ABSTRACT
Beta-methylamino-L-alanine (BMAA) has been proposed as a global contributor to neurodegenerative diseases, including Parkinson-dementia complex (PDC) of Guam and Alzheimer's disease (AD). The literature on the effects of BMAA is conflicting with some but not all in vitro data supporting a neurotoxic action, and experimental animal data failing to replicate the pattern of neurodegeneration of these human diseases, even at very high exposures. Recently, BMAA has been reported in human brain from individuals afflicted with PDC or AD. Some of the BMAA in human tissue reportedly is freely extractable (free) while some is protein-associated and liberated by techniques that hydrolyze the peptide bond. The latter is especially intriguing since BMAA is a non-proteinogenic amino acid that has no known tRNA. We attempted to replicate these findings with techniques similar to those used by others; despite more than adequate sensitivity, we were unable to detect free BMAA. Recently, using a novel stable isotope dilution assay, we again were unable to detect free or protein-associated BMAA in human cerebrum. Here we review the development of our new assay for tissue detection of BMAA and show that we are able to detect free BMAA in liver but not cerebrum, nor do we detect any protein-associated BMAA in mice fed this amino acid. These studies demonstrate the importance of a sensitive and specific assay for tissue BMAA and seriously challenge the proposal that BMAA is accumulating in human brain.
Subject(s)
Amino Acids, Diamino/metabolism , Cerebrum/metabolism , Dementia/metabolism , Indicator Dilution Techniques , Liver/metabolism , Parkinson Disease/metabolism , Administration, Oral , Aged , Aged, 80 and over , Amino Acids, Diamino/administration & dosage , Animals , Biomarkers/metabolism , Calibration , Case-Control Studies , Cyanobacteria Toxins , Dementia/ethnology , Dementia/etiology , Deuterium , Female , Gas Chromatography-Mass Spectrometry , Guam/epidemiology , Humans , Indicator Dilution Techniques/standards , Magnetic Resonance Spectroscopy , Male , Mice , Middle Aged , Parkinson Disease/ethnology , Parkinson Disease/etiology , Sensitivity and Specificity , Washington/epidemiologySubject(s)
Amyotrophic Lateral Sclerosis/epidemiology , Cycas/chemistry , Dementia/epidemiology , Parkinsonian Disorders/epidemiology , Plant Extracts/poisoning , Amino Acids, Diamino/poisoning , Bacterial Toxins/poisoning , Causality , Cyanobacteria Toxins , Data Interpretation, Statistical , Epidemiologic Research Design , Epidemiologic Studies , Flour/poisoning , Guam/epidemiology , Hazardous Substances/toxicity , Humans , Incidence , Marine Toxins/poisoning , Microcystins/poisoning , Sex Distribution , SyndromeABSTRACT
Beta-methylamino-L-alanine (BMAA) is an excitotoxin allegedly involved in ALS-parkinsonism-dementia complex (ALS-PDC), a neurological disorder found in Guam and its surrounding islands, in which motor neuron disease symptoms can present alone or can co-occur with parkinsonism and dementia. Although in vitro experiments have shown BMAA's neurotoxic properties, studies using adult animals and systemic administration which better model the case of environmentally-induced human neurodegenerative diseases have not supported the involvement of BMAA in these disorders. In order to better test the hypothesized role of BMAA in neurodegeneration, we fed adult mice BMAA at a dose (28 mg/kg body weight, daily for 30 days) that reproduces the natural levels and tested the animals with a battery of behavioural tests, the latter including the evaluation of motor coordination, motor neuron-mediated reflexes, locomotion, muscular strength and memory. We also assessed whether BMAA exposure triggers cell death in the central nervous system (CNS) of mice by examining neuronal numbers and glial response in the spinal cord and the brain. No motor, cognitive or neuropathological outcome resulted from this feeding paradigm. Our findings support neither the causal role of BMAA in neurodegeneration nor the specific involvement of this amino acid in ALS-PDC.
Subject(s)
Amino Acids, Diamino/pharmacology , Behavior, Animal/drug effects , Motor Activity/drug effects , Neurotoxins/pharmacology , Animals , Cognition/drug effects , Cyanobacteria Toxins , Male , Mice , Motor Neurons/drug effectsABSTRACT
Beta-nerve growth factor (B-NGF) is a trophic factor in teh nervous system. We aimed to isolate and characterize this protein in view of its potential therapeutic use in neurodegenerative diseases. For purification a two-step ion-exchange procedure was followed. The characterization was performed using separation and immunological techniques, as well as a biological assay. These studies showed that the obtained protein consisted of a mixture of B-NGF molecules, intact at their NH2 -terminal extreme, and molecules which have lost the NH2 - terminal octapeptide and exhibit modifications increasingt its hydrophobicity. All these molecular species were recognized immunologically and showed biological activity(AU)
Subject(s)
Nerve Growth FactorsABSTRACT
Purpose: To test the influence of nerve growth factor (NGF) on striatal glutathione (GSH) content and the activities of GSH-related enzymes from quinolinic acid-lesioned rats. Methods: Rats were intrastriatally injected with QA and NGF. Enzymatic and GSH assays were performed one week later. Results: NGF prevented the QA-induced decline in glutathione reductase activity and GSH content. Conclusions: NGF is able to prevent some of the disturbances induced by the excitotoxic insult in the striatal GSH metabolism.
ABSTRACT
Purpose. To test the influence of nerve growth factor (NGF) on striatal glutathione (GSH) content and the activities of GSH-related enzymes from quinolinic acid-lesioned rats. Methods. Rats were intrastriatally injected with QA and NGF. Enzymatic and GSH assays were performed one week later. Resuts. NGF prevented the QA-induced decline in glutathione reductase activity and GSH content. Conclusions. NGF is able to prevent some of the disturbances induced by the excitotoxic insult in the striatal GSH metabolism(AU)
Subject(s)
Huntington Disease , Nerve Growth Factor , Quinolinic Acids , Glutathione , Oxidative StressABSTRACT
Although the involvement of oxidative mechanisms in thecytotoxicity of excitatory amino acids has been well documented, it is not known whether the instrastriatal injection of quinolinic acid (QA) induces changes in gluthatione (GSH) metabolism. In this work, the activities of the enzynes GSH reductase (GRD), GSH peroxidase (GPX), and GSH S-transferase (GST), as well as the GSH content, were studied in the striatum, hippocampus, and frontal cortex of rats 1 and 6 weeks following the instrastriatal injection of QA (225 nmol). One group of animals remained untreated. This lesion resulted in a 20 porciento decrease in striatal GRD activity at both the 1- and 6-week postlesion time. GSH related enzyme activities and GSH content from other areas outside the lesioned striatum were not affected. GST activation could represent a beneficial compensatory response to neurtralize some of the oxidant agents generated by the lesion. However, this effect together with the reduction in GRD activity could be the cause or a contributing factor to the observed QA-induced deficit in GSH availability and, consequently, further disrupt the oxidant homeostasis of the injured striatal tissue. Therefore, these results provide evidence that the in vivo excitotoxic injury to the brain might affect oxidant/antioxidant equilibrium by eliciting changes in gluthatione metabolism(AU)
Subject(s)
Quinolinic Acid , Rats , Glutathione , Excitatory Amino Acids , Oxidative StressABSTRACT
The activities of the enzymes glutathione reductase (GRD), glutathione peroxidase (GPX), and glutathione S-transferase (GST) were studied in several rat brain areas following the aspirative transection of the septohippocampal pathway (fimbria fornix) and the administration of nerve growth factor (NGF) or cytochrome c. One group of animals remained untreated. This lesion resulted in a decreased hippocampal GRD and septal GST activities, as well as, in an increase in GPX activity from the frontal cortex, striatum, and septum, NGF prevented the lesion-induced changes in hippocampal GRD and septal GPX. These findings show that the insult resulting from the aspiration of the fimbria fornix bundle involves modifications in glutathione-related enzymes, and, therefore, in the antioxidant status of brain tissue. These changes in gluthatione metabolism could be a consequence of the oxidative damage to GRD and GST protein or represent a compensatory response of GPX to the oxidative threat. The restirubg effects if BGF ib aktered ebztne activities are possibly linked to its known neuroprotective action(AU)
Subject(s)
Nerve Growth Factors , Glutathione , Disease Models, Animal , Rats , HippocampusABSTRACT
Las especies reactivas del oxígeno constituyen los radicales libres más importantes en los sistemas biológicos dada la esencialidad del oxígeno para las formas aeróbicas de vida. En determinadas condiciones la producción de estas especies logra sobrecargar los mecanismos enzimáticos y no enzimáticos de los que dispone la célula para la defensa antioxidante. Las particularidades del metabolismo cerebral hacen al tejido nervioso particularmente susceptible al daño oxidativo; así, este se constituye en un evento común en el origen y perpetuación de múltiples entornos neuropsiquiátricos. La "hipótesis del estrés oxidativo" es una de las más ampliamente difundidas para explicar la muerte neuronal presente en las enfermedades de Parkinson y Alzheimer. Los vínculos entre la excitotoxicidad, el déficit energético y el daño oxidativo han sugerido la participación de este último en la etiopatogenia molecular de la corea de Huntington y la isquemia cerebral. Los pacientes con la forma familiar de la esclerosis lateral amiotrófica exhiben mutaciones en el gen de la superóxido dismutasa, importante enzima antioxidante. Por último, algunas investigaciones muestran alteraciones en el metabolismo oxigenado de los esquizofrénicos. A pesar de las múltiples evidencias que se discuten en esta reseña, el sitio exacto del estrés oxidativo en las disfunciones del sistema nervioso está aún por conocerse
Subject(s)
Humans , Free Radicals , Homeostasis , Mental Disorders , Nervous System , Oxidative Stress , Biological PsychiatryABSTRACT
Las especies reactivas del oxígeno constituyen los radicales libres más importantes en los sistemas biológicos dada la esencialidad del oxígeno para las formas aeróbicas de vida. En determinadas condiciones la producción de estas especies logra sobrecargar los mecanismos enzimáticos y no enzimáticos de los que dispone la célula para la defensa antioxidante. Las particularidades del metabolismo cerebral hacen al tejido nervioso particularmente susceptible al daño oxidativo; así, este se constituye en un evento común en el origen y perpetuación de múltiples entornos neuropsiquiátricos. La "hipótesis del estrés oxidativo" es una de las más ampliamente difundidas para explicar la muerte neuronal presente en las enfermedades de Parkinson y Alzheimer. Los vínculos entre la excitotoxicidad, el déficit energético y el daño oxidativo han sugerido la participación de este último en la etiopatogenia molecular de la corea de Huntington y la isquemia cerebral. Los pacientes con la forma familiar de la esclerosis lateral amiotrófica exhiben mutaciones en el gen de la superóxido dismutasa, importante enzima antioxidante. Por último, algunas investigaciones muestran alteraciones en el metabolismo oxigenado de los esquizofrénicos. A pesar de las múltiples evidencias que se discuten en esta reseña, el sitio exacto del estrés oxidativo en las disfunciones del sistema nervioso está aún por conocerse (AU)
Subject(s)
Humans , Homeostasis , Mental Disorders , Oxidative Stress , Free Radicals , Nervous System , Biological PsychiatryABSTRACT
Las especies reactivas del oxígeno constituyen los radicales libres más importantes en los sistemas biológicos dada la esencialidad del oxígeno para las formas aeróbicas de vida. En determinadas condiciones la producción de estas especies logra sobrecargar los mecanismos enzimáticos y no enzimáticos de los que dispone la célula para la defensa antioxidante. Las particularidades del metabolismo cerebral hacen al tejido nervioso particularmente susceptible al daño oxidativo; así, este se constituye en un evento común en el origen y perpetuación de múltiples entornos neuropsiquiátricos. La "hipótesis del estrés oxidativo" es una de las más ampliamente difundidas para explicar la muerte neuronal presente en las enfermedades de Parkinson y Alzheimer. Los vínculos entre la excitotoxicidad, el déficit energético y el daño oxidativo han sugerido la participación de este último en la etiopatogenia molecular de la corea de Huntington y la isquemia cerebral. Los pacientes con la forma familiar de la esclerosis lateral amiotrófica exhiben mutaciones en el gen de la superóxido dismutasa, importante enzima antioxidante. Por último, algunas investigaciones muestran alteraciones en el metabolismo oxigenado de los esquizofrénicos. A pesar de las múltiples evidencias que se discuten en esta reseña, el sitio exacto del estrés oxidativo en las disfunciones del sistema nervioso está aún por conocerse (AU)
Subject(s)
Humans , Homeostasis , Mental Disorders , Oxidative Stress , Free Radicals , Nervous System , Biological PsychiatryABSTRACT
Las especies reactivas del oxígeno constituyen los radicales libres más importantes en los sistemas biológicos dada la esencialidad del oxígeno para las formas aeróbicas de vida. En determinadas condiciones la producción de estas especies logra sobrecargar los mecanismos enzimáticos y no enzimáticos de los que dispone la célula para la defensa antioxidante. Las particularidades del metabolismo cerebral hacen al tejido nervioso particularmente susceptible al daño oxidativo; así, este se constituye en un evento común en el origen y perpetuación de múltiples entornos neuropsiquiátricos. La "hipótesis del estrés oxidativo" es una de las más ampliamente difundidas para explicar la muerte neuronal presente en las enfermedades de Parkinson y Alzheimer. Los vínculos entre la excitotoxicidad, el déficit energético y el daño oxidativo han sugerido la participación de este último en la etiopatogenia molecular de la corea de Huntington y la isquemia cerebral. Los pacientes con la forma familiar de la esclerosis lateral amiotrófica exhiben mutaciones en el gen de la superóxido dismutasa, importante enzima antioxidante. Por último, algunas investigaciones muestran alteraciones en el metabolismo oxigenado de los esquizofrénicos. A pesar de las múltiples evidencias que se discuten en esta reseña, el sitio exacto del estrés oxidativo en las disfunciones del sistema nervioso está aún por conocerse (AU)
