6-fold mitochondrial chain complex IV expression in spinal cord, while in skeletal muscle it reduced the relation oxidized glutathione/reduced glutathione. Since LGF partially restores motor coordination, we propose LGF as a novel factor that may be useful in the treatment of FA.
Assuntos
Bilirrubina/uso terapêutico , Ataxia de Friedreich/tratamento farmacológico , Ataxia de Friedreich/metabolismo , Proteínas de Ligação ao Ferro/metabolismo , Albumina Sérica/uso terapêutico , Animais , Western Blotting , Glutationa/metabolismo , Coração/efeitos dos fármacos , Imuno-Histoquímica , Proteínas de Ligação ao Ferro/genética , Masculino , Camundongos , Camundongos Transgênicos , Estresse Oxidativo/efeitos dos fármacos , Albumina Sérica Humana , Medula Espinal/efeitos dos fármacos , Medula Espinal/metabolismo , FrataxinaRESUMO
Cerebellar ataxias (CA) comprise a heterogeneous group of neurodegenerative diseases characterized by a lack of motor coordination. They are caused by disturbances in the cerebellum and its associated circuitries, so the major therapeutic goal is to correct cerebellar dysfunction. Neurotrophic factors enhance the survival and differentiation of selected types of neurons. Liver growth factor (LGF) is a hepatic mitogen that shows biological activity in neuroregenerative therapies. We investigate the potential therapeutic activity of LGF in the 3-acetylpiridine (3-AP) rat model of CA. This model of CA consists in the lesion of the inferior olive-induced by 3-AP (40 mg/kg). Ataxic rats were treated with 5 µg/rat LGF or vehicle during 3 weeks, analyzing: (a) motor coordination by using the rota-rod test; and (b) the immunohistochemical and biochemical evolution of several parameters related with the olivo-cerebellar function. Motor coordination improved in 3-AP-lesioned rats that received LGF treatment. LGF up-regulated NeuN and Bcl-2 protein levels in the brainstem, and increased calbindin expression and the number of neurons receiving calbindin-positive projections in the cerebellum. LGF also reduced extracellular glutamate and GABA concentrations and microglia activation in the cerebellum. In view of these results, we propose LGF as a potential therapeutic agent in cerebellar ataxias.
Assuntos
Bilirrubina/farmacologia , Ataxia Cerebelar/tratamento farmacológico , Fármacos Neuroprotetores/farmacologia , Albumina Sérica/farmacologia , Animais , Antígenos Nucleares/metabolismo , Calbindinas/metabolismo , Diferenciação Celular/efeitos dos fármacos , Ataxia Cerebelar/metabolismo , Cerebelo/efeitos dos fármacos , Cerebelo/metabolismo , Modelos Animais de Doenças , Feminino , Ácido Glutâmico/metabolismo , Microglia/efeitos dos fármacos , Microglia/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Piridinas/farmacologia , Ratos , Ratos Sprague-Dawley , Albumina Sérica Humana , Ácido gama-Aminobutírico/metabolismoRESUMO
Cholesterol biosynthesis inhibitors (statins) protect hypercholesterolemic patients against developing active tuberculosis, suggesting that these drugs could help the host to control the pathogen at the initial stages of the disease. This work studies the effect of fluvastatin on the early response of healthy peripheral blood mononuclear cells (PBMCs) to inactivated Mycobacterium tuberculosis (Mtb) H37Ra. We found that in fluvastatin-treated PBMCs, most monocytes/macrophages became foamy cells that overproduced NLRP3 inflammasome components in the absence of immune stimulation, evidencing important cholesterol metabolism/immunity connections. When both fluvastatin-treated and untreated PBMCs were exposed to Mtb H37Ra, a small subset of macrophages captured large amounts of bacilli and died, concentrating the bacteria in necrotic areas. In fluvastatin-untreated cultures, most of the remaining macrophages became epithelioid cells that isolated these areas of cell death in granulomatous structures that barely produced IFNγ. By contrast, in fluvastatin-treated cultures, foamy macrophages surrounded the accumulated bacteria, degraded them, markedly activated caspase-1 and elicited a potent IFNγ/cytotoxic response. In rabbits immunized with the same bacteria, fluvastatin increased the tuberculin test response. We conclude that statins may enhance macrophage efficacy to control Mtb, with the help of adaptive immunity, offering a promising tool in the design of alternative therapies to fight tuberculosis.
Assuntos
Inibidores de Hidroximetilglutaril-CoA Redutases , Mycobacterium tuberculosis , Tuberculose , Animais , Humanos , Coelhos , Fluvastatina/metabolismo , Células Espumosas/metabolismo , Leucócitos Mononucleares/metabolismo , Macrófagos/metabolismo , Colesterol/metabolismoRESUMO
Parkinson's disease is a neurodegenerative disorder characterized by the progressive death of dopaminergic (DA) neurons in the substantia nigra (SN), which leads to a loss of the neurotransmitter dopamine in the basal ganglia. Current treatments relieve the symptoms of the disease, but none stop or delay neuronal degeneration. Liver growth factor (LGF) is an albumin-bilirubin complex that stimulates axonal growth in the striatum and protects DA neurons in the SN of 6-hydroxydopamine-lesioned rats. Our previous results suggested that these effects observed in vivo are mediated by microglia and/or astrocytes. To determine if these cells are LGF targets, E14 (embryos from Sprague Dawley rats of 14 days) rat mesencephalic glial cultures were used. Treatment with 100 pg/mL of LGF up-regulated the mitogen-activated protein kinases (MAPKs) extracellular signal-regulated kinases 1/2 (ERK1/2) and the cyclic AMP response element binding protein (CREB) phosphorylation in glial cultures, and it increased the microglia marker Iba1 and tumor necrosis factor alpha (TNF-alpha) protein levels. The treatment of E14 midbrain neurons with a glial-conditioned medium from LGF-treated glial cultures (GCM-LGF) prevented the loss of DA neurons caused by 6-hydroxy-dopamine. This neuroprotective effect was not observed when GCM-LGF was applied in the presence of a blocking antibody of TNF-alpha activity. Altogether, our findings strongly suggest the involvement of microglia and TNF-alpha in the neuroprotective action of LGF on DA neurons observed in vitro.
RESUMO
Nitrones have a well-recognized capacity as spin-traps and are considered powerful free radical scavengers, which are two important issues in hypoxia-induced oxidative stress and cell death in brain ischemia. Consequently, nitrones have been proposed as therapeutic agents in acute ischemic stroke (AIS). In this paper, we update the biological and pharmacological characterization of ISQ-201, a previously identified cholesteronitrone hybrid with antioxidant and neuroprotective activity. This study characterizes ISQ-201 as a neuroprotective agent against the hypoxia-induced ischemic injury. Transitory four-vessel occlusion and middle cerebral artery occlusion (tMCAO) were used to induce cerebral ischemia. Functional outcomes were determined using neurofunctional tests. Infarct area, neuronal death, and apoptosis induction were evaluated. In addition, ISQ-201 reactivity towards free radicals was studied in a theoretical model. ISQ-201 significantly decreased the ischemia-induced neuronal death and apoptosis, in a dose-dependent manner, showing its therapeutic effect when administered up until 6 h after post-ischemic reperfusion onset, effects that remained after 3 months from the ischemic episode. Furthermore, ISQ-201 significantly reduced infarct volume, leading to recovery of the motor function in the tMCAO model. Finally, the theoretical study confirmed the reactivity of ISQ-201 towards hydroxyl radicals. The results reported here prompted us to suggest ISQ-201 as a promising candidate for the treatment of AIS.
RESUMO
The high potassium-evoked taurine efflux in the nervous tissue has been entirely considered to be the result of the cell swelling produced by KCl influx via passive Donnan forces. However, the extracellular taurine increase evoked in the hippocampus by applying 6-100 mM KCl through microdialysis probes, which saturates at a concentration of 25 mM KCl, is not congruent with the mentioned osmosensitive release of taurine stimulated by high potassium. Therefore, we studied whether the taurine release elicited by different high KCl concentrations (25, 50, 75, or 100 mM) was blocked under hypertonic conditions (+100 mM sucrose). Taurine release stimulated by 25 mM KCl was totally osmosensitive, but that released by higher KCl concentrations became progressively osmoresistant, achieving more than the 60% of the extracellular taurine enhancement during 100 mM KCl perfusion. The osmoresistant taurine release evoked by 100 mM KCl perfusion was partially reduced by a solution without Ca(2+) and with high Mg(2+), or by D,L-2-amino-5-phosphopentanoic acid, an N-methyl-D-aspartic acid (NMDA) receptor antagonist. Moreover, the release of taurine induced by a hypoosmotic solution was reduced by the presence of either high K(+) (75 mM) or NMDA (100 microM). These results indicate that although moderately high [K(+)] evoke the osmosensitive release of taurine, higher [K(+)] inhibit it and trigger the release of taurine by an osmoresistant mechanism. This last component is partially mediated by NMDA receptors activated by the glutamate released during potassium-induced depolarization.
Assuntos
Hipocampo/efeitos dos fármacos , Cloreto de Potássio/farmacologia , Taurina/metabolismo , Equilíbrio Hidroeletrolítico/efeitos dos fármacos , Análise de Variância , Animais , Relação Dose-Resposta a Droga , Antagonistas de Aminoácidos Excitatórios/farmacologia , Espaço Extracelular/efeitos dos fármacos , Hipocampo/metabolismo , Soluções Hipertônicas/farmacologia , Masculino , Microdiálise/métodos , N-Metilaspartato/farmacologia , Ratos , Ratos Sprague-Dawley , Valina/análogos & derivados , Valina/farmacologiaRESUMO
Neural stem cells with self-renewal and multilineage potential persist in the subventricular zone of the adult mammalian forebrain. These cells remain relatively quiescent but, under certain conditions, can be stimulated, giving rise to new neurons. Liver growth factor (LGF) is a mitogen for liver cells that shows biological activity in extrahepatic sites and is useful for neuroregenerative therapies. The aim of this study was to investigate the potential neurogenic activity of LGF in the 6-hydroxydopamine rat model of Parkinson's disease. Proliferation was significantly increased in the subventricular zone and denervated striatum of rats receiving ICV LGF infusions, and 25% of the proliferating cells were doublecortin-positive neurons. Doublecortin-positive cells with the morphology of migrating neuroblasts were also observed in the dorsal and ventral regions of the striatum of LGF-infused animals. Moreover, some newly generated cells were neuronal nuclei-positive mature neurons. LGF also stimulated microglia and induced astrogliosis, both phenomena associated with generation and migration of new neurons in the adult brain. In summary, our study shows that LGF stimulates neurogenesis when applied intraventricularly in 6-hydroxydopamine-lesioned rats. Considering that this factor also promotes neuronal migration into damaged tissue, we propose LGF as a novel factor useful for neuronal replacement in neurodegenerative diseases.
Assuntos
Bilirrubina/farmacologia , Mitógenos/farmacologia , Neurônios/efeitos dos fármacos , Oxidopamina , Doença de Parkinson Secundária/patologia , Albumina Sérica/farmacologia , Células-Tronco/efeitos dos fármacos , Animais , Bilirrubina/administração & dosagem , Movimento Celular , Proliferação de Células , Ventrículos Cerebrais/efeitos dos fármacos , Ventrículos Cerebrais/patologia , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/patologia , Proteína Duplacortina , Feminino , Injeções Intraventriculares , Macrófagos/efeitos dos fármacos , Macrófagos/fisiologia , Microglia/efeitos dos fármacos , Microglia/fisiologia , Mitógenos/administração & dosagem , Atividade Motora/efeitos dos fármacos , Neurogênese , Neurônios/fisiologia , Doença de Parkinson Secundária/induzido quimicamente , Doença de Parkinson Secundária/fisiopatologia , Ratos , Ratos Sprague-Dawley , Albumina Sérica/administração & dosagem , Albumina Sérica Humana , Células-Tronco/fisiologia , Comportamento Estereotipado/efeitos dos fármacos , Tirosina 3-Mono-Oxigenase/metabolismoRESUMO
We describe herein the synthesis and neuroprotective capacity of an array of 31 compounds comprising quinolyloximes, quinolylhydrazones, quinolylimines, QNs, and related heterocyclic azolylnitrones. Neuronal cultures subjected to oxygen-glucose deprivation (OGD), as experimental model for ischemic conditions, were treated with our molecules at the onset of recovery period after OGD and showed that most of these QNs, but not the azo molecules, improved neuronal viability 24 h after recovery. Especially, QN ( Z)- N-tert-butyl-1-(2-chloro-6-methoxyquinolin-3-yl)methanimine oxide (23) was shown as a very potent neuroprotective agent. Antioxidant analysis based on the ability of QN 23 to trap different types of toxic radical oxygenated species supported and confirmed its strong neuroprotective capacity. Finally, QN 23 showed also neuroprotection induction in two in vivo models of cerebral ischemia, decreasing neuronal death and reducing infarct size, allowing us to conclude that QN 23 can be considered as new lead-compound for ischemic stroke treatment.
Assuntos
Sequestradores de Radicais Livres/uso terapêutico , Iminas/uso terapêutico , Ataque Isquêmico Transitório/tratamento farmacológico , Fármacos Neuroprotetores/uso terapêutico , Quinolinas/uso terapêutico , Animais , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Apoptose/efeitos dos fármacos , Células Cultivadas , Sequestradores de Radicais Livres/síntese química , Sequestradores de Radicais Livres/farmacologia , Iminas/síntese química , Iminas/farmacologia , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/farmacologia , Quinolinas/síntese química , Quinolinas/farmacologia , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismoRESUMO
Stroke is one of the leading causes of death worldwide and while there is increasing evidence that a Mediterranean diet might decrease the risk of a stroke, the effects of dietary fat composition on stroke outcomes have not been fully explored. We hypothesize that the brain damage provoked by a stroke would be different depending on the source of dietary fat. To test this, male C57BL/6J mice were fed for 4 weeks with a standard low-fat diet (LFD), a high-fat diet (HFD) rich in saturated fatty acids (HFD-SFA), an HFD containing monounsaturated fatty acids (MUFAs) from olive oil (HFD-OO), or an HFD containing MUFAs from olive oil plus polyunsaturated fatty acids (PUFAs) docosahexaenoic acid/eicosapentaenoic acid (DHA/EPA) (HFD-OO-ω3). These mice were then subjected to transient middle cerebral artery occlusion (tMCAo). Behavioural tests and histological analyses were performed 24 and/or 48 h after tMCAo in order to elucidate the impact of these diets with different fatty acid profiles on the ischemic lesion and on neurological functions. Mice fed with HFD-OO-ω3 displayed better histological outcomes after cerebral ischemia than mice that received an HFD-SFA or LFD. Furthermore, PUFA- and MUFA-enriched diets improved the motor function and neurological performance of ischemic mice relative to those fed with an LFD or HFD-SFA. These findings support the use of DHA/EPA-omega-3-fatty acid supplementation and olive oil as dietary source of MUFAs in order to reduce the damage and protect the brain when a stroke occurs.
Assuntos
Isquemia Encefálica/tratamento farmacológico , Ácidos Docosa-Hexaenoicos/farmacologia , Ácido Eicosapentaenoico/farmacologia , Azeite de Oliva/farmacologia , Animais , Antioxidantes/metabolismo , Comportamento Animal , Dieta Hiperlipídica/efeitos adversos , Ácidos Docosa-Hexaenoicos/administração & dosagem , Ingestão de Alimentos , Ácido Eicosapentaenoico/administração & dosagem , Marcha , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Artéria Cerebral Média , Azeite de Oliva/administração & dosagem , Redução de Peso/efeitos dos fármacosRESUMO
Stroke is one of the main causes of death and disability in the elderly. In the last few years, there has been increasing evidence that suggests the influence of the diet on the decrease of stroke risk. Probably, because of the presence of bioactive components with beneficial effects such as antioxidant or anti-inflammatory properties. This article reviews several dietary bioactive compounds from studies in models of cerebral ischemia that have obtained promising results decreasing cerebral damage. We propose that many of these compounds present in diet could be good candidates to test new neuroprotection approaches focused on reducing the damage and protecting the brain before stroke occurs.
Assuntos
Dieta Mediterrânea , Neuroproteção/fisiologia , Acidente Vascular Cerebral/dietoterapia , Acidente Vascular Cerebral/metabolismo , Animais , Ácidos Graxos Ômega-3/administração & dosagem , Humanos , Ácido Oleico/administração & dosagem , Polifenóis/administração & dosagem , Acidente Vascular Cerebral/prevenção & controleRESUMO
There is a need to develop additional effective therapies for ischemic stroke. Nitrones, which were first developed as reactive oxygen species (ROS)-trapping compounds, have been proposed as neuroprotective agents for ischemic stroke, a ROS-related disorder. The previous reported ROS-trapping compound, quinolyl nitrone RP19, is here being assayed to induce neuroprotection to ischemia-reperfusion injury in three experimental ischemia models: (i) oxygen-glucose deprivation (OGD) on primary neuronal cultures; (ii) transient global cerebral ischemia in four-vessel occlusion model; and (iii) transient focal cerebral ischemia in middle cerebral artery occlusion (tMCAO) model. RP19 (50 µM) induced long-term neuroprotection at 5 days of recovery after OGD in primary neuronal cultures, evaluated by cell viability assay, and decreased both ROS formation and lipid peroxidation upon recovery after OGD. Furthermore, treatment of animals with RP19 at the onset of reperfusion after either global or focal ischemia, at the dose range that was demonstrated to be neuroprotective in neuronal cultures, decreased neuronal death and apoptosis induction, reduced the size of infarct, and improved the neurological deficit scores after 48 h or 5 days of reperfusion after ischemia. The molecule proposed, quinolyl nitrone RP19, induced substantial neuroprotection on experimental ischemia in neuronal cells, and against ischemic injury following transient brain ischemia in treated animals. This molecule may have potential therapeutic interest in ischemic stroke and to reduce the reoxygenation-induced injury after induced reperfusion.
Assuntos
Isquemia Encefálica/tratamento farmacológico , Fármacos Neuroprotetores/farmacologia , Óxidos de Nitrogênio/farmacologia , Quinolinas/farmacologia , Acidente Vascular Cerebral/tratamento farmacológico , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Morte Celular/efeitos dos fármacos , Modelos Animais de Doenças , Infarto da Artéria Cerebral Média/tratamento farmacológico , Neurônios/efeitos dos fármacos , Ratos Sprague-DawleyRESUMO
Liver growth factor (LGF) is a mitogen for liver cells that shows biological activity in extrahepatic sites and may be useful for neuroregenerative therapies. The aim of this work was to investigate the effects of the intrastriatal (IS) infusion of LGF in the 6-hydroxydopamine rat model of Parkinson's disease. Tyrosine hydroxylase-positive innervation was significantly increased in the dopamine-denervated striatum of rats receiving intrastriatal LGF infusions (160 ng/day/rat x 15 days) as compared with a vehicle-infused group. There was no evidence of dopaminergic neurogenesis in the striatum or substantia nigra in any experimental group at the times studied. However, in those animals undergoing IS-LGF infusion for 48 hr, we found a significant increase in both microglial proliferation and in the number of microglial cells that acquired the ameboid morphology. This is characteristic of activated microglia/macrophages that has been reported to play an important role in dopamine terminal sprouting. In summary, our study shows that IS infusion of LGF stimulates the outgrowth of tyrosine hydroxylase-positive terminals in the striatum of 6-hydroxydopamine-treated rats. As apomorphine-induced rotational behavior was also reduced in these animals, we propose LGF as a novel factor that, when delivered to the striatum, may be useful in the treatment of Parkinson's disease.
Assuntos
Bilirrubina/farmacologia , Corpo Estriado/efeitos dos fármacos , Dopamina/metabolismo , Substâncias de Crescimento/farmacologia , Atividade Motora/efeitos dos fármacos , Doença de Parkinson Secundária/fisiopatologia , Terminações Pré-Sinápticas/fisiologia , Albumina Sérica/farmacologia , Animais , Bilirrubina/administração & dosagem , Corpo Estriado/metabolismo , Corpo Estriado/patologia , Feminino , Microglia/efeitos dos fármacos , Microglia/patologia , Oxidopamina , Doença de Parkinson Secundária/induzido quimicamente , Doença de Parkinson Secundária/patologia , Terminações Pré-Sinápticas/metabolismo , Ratos , Ratos Sprague-Dawley , Albumina Sérica/administração & dosagem , Albumina Sérica Humana , Comportamento Estereotipado/efeitos dos fármacos , Tirosina 3-Mono-Oxigenase/metabolismoRESUMO
Liver growth factor (LGF) is a hepatic mitogen purified by our group in 1986. In the following years we demonstrated its activity both in "in vivo" and "in vitro" systems, stimulating hepatocytes mitogenesis as well as liver regeneration in several models of liver injury. Furthermore, we established its chemical composition (albumin-bilirubin complex) and its mitogenic actions in liver. From 2000 onwards we used LGF as a tissue regenerating factor in several models of extrahepatic diseases. The use of Liver growth factor as a neural tissue regenerator has been recently protected (Patent No US 2014/8,642,551 B2). LGF administration stimulates neurogenesis and neuron survival, promotes migration of newly generated neurons, and induces the outgrowth of striatal dopaminergic terminals in 6-hidroxydopamine-lesioned rats. Furthermore, LGF treatment raises striatal dopamine levels and protects dopaminergic neurons in hemiparkinsonian animals. LGF also stimulates survival of grafted foetal neural stem cells in the damaged striatum, reduces rotational behaviour and improves motor coordination. Interestingly, LGF also exerts a neuroprotective role both in an experimental model of cerebellar ataxia and in a model of Friedrich´s ataxia. Microglia seem to be the cellular target of LGF in the CNS. Moreover, the activity of the factor could be mediated by the stimulation of MAPK´s signalling pathway and by regulating critical proteins for cell survival, such as Bcl-2 and phospho-CREB. Since the factor shows neuroprotective and neurorestorative effects we propose LGF as a patented novel therapeutic tool that may be useful for the treatment of Parkinson´s disease and cerebellar ataxias. Currently, our studies have been extended to other neurological disorders such as Alzheimer's disease (Patent No: US 2014/0113859 A1).
Assuntos
Bilirrubina/uso terapêutico , Regeneração Nervosa/efeitos dos fármacos , Doenças Neurodegenerativas/tratamento farmacológico , Albumina Sérica/uso terapêutico , Animais , Bilirrubina/farmacologia , Modelos Animais de Doenças , Humanos , Doenças Neurodegenerativas/fisiopatologia , Albumina Sérica/farmacologia , Albumina Sérica HumanaRESUMO
Liver growth factor (LGF) is a hepatic mitogen purified some years ago that promotes proliferation of different cell types and the regeneration of damaged tissues, including brain tissue. Considering the possibility that LGF could be used as a therapeutic agent in Parkinson's disease, we analyzed its potential neuroregenerative and/or neuroprotective activity when peripherally administered to unilaterally 6-hydroxydopamine (6-OHDA)-lesioned rats. For these studies, rats subjected to nigrostriatal lesions were treated intraperitoneally twice a week with LGF (5 microg/rat) for 3 weeks. Animals were sacrificed 4 weeks after the last LGF treatment. The results show that LGF stimulates sprouting of tyrosine hydroxylase-positive terminals and increases tyrosine hydroxylase and dopamine transporter expression, as well as dopamine levels in the denervated striatum of 6-OHDA-lesioned rats. In this structure, LGF activates microglia and raises tumor necrosis factor-alpha protein levels, which have been reported to have a role in neuroregeneration and neuroprotection. Besides, LGF stimulates the phosphorylation of MAPK/ERK1/2 and CREB, and regulates the expression of proteins which are critical for cell survival such as Bcl2 and Akt. Because LGF partially protects dopamine neurons from 6-OHDA neurotoxicity in the substantia nigra, and reduces motor deficits in these animals, we propose LGF as a novel factor that may be useful in the treatment of Parkinson's disease.
Assuntos
Bilirrubina/farmacologia , Corpo Estriado/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Doença de Parkinson Secundária/tratamento farmacológico , Albumina Sérica/farmacologia , Substância Negra/efeitos dos fármacos , Animais , Comportamento Animal/efeitos dos fármacos , Bilirrubina/isolamento & purificação , Corpo Estriado/metabolismo , Corpo Estriado/patologia , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Modelos Animais de Doenças , Dopamina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Dopamina/genética , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Feminino , Regulação da Expressão Gênica , Proteína Quinase 1 Ativada por Mitógeno/genética , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/genética , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Fármacos Neuroprotetores/isolamento & purificação , Oxidopamina , Doença de Parkinson Secundária/induzido quimicamente , Doença de Parkinson Secundária/genética , Doença de Parkinson Secundária/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Albumina Sérica/isolamento & purificação , Albumina Sérica Humana , Transdução de Sinais , Substância Negra/metabolismo , Substância Negra/patologia , Fator de Necrose Tumoral alfa/biossíntese , Fator de Necrose Tumoral alfa/metabolismo , Tirosina 3-Mono-Oxigenase/genética , Tirosina 3-Mono-Oxigenase/metabolismo , Proteína de Morte Celular Associada a bcl/genética , Proteína de Morte Celular Associada a bcl/metabolismoRESUMO
Neural stem cells (NSCs) with self-renewal and multilineage potential are considered good candidates for cell replacement of damaged nerve tissue. Several studies have focused on the ability of the neurotrophic factors coadministration to improve the efficiency of grafted NSCs. Liver growth factor (LGF) is an hepatic mitogen that promotes regeneration of damaged tissues, including brain tissue. It has neurogenic activity and has partially restored the nigrostriatal dopaminergic system in an experimental model of Parkinson's disease. Present results demonstrate that in the dopamine- depleted striatum of 6-hydroxydopamine-lesioned rats, grafted NSCs retained their ability to differentiate into neurons, astrocytes, and oligodendrocytes. NSCs also differentiated into microglia/macrophages and endothelial cells. Thus, 23 ± 5.6% of them were inmunoreactive for isolectin IB4, and a small population integrated into blood vessels, showing an endothelial-like morphology. Intrastriatal infusion of LGF promoted the viability of the implants, and favored their differentiation to an endothelial-like phenotype. Moreover, LGF infusion raised the expression of the anti-apoptotic protein Bcl-2 by 3.9 ± 0.9 fold without affecting the levels of the pro-apoptotic protein Bax. Since LGF-treated rats also showed a significant reduction in apomorphine-induced rotational behavior, our results suggest that administration of this factor might be a convenient treatment for Parkinson's disease cell replacement therapies based on NSCs transplantation.