RESUMEN
Objectives: The mechanism behind the progression of Mild Cognitive Impairment (MCI) to Alzheimer's disease (AD) remains poorly understood. However some evidence pointed out that the co-occurrence of metabolic conditions affecting glucose homeostasis, as type 2 diabetes mellitus (T2DM), may be an important catalyst in this context. Notably, candidate drugs which modulate common pathways in the development of MCI-to-AD mediated by T2DM may offer likely therapy for AD. Nonetheless, limited pharmacological alternatives that modulate common pathways in T2DM, MCI, and AD are available. In the recent decades, studies have shown that resveratrol may act as a neuroprotective compound, but little is known about its potential in improving cognitive and metabolic aspects associated with AD progression mediated by the co-association between TDM2-MCI.Methods: In this review, we discuss possible protective mechanisms of resveratrol on shared pathways associated with AD progression mediated by T2DM-MCI co-occurrence.Results: Some studies indicated that insulin resistance and hyperglycemia may be also a T2DM risk factor for the progression of MCI-to-AD, promoting alterations in metabolic pathways associated with neuronal plasticity, and increasing pro-inflammatory environment. Interestingly, basic research and clinical trials indicate that resveratrol may modulate those pathways, showing a potential neuroprotective effect of this polyphenol.Conclusion: Therefore, there is not enough clinical data supporting the translational therapeutic use of resveratrol in this scenario.
Asunto(s)
Enfermedad de Alzheimer , Disfunción Cognitiva , Diabetes Mellitus Tipo 2 , Enfermedades Neurodegenerativas , Humanos , Resveratrol/uso terapéutico , Enfermedades Neurodegenerativas/tratamiento farmacológico , Enfermedades Neurodegenerativas/complicaciones , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/prevención & control , Enfermedad de Alzheimer/complicaciones , Disfunción Cognitiva/tratamiento farmacológico , Disfunción Cognitiva/complicacionesRESUMEN
Studies revealed that the venom of the Brazilian "armed" spider Phoneutria nigriventer contains potent neurotoxins that caused excitatory symptoms such as salivation, lachrymation, priapism, convulsions, flaccid and spastic paralysis. It was also reported that the main mechanism of action of those neurotoxins are effects on ion channels such as inhibition of the inactivation of Na+ channels, blockage of K+ channels and blockage of calcium channels. The venom from Phoneutria keyserlingi, as might be expected, contains a series of polypeptides that are very similar, but not identical, to the proteins previously obtained from the venom of P. nigriventer in terms of their amino acid sequences and biological activities. We evaluated the effects of some of the toxins of P. nigriventer and P. keyserlingi on glutamate release and the decrease in [Ca2+]i by using synaptosomes of rat brain cortices and fluorimetric assays. Sequence comparisons between the Phoneutria toxins of both the species showed great similarity in the location of cysteine residues. However, thus far, no pharmacological assays were performed to evaluate the extension of those biochemical modifications. Our results showed that differences between the amino acid sequences of Phoneutria toxins of both the species lead to the significant changes in the pharmacological properties of these toxins.
Asunto(s)
Calcio/metabolismo , Ácido Glutámico/metabolismo , Venenos de Araña/farmacología , Sinaptosomas/metabolismo , Secuencia de Aminoácidos , Animales , Canales de Calcio/metabolismo , Fluorometría , Canales Iónicos/antagonistas & inhibidores , Canales Iónicos/metabolismo , Datos de Secuencia Molecular , Canales de Potasio/metabolismo , Ratas , Alineación de Secuencia , Homología de Secuencia de Aminoácido , Canales de Sodio/metabolismo , Arañas/metabolismoRESUMEN
Gyroxin is a thrombin-like toxin obtained from the venom of the South American rattlesnake, Crotalus durissus terrificus. Literature has reported "gyroxin syndrome" characterized, in mice, as series of aberrant motor behavior, known as barrel rotation, mainly after intraperitoneal administration. Despites several studies, a physiological mechanism of "gyroxin syndrome" are still not completely understood. In this context, alterations on the central nervous system (CNS), especially causing neurotoxic events, are pointed out as likely candidates. Then, we decided to investigate whether gyroxin induces alterations in glutamate release, one of the most important neurotransmitter involved in neurotoxicity. For that, we performed all experiments, in vitro, using a model of mice brain cortical synaptosomes. Notably, our results indicate that the administration of gyroxin on purified presynaptic brain cortical terminals resulted in an extracellular Ca2+- dependent raise in glutamate release. Indeed, our results also showed that gyroxin increases intrasynaptosomal calcium (Ca2+) levels through acting on voltage gated calcium channels (VGCC), specifically N and P/Q subtypes. Moreover, our data show that gyroxin increases exocytosis rate. Interestingly, these data suggest that gyroxin might induce neurotoxicity by increasing glutamate levels. However, future investigations are needed in order to elucidate the nature of the following events.
Asunto(s)
Calcio/metabolismo , Corteza Cerebral/efectos de los fármacos , Venenos de Crotálidos/farmacología , Ácido Glutámico/metabolismo , Neurotoxinas/farmacología , Sinaptosomas/efectos de los fármacos , Animales , Corteza Cerebral/metabolismo , Ratones , Sinaptosomas/metabolismoRESUMEN
Cognitive dysfunction is a major sign of cerebral malaria (CM). However, the underlying mechanisms of CM cognitive outcome remain poorly understood. A body of evidence suggests that adult neurogenesis may play a role in learning and memory processes. It has also been reported that these phenomena can be regulated by the immune system. We hypothesized that memory dysfunction in CM results from hippocampal neurogenesis impairment mediated by the deregulated immune response during the acute phase of CM. C57Bl/6 mice were infected with Plasmodium berghei ANKA (PbA) strain, using a standardized inoculation of 10(6) parasitized erythrocytes. Long-term working memory was evaluated using the novel object recognition test. The mRNA expression of brain-derived neurotrophic factor (BDNF), tropomyosin-receptor-kinase (TRK-B) and nerve growth factor (NGF) in the frontal cortex and hippocampus was estimated by real-time polymerase chain reaction (PCR). The protein levels of cytokine interleukin-2 (IL-2), IL-4, IL-6, IL-10, interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), and CCL11 and neurotrophins BDNF and NGF were determined using a cytometric bead array (CBA) kit or enzyme-linked immunosorbent assay. Cell viability in the hippocampus was analyzed by Confocal Microscopy. Neurogenesis in the dentate gyrus was determined through quantification of doublecortin (DCX) positive cells. PbA-infected mice presented working memory impairment on day 5 post-infection. At this same time point, CM mice exhibited a decrease in DCX-positive cells in the dentate gyrus in parallel with increased cell death and elevated inflammatory cytokines (IL-6, TNF-α, IFN-γ and CCL11) in the hippocampus and frontal cortex. A significant reduction of BDNF mRNA expression was also found. IL-6 and TNF-α correlated negatively with BDNF and NGF levels in the hippocampus of CM mice. In summary, we provide further evidence that neuroinflammation following PbA-infection influences neurotrophin expression, impairs adult hippocampal neurogenesis and increases hippocampal cell death in association with memory impairment following CM course. The current study identified potential mediators of memory impairment in CM.
Asunto(s)
Muerte Celular/fisiología , Trastornos del Conocimiento/fisiopatología , Hipocampo/fisiopatología , Malaria Cerebral/fisiopatología , Neurogénesis/fisiología , Plasmodium berghei , Animales , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Trastornos del Conocimiento/patología , Citocinas/metabolismo , Modelos Animales de Enfermedad , Proteína Doblecortina , Femenino , Lóbulo Frontal/patología , Lóbulo Frontal/fisiopatología , Hipocampo/patología , Malaria Cerebral/patología , Trastornos de la Memoria/patología , Trastornos de la Memoria/fisiopatología , Ratones Endogámicos C57BL , ARN Mensajero/metabolismo , Receptor trkB/metabolismoRESUMEN
Some of the complexities of surgical interventions include neurological and psychiatric disturbances. Prompt identification and early treatment of these complications are pivotal in achieving excellent clinical results. Recognizing major adverse events such as stroke, seizure or delirium is usually straight-forward, however the discovery of less frequent or more subtle post-operative changes such as cognitive dysfunction might be delayed due to lack of appropriate diagnostic tools. This review summarizes biological markers that can be utilized as surrogates in evaluating surgery-related neuro-psychiatric disorders.
Asunto(s)
Procedimientos Quirúrgicos Cardíacos/efectos adversos , Trastornos del Conocimiento/metabolismo , Delirio/metabolismo , Cardiopatías/cirugía , Animales , Biomarcadores/metabolismo , Trastornos del Conocimiento/etiología , Delirio/etiología , Cardiopatías/metabolismo , Humanos , Periodo Perioperatorio , Factores de RiesgoRESUMEN
BACKGROUND AND PURPOSE: Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by a polyglutamine expansion in the huntingtin protein. We have previously demonstrated that the cell signalling of the metabotropic glutamate receptor 5 (mGluR5) is altered in a mouse model of HD. Although mGluR5-dependent protective pathways are more activated in HD neurons, intracellular Ca²âº release is also more pronounced, which could contribute to excitotoxicity. In the present study, we aim to investigate whether mGluR5 positive allosteric modulators (PAMs) could activate protective pathways without triggering high levels of Ca²âº release and be neuroprotective in HD. EXPERIMENTAL APPROACH: We performed a neuronal cell death assay to determine which drugs are neuroprotective, Western blot and Ca²âº release experiments to investigate the molecular mechanisms involved in this neuroprotection, and object recognition task to determine whether the tested drugs could ameliorate HD memory deficit. KEY RESULTS: We find that mGluR5 PAMs can protect striatal neurons from the excitotoxic neuronal cell death promoted by elevated concentrations of glutamate and NMDA. mGluR5 PAMs are capable of activating Akt without triggering increased intracellular Ca²âº concentration ([Ca²âº]i ); and Akt blockage leads to loss of PAM-mediated neuroprotection. Importantly, PAMs' potential as drugs that may be used to treat neurodegenerative diseases is highlighted by the neuroprotection exerted by mGluR5 PAMs on striatal neurons from a mouse model of HD, BACHD. Moreover, mGluR5 PAMs can activate neuroprotective pathways more robustly in BACHD mice and ameliorate HD memory deficit. CONCLUSIONS AND IMPLICATIONS: mGluR5 PAMs are potential drugs that may be used to treat neurodegenerative diseases, especially HD.
Asunto(s)
Enfermedad de Huntington/tratamiento farmacológico , Trastornos de la Memoria/prevención & control , Proteínas del Tejido Nervioso/agonistas , Fármacos Neuroprotectores/uso terapéutico , Nootrópicos/uso terapéutico , Receptor del Glutamato Metabotropico 5/agonistas , Regulación Alostérica/efectos de los fármacos , Animales , Conducta Animal/efectos de los fármacos , Muerte Celular/efectos de los fármacos , Células Cultivadas , Cuerpo Estriado/citología , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/metabolismo , Embrión de Mamíferos/citología , Activación Enzimática/efectos de los fármacos , Proteína Huntingtina , Enfermedad de Huntington/metabolismo , Enfermedad de Huntington/fisiopatología , Trastornos de la Memoria/etiología , Ratones , Ratones Endogámicos , Ratones Transgénicos , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Neuronas/citología , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Fármacos Neuroprotectores/efectos adversos , Fármacos Neuroprotectores/farmacología , Nootrópicos/efectos adversos , Nootrópicos/farmacología , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Fosforilación/efectos de los fármacos , Procesamiento Proteico-Postraduccional/efectos de los fármacos , Proteínas Proto-Oncogénicas c-akt/agonistas , Proteínas Proto-Oncogénicas c-akt/metabolismo , Receptor del Glutamato Metabotropico 5/metabolismoRESUMEN
Phα1ß is a potent toxin obtained from the spider Phoneutria nigriventer that blocks neuronal voltage-sensitive Ca(2+) channels. This study compared the antiallodynic effects of Phα1ß, ω-conotoxin MVIIA and morphine in mice and their side effects in rats. Mechanical allodynia was measured in mice receiving single intrathecal administration of Phα1ß, ω-conotoxin MVIIA or morphine before or after the incisional plantar procedure. The effect of the treatments on cardiovascular profile and global neurological were evaluated in rats. The expression of pro or anti-inflammatory cytokines of human polymorph mononuclear cells was also evaluated. Preemptive use of ω-conotoxin MVIIA (1.0 or 10 pmol/site) or morphine (1000 pmol/site) induced shorter antiallodynic effect than Phα1ß (100 pmol/site) in mice. Post-incision administration of Phα1ß (200 pmol/site) induced longer mechanical antiallodynic effect than ω-conotoxin MVIIA (1.0 or 10 pmol/site) or morphine (1000 pmol/site). Intrathecal injection of Phα1ß (200 pmol/site) and morphine (433 pmol/site) did not change while ω-conotoxin MVIIA (100 pmol/site) increased the heart rate in rats 3 h after its administration. Phα1ß (200 pmol/site), ω-conotoxin MVIIA (100 pmol/site) and morphine (433 pmol/site) did not change mean arterial pressure 0.5 and 3 h after their administration. The treatments did not alter neurological performance assessed by global neurological evaluation and open-field test. The tested drugs did not induced expression of pro or anti-inflammatory cytokines in CD4 monocytes. In conclusion, preemptive administration Phα1ß in mice induced longer antiallodynic effect than ω-conotoxin MVIIA and morphine. Phα1ß also induced a longer mechanical antiallodynic effect than ω-conotoxin MVIIA and morphine when used after the surgical incision. The present results suggest that Phα1ß has a potential application in the management of postoperative pain with low side effects.
Asunto(s)
Hiperalgesia/tratamiento farmacológico , Morfina/farmacología , Neuropéptidos/toxicidad , Neurotoxinas/toxicidad , Venenos de Araña/toxicidad , omega-Conotoxinas/farmacología , Adulto , Animales , Presión Sanguínea/efectos de los fármacos , Bloqueadores de los Canales de Calcio/toxicidad , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Citocinas/metabolismo , Conducta Exploratoria/efectos de los fármacos , Femenino , Frecuencia Cardíaca/efectos de los fármacos , Humanos , Hiperalgesia/inducido químicamente , Inyecciones Espinales , Leucocitos Mononucleares/efectos de los fármacos , Leucocitos Mononucleares/metabolismo , Masculino , Ratones , Persona de Mediana Edad , Actividad Motora/efectos de los fármacos , Examen Neurológico , Dolor/tratamiento farmacológico , Dolor/fisiopatología , Ratas , Ratas WistarRESUMEN
Cognitive dysfunction following surgery is a common complication, which increases the incidence of other co-morbid conditions, hospital and health-care costs. The reported rate of the occurrence of post-operative cognitive decline varies with different studies, depending on population profile, type of surgery, definition of cognitive disorder and detection methods, design of study, etc. It remains unclear whether these psychiatric signs and symptoms are direct results of the effects of surgery or general anesthesia. Nonetheless they are more frequent after cardiac surgery and are likely to be multi-factorial, but the patho-mechanisms are not yet fully characterized. This communication provides a synopsis of proteomics tools and delineates novel SELDI-TOF results to evaluate biomarkers in this regard. Presented for the first time is a classification of the clinically relevant forms of post-operative cognitive decline with the advent of a novel subclass.
Asunto(s)
Líquido Cefalorraquídeo/química , Cognición/fisiología , Puente de Arteria Coronaria , Análisis por Matrices de Proteínas , Proteoma/análisis , Proteómica/métodos , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción , Animales , Humanos , SíndromeRESUMEN
Cerebral malaria (CM) is a severe complication resulting from Plasmodium falciparum infection. This condition has been associated with cognitive, behavioral and motor dysfunctions, seizures and coma. The underlying mechanisms of CM are incompletely understood. Glutamate and other metabolites such as lactate have been implicated in its pathogenesis. In the present study, we investigated the involvement of glutamate in the behavioral symptoms of CM. Seventeen female C57BL/6 mice (20-25 g) aged 6-8 weeks were infected with P. berghei ANKA by the intraperitoneal route using a standardized inoculation of 106 parasitized red blood cells suspended in 0.2 mL PBS. Control animals (N = 17) received the same volume of PBS. Behavioral and neurological symptoms were analyzed by the SmithKline/Harwell/Imperial College/Royal Hospital/Phenotype Assessment (SHIRPA) battery. Glutamate release was measured in the cerebral cortex and cerebrospinal fluid of infected and control mice by fluorimetric assay. All functional categories of the SHIRPA battery were significantly altered in the infected mice at 6 days post-infection (dpi) (P ≤ 0.05). In parallel to CM symptoms, we found a significant increase in glutamate levels in the cerebral cortex (mean ± SEM; control: 11.62 ± 0.90 nmol/mg protein; infected at 3 dpi: 10.36 ± 1.17 nmol/mg protein; infected at 6 dpi: 26.65 ± 0.73 nmol/mg protein; with EGTA, control: 5.60 ± 1.92 nmol/mg protein; infected at 3 dpi: 6.24 ± 1.87 nmol/mg protein; infected at 6 dpi: 14.14 ± 0.84 nmol/mg protein) and in the cerebrospinal fluid (control: 128 ± 51.23 pmol/mg protein; infected: 301.4 ± 22.52 pmol/mg protein) of infected mice (P ≤ 0.05). These findings suggest a role of glutamate in the central nervous system dysfunction found in CM.
Asunto(s)
Síntomas Conductuales/fisiopatología , Corteza Cerebral/química , Líquido Cefalorraquídeo/química , Ácido Glutámico/metabolismo , Malaria Cerebral/metabolismo , Plasmodium berghei , Animales , Femenino , Malaria Cerebral/líquido cefalorraquídeo , Malaria Cerebral/fisiopatología , Ratones , Ratones Endogámicos C57BLAsunto(s)
Neovascularización Patológica/fisiopatología , Factor de Activación Plaquetaria/análogos & derivados , Factor de Activación Plaquetaria/toxicidad , Piel/irrigación sanguínea , Venenos de Serpiente/farmacología , Animales , Masculino , Ratones , Ratones Endogámicos BALB C , Modelos Cardiovasculares , Neovascularización Patológica/inducido químicamente , Neovascularización Patológica/patología , Prótesis e Implantes , Flujo Sanguíneo Regional/efectos de los fármacos , Piel/efectos de los fármacos , Piel/patologíaRESUMEN
Various neurotoxins have been described from the venom of the Brazilian spider Phoneutria nigriventer, but little is known about the venoms of the other species of this genus. In the present work, we describe the purification and some structural and pharmacological features of a new toxin (PRTx3-7) from Phoneutria reidyi that causes flaccid paralysis in mice. The observed molecular mass (4627.26 Da) was in accordance with the calculated mass for the amidated form of the amino acid sequence (4627.08 Da). The presence of an alpha-amidated C-terminus was confirmed by MS/MS analysis of the C-terminal peptide, isolated after enzymatic digestion of the native protein with Glu-C endoproteinase. The purified protein was injected (intracerebro-ventricular) into mice at dose levels of 5 microg/mouse causing immediate agitation and clockwise gyration, followed by the gradual development of general flaccid paralysis. PRTx3-7 at 1 microM inhibited by 20% the KCl-induced increase on [Ca2+]i in rat brain synaptosomes. The HEK cells permanently expressing L, N, P/Q and R HVA Ca2+ channels were also used to better characterize the pharmacological features of PRTx3-7. To our surprise, PRTx3-7 shifted the voltage-dependence for activation towards hyperpolarized membrane potentials for L (-4 mV), P/Q (-8 mV) and R (-5 mV) type Ca2+ currents. In addition, the new toxin also affected the steady state of inactivation of L-, N- and P/Q-type Ca2+ currents.
Asunto(s)
Canales de Calcio/efectos de los fármacos , Activación del Canal Iónico/efectos de los fármacos , Venenos de Araña/farmacología , Secuencia de Aminoácidos , Animales , Canales de Calcio/genética , Canales de Calcio/fisiología , Células Cultivadas , Electrofisiología , Femenino , Humanos , Masculino , Ratones , Datos de Secuencia Molecular , Ratas , Ratas Wistar , Homología de Secuencia de Aminoácido , Venenos de Araña/química , Venenos de Araña/aislamiento & purificación , Arañas , Sinaptosomas/efectos de los fármacos , TransfecciónRESUMEN
Cerebral malaria (CM) is a severe complication resulting from Plasmodium falciparum infection. This condition has been associated with cognitive, behavioral and motor dysfunctions, seizures and coma. The underlying mechanisms of CM are incompletely understood. Glutamate and other metabolites such as lactate have been implicated in its pathogenesis. In the present study, we investigated the involvement of glutamate in the behavioral symptoms of CM. Seventeen female C57BL/6 mice (20-25 g) aged 6-8 weeks were infected with P. berghei ANKA by the intraperitoneal route using a standardized inoculation of 10(6) parasitized red blood cells suspended in 0.2 mL PBS. Control animals (N = 17) received the same volume of PBS. Behavioral and neurological symptoms were analyzed by the SmithKline/Harwell/Imperial College/Royal Hospital/Phenotype Assessment (SHIRPA) battery. Glutamate release was measured in the cerebral cortex and cerebrospinal fluid of infected and control mice by fluorimetric assay. All functional categories of the SHIRPA battery were significantly altered in the infected mice at 6 days post-infection (dpi) (P ≤ 0.05). In parallel to CM symptoms, we found a significant increase in glutamate levels in the cerebral cortex (mean ± SEM; control: 11.62 ± 0.90 nmol/mg protein; infected at 3 dpi: 10.36 ± 1.17 nmol/mg protein; infected at 6 dpi: 26.65 ± 0.73 nmol/mg protein; with EGTA, control: 5.60 ± 1.92 nmol/mg protein; infected at 3 dpi: 6.24 ± 1.87 nmol/mg protein; infected at 6 dpi: 14.14 ± 0.84 nmol/mg protein) and in the cerebrospinal fluid (control: 128 ± 51.23 pmol/mg protein; infected: 301.4 ± 22.52 pmol/mg protein) of infected mice (P ≤ 0.05). These findings suggest a role of glutamate in the central nervous system dysfunction found in CM.
Asunto(s)
Animales , Femenino , Ratones , Síntomas Conductuales/fisiopatología , Corteza Cerebral/química , Líquido Cefalorraquídeo/química , Ácido Glutámico/metabolismo , Malaria Cerebral/metabolismo , Plasmodium berghei , Malaria Cerebral/líquido cefalorraquídeo , Malaria Cerebral/fisiopatologíaRESUMEN
Angiogenesis accompanies inflammatory processes and many other pathological conditions. We have studied the effect of platelet-activating factor (PAF) a well-known inflammatory mediator, as a promoter of angiogenesis in the sponge implant model in mice. Development of blood vessels and blood flow were monitored by use of a 133Xe washout technique. The results showed PAF to have angiogenic activity, which was inhibited by WEB 2086, and the PAF-induced vasculature to have normal pharmacological reactivity.
Asunto(s)
Neovascularización Patológica , Factor de Activación Plaquetaria/farmacología , Prótesis e Implantes , Angiotensina II/farmacología , Animales , Endotelinas/farmacología , Cinética , Ratones , Ratones Endogámicos BALB C , Radioisótopos de XenónRESUMEN
The combination of sponge implant and 133Xe washout technique described in this paper provides a model to study neovascularization in mice which can be observed over several days in the same animal. The local blood flow within the ingrowing granulation tissue has been determined by measuring the washout rate of 133Xe injected into the implants. Tissue infiltration of the sponges was assessed by histological examination and by measurement of sponge wet weight, protein and glycosaminoglycans (GAG) content. The newly formed blood vessels, despite having abnormal configuration, responded to platelet activating factor (PAF) and to endothelin-1 (ET-1) similarly to the normal mature vessels in adjacent skin. However, the sponge blood vessels were more sensitive to angiotensin II than the skin blood vessels. Using this model we have also demonstrated an angiogenic activity of PAF substantiated by increased blood flow and biochemical variables in the implanted sponges.