Stress-another possible mechanism of neurotoxicity in neurodegenerative diseases

Theliteratureassociatesoxidativestresswiththeproductionoffreeradicals,whichleadtoneurodegeneration.Theypresentinnumerablehypotheses,amongwhichareabnormalitiesinthefunctioningofthehypothalamic-pituitary-adrenalaxis,neurotoxiceffectsandneuronaloxidativedamage.ClinicalobservationhasshownthatinneurodegenerativediseasessuchasMultipleSclerosis(MS)andAmyotrophicLateralSclerosis(ALS)thereisareportofprolonged or violent emotionalstressprecedingthesymptoms.Aims:UsingtheCarilloComplexSystemsModel,presentsomepossibilitiesonhowstresscancontributetoneurodegeneration.Methodology:NinecasesofALSandsixcasesofMSwereevaluated,pathologiesalreadyclassifiedasbelongingtosyphilinism.Literaturereviewonstressandneurotoxicitycarriedout.Resultsanddiscussion:Syphilinism is instability with a predominantly intrinsicorigin to the system with a chronic caracter.This diathesis is characterized by a dissipative deficiency, predominantly hepatic, to the processing of certain elements or potentially toxic substances with exogenous origin or endogenous Such non-processed substances are unstable factors in the system, with greater affinity for certain tissues,like the nervous system. Among the toxins, we find alcohol, esters, formaldehyde, aloe, ketones, aldehydes, etc. The final hepatic metabolism of cortisol results in cortic acids and cortol, which use the same enzymatic system as alcohol, and can be considered syphilinic toxins. Ethanol can act directly at the circadian rhythm, disrupting it and generating stressful substances such as cortisol, regardless of an external event, increasing the toxin level. The inflammatory process generated by the production of free radicals and metabolic abnormalities, including the reduction of neuropeptide Y that modulates inflammatory activity in the nervous system, leads to changes that can result in neurodegeneration. Conclusion: Inflammation caused by toxins from prolonged/violent emotional stress can lead to several changes in syphilinic individuals, due to failure in the dissipative process, including neurodegeneration.

Relevancia del metabolismo del folato en el contexto de enfermedades neurodegenerativas / Relevance of folate metabolism in neurodegenerative disorders

Introducción: Varias enfermedades neurodegenerativas están asociadas a alteraciones en el metabolismo del folato, lo que tiene sustanciales implicaciones fisiopatológicas, clínicas y terapéuticas potenciales. Objetivo: Reflejar la relevancia del metabolismo del folato para enfermedades neurodegenerativas, destacando su significación fisiopatológica y clínica, y sus implicaciones terapéuticas. Material y métodos: Se consultaron las bases de datos especializadas en busca de artículos publicados hasta marzo de 2020. Se emplearon descriptores específicos y operadores booleanos. Se empleó la estrategia de búsqueda avanzada para la selección de los artículos, teniendo en cuenta la calidad metodológica o validez de los estudios. Desarrollo: Fueron identificadas evidencias de asociación entre alteraciones del metabolismo del folato y enfermedades neurodegenerativas. Se han identificado variantes en genes que codifican enzimas involucradas en el metabolismo del folato, y modificaciones en patrones de metilación de ADN, asociadas al riesgo o a la gravedad clínica de las enfermedades de Alzheimer, Parkinson, Huntington, Temblor Esencial y Ataxia Espinocerebelosa tipo 2. Fueron encontradas asociaciones entre enfermedades neurodegenerativas y alteraciones en los niveles de metabolitos del folato, y la frecuencia de micronúcleos. Se han realizado varios estudios observacionales o experimentales que indican que la suplementación con ácido fólico y vitaminas B6 y B12, tiene utilidad terapéutica potencial en el contexto de enfermedades neurodegenerativas. Conclusiones: El metabolismo del folato es de relevancia fisiopatológica, clínica y terapéutica para enfermedades neurodegenerativas. El uso de estrategias dirigidas a restaurar los niveles normales de folatos o de co-factores enzimáticos involucrados en el metabolismo del folato, o a reducir la acumulación de homocisteína, tiene potenciales aplicaciones terapéuticas en el contexto de estas enfermedades(AU)

Introduction: Several neurodegenerative disorders are associated with alterations in folate metabolism, having essential physiopathological, clinical and therapeutic implications. Objective: To assess the relevance of folate metabolism in neurodegenerative disorders, highlighting its physiopathological, clinical and therapeutic significance. Material and Methods: Specialized biomedical databases were searched for studies published up to March 2020. Descriptors and Boolean operators were used. Advanced search strategy was used for the selection of articles, taking into account the methodological quality and validity of the studies. Results: Strong evidence of the association between folate metabolism and neurodegenerative disorders were identified. Enzyme-coding genes involved in folate metabolism and epigenetic DNA modifications associated with increased risk or disease severity in Alzheimer´s, Parkinson´s, and Huntington´s diseases, Essential Tremor, and Spinocerebellar ataxia type 2 were also identified. Associations between neurodegenerative disorders and altered levels of folate metabolites and the frequency of micronuclei were found. A number of observational and experimental studies have demonstrated that the supplementation with folic acid and vitamin B6 and B12 has therapeutic potential in the context of neurodegenerative disorders. Conclusions: Folate metabolism is of physiopathological, clinical and therapeutic relevance for neurodegenerative disorders. The use of strategies to normalize folate levels or enzyme cofactors involved in folate metabolism or to reduce homocysteine levels has potential therapeutic applications for these disorders(AU)

Protective effect of CD73 inhibitor α, ß-methylene ADP against amyloid-ß-induced cognitive impairment by inhibiting adenosine production in hippocampus

BACKGROUND: Alzheimer's disease (AD) is a chronic, progressive neurodegenerative disease. Recent studies have reported the close association between cognitive function in AD and purinergic receptors in the central nervous system. In the current study, we investigated the effect of CD73 inhibitor α, ß-methylene ADP (APCP) on cognitive impairment of AD in mice, and to explore the potential underlying mechanisms. RESULTS: We found that acute administration of Aß1­42 (i.c.v.) resulted in a significant increase in adenosine release by using microdialysis study. Chronic administration of APCP (10, 30 mg/kg) for 20 d obviously mitigated the spatial working memory impairment of Aß1­42-treated mice in both Morris water maze (MWM) test and Y-maze test. In addition, the extracellular adenosine production in the hippocampus was inhibited by APCP in Aß-treated mice. Further analyses indicated expression of acetyltransferase (ChAT) in hippocampus of mice of was significantly reduced, while acetylcholinesterase (AChE) expression increased, which compared to model group. We observed that APCP did not significantly alter the NLRP3 inflammasome activity in hippocampus, indicating that anti-central inflammation seems not to be involved in APCP effect. CONCLUSIONS: In conclusion, we report for the first time that inhibition of CD73 by APCP was able to protect against memory loss induced by Aß1­42 in mice, which may be due to the decrease of CD73-driven adenosine production in hippocampus. Enhancement of central cholinergic function of the central nervous system may also be involved in the effects of APCP.

The Gut Brain-Axis in Neurological Diseases

Abstract Recent evidence suggests that dysfunction of the gut-brain axis may be an important factor contributing to many diseases of the nervous system. Increased gut permeability associated with chronic gastrointestinal dysfunction, as well as changes in the composition of the gut microbiota could contribute to exposure of the enteric and central nervous system to pathogens and its metabolites, including endotoxins and pro-inflammatory cytokines. As a consequence, dysfunction of the host's immune system could contribute to an abnormal immunological response leading to auto-immune conditions, such as multiple sclerosis. So far, gut dysbiosis has been reported in association with Parkinson's disease, Alzheimer's disease, multiple sclerosis, neurodevelopmental and neuropsychiatric conditions, and cerebrovascular disease. These findings suggest that the possibility of targeting the gut microbiota could become a future therapeutic option to treat these conditions. However, before this knowledge can be useful in the clinical setting, more data is needed to establish clear causal relationships between dysfunction of the gut-brain axis and neurological diseases.

Optical coherence tomography findings in bipolar disorder: a preliminary receiver operating characteristic analysis on ganglion cell layer volume for diagnosis

Abstract Background Optical coherence tomography (OCT) has been recently used to investigate neuropsychiatric disorders. Objective The aim of this study was to compare the retinal nerve fiber layer thickness (RNFLT) and the ganglion cell layer (GCL) volume in patients with type 1 bipolar disorder (BPD1, diagnosed according to DSM 5) to the values in healthy controls. Methods Eighty consecutive outpatients with a diagnosis of euthymic BPD1 and 80 healthy controls were enrolled in the study. Following assessment with the Sociodemographic Data Form, Structured Clinical Interview for DSM-IV (SCID-I), Hamilton Depression Scale and Young Mania Evaluation Scale, both groups underwent Optical coherence tomography (OCT). Results The mean RNFL thickness and mean GCL volume were significantly lower in the BPD1 group than in the controls (p < 0.05). The GCL global value had a significant and independent effect in distinguishing the BPD1 patients from the controls. A cut-off value of 101 mm3 for global GCL volume was proposed to distinguish BPD1 patients from controls with a sensitivity of 87.5%. Discussion Lower values of GCL volume and RNFLT in patients suffering from BPD1 suggest that neurodegeneration may occur during the course of BPD and that this degeneration can be characterized in particular by a thinning of the GCL volume.

Estudos dos produtos da oxidação não enzimática do ácido docosahexaenoico como possíveis biomarcadores para doenças neurodegenerativas / Study of Docosahexaenoic acid non-enzymatic oxidation products as biomarkers for neurodegenerative diseases

Os n-3 e n-6 são duas famílias de ácidos graxos poli-insaturados. Os ácidos graxos de cadeia longa como o ácido araquidônico (AA) e docosahexaenoico (DHA) apresentam importantes funções no desenvolvimento e funcionamento do cérebro. Os produtos de oxidação dos ácidos graxos poli-insaturados estão presentes ou aumentados ao longo do desenvolvimento de doenças neurodegenerativas. A caracterização de tais produtos é crítica para o estudo que busca entender o seu papel fisiopatológico no desenvolvimento de tais doenças. No presente trabalho, buscou-se o desenvolvimento de uma ferramenta analítica sensível e específica para a detecção e quantificação dos hidroperóxidos e hidróxidos do AA (HpETE e HETE), do seu precursor, o ácido linoleico (HpODE e HODE) e do DHA (HpDoHE e HDoHE). Estes hidroperóxidos foram sintetizados por fotooxidação e os hidróxidos correspondentes foram obtidos através da redução com o NaBH4. Os isômeros isolados foram caracterizados por LC-MS/MS. Os íons produto específicos de cada isômero foram escolhidos para a construção do método de monitoramento de reação selecionada (selected reaction monitoring - SRM) para a realização da análise quantitativa dos analitos de interesse. Cabe salientar que os dados obtidos poderão ser utilizados em bibliotecas de análise lipidômica e oxi-lipidômica pois serão essenciais para a identificação e quantificação dos analítos de interesse do presente estudo em diversas doenças. Utilizando o método padronizado, buscamos investigar o papel dos hidroperóxidos e hidróxidos do DHA, LA e AA em um modelo animal para a esclerose lateral amiotrófica (ELA), uma doença neurodegenerativa que acomete neurônios motores. Foi observado um aumento nos níveis de 13-HpODE, 9-HpODE e 12-HETE no córtex motor dos animais avaliados. Adicionalmente, foram observadas alterações nas taxas lipólica e lipogênica no tecido adiposo para os animais ELA em relação aos respectivos controles. Em conjunto, os dados apresentados no presente trabalho corroboram com os trabalhos da literatura que associam alteração dos níveis dos produtos de oxidação dos ácidos graxos poli-insaturados em doenças neurodegenerativas e o metabolismo energético alterado em ELA. Futuramente é necessária uma investigação mais ampla dos níveis dos hidroperóxidos e hidróxidos lipídicos em diferentes tecidos e do metabolismo lipídico, e os conhecimentos gerados poderão ser uma importante fonte de novas opções terapêuticas para os pacientes portadores de ELA

The n-3 and n-6 are two olyunsaturated fatty acids families. The long chain fatty acids such as arachidonic (AA) and docosahexaenoic acid (DHA) have important roles in the development and function of the brain. Polyunsaturated fatty acids (PUFAs) oxidation products are present or increased during the progression of neurodegenerative diseases. The characterization of DHA oxidation products is critical to understand their roles in the development of such diseases. In the present study, we sought to develop a sensitive and specific analytical tool for the detection and quantification of AA hydroperoxides and hydroxides (HPETE and HETE), its precursor linoleic acid (HPODE and HODE) and DHA (HpDoHE and HDoHE). These hydroperoxides were synthesized by photooxidation and the corresponding hydroxides were obtained by reduction with NaBH4. The isolated isomers were characterized by LC-MS/MS, and unique and specific fragment ions were chosen to construct a selected reaction monitoring (SRM) method for the targeted quantitative analysis. It should be emphasized that the data obtained - in the form of lipidomics and oxy-lipidomics libraries - may be used to assist in several diseases. Using the standardized method, we investigated the role of hydroperoxides and hydroxides of DHA, LA and AA in an animal model of amyotrophic lateral sclerosis (ALS), a neurodegenerative disease that affects motor neurons. Increased levels of 13-HPODE, 9-HPODE and 12-HETE were observed in the animals motor cortex. Additionally, results show changes in lipogenic and lipolytic rates in adipose tissue for ALS animals when compared to their respective controls. Altogether, the data presented herein corroborate with the literature by linking altered levels of PUFAs oxidation products in neurodegenerative diseases with altered energetic metabolism in ALS. In the future, a more extensive investigation of the hydroperoxide and hydroxide level in different tissues as well as the lipid metabolism must be done, which could lead to new therapeutic options for ALS patients

Ácido docosahexaenoico (DHA): una perspectiva nutricional para la prevención de la enfermedad de Alzheimer / Docosahexaenoic acid (DHA): a nutritional view for the prevention of Alzheimer's disease

Alzheimer's disease (AD) is a major public health problem in many countries of the world; however the specific cause of this disease is still unknown. Currently, a bulk of evidence supports the hypothesis that beta-amiloidpeptide could be the cause of synaptic injuries and neuronal death observed at the initial stages of the disease. Patients with AD show lower levels of docosahexaenoic acid (DHA, C22:6; omega-3) in plasma and brain tissue, as compared with age-matched controls. In addition, epidemiological studies indicate that a high intake of DHA may have protective properties against neurodegenerative diseases. These observations are supported by in vivo studies showing that diets rich in DHA reduce synaptic injuries and cognitive defects induced by the beta-amyloid peptide. Although the molecular basis of these neuroprotective effects are still unknown, a number of mechanisms have been proposed to explain this protection, such as: regulation in the expression of potentially protective genes, activation of anti-inflammatory pathways, and modulation of the functional properties of neuronal membranes along with changes in their structural characteristics and physical-chemical properties. The present work reviews and discusses the molecular basis of the hypothesis on the protective role of DHA in the prevention of AD.

La enfermedad de Alzheimer (EA) constituye un importante problema de salud pública en muchos países del mundo, sin embargo la causa específica de esta enfermedad todavía es desconocida. Actualmente, numerosas evidencias apoyan la hipótesis que modificaciones del péptido beta-amiloide podrían ser la causa más próxima de las lesiones sinápticas y muerte neuronal que ocurren en las etapas iniciales de la enfermedad. Los pacientes con EA muestran niveles más bajos de ácido docosahexaenoico (DHA, C22: 6; omega-3) en plasma y tejido cerebral, en comparación con controles pareados por edad. Además, los estudios epidemiológicos indican que una alta ingesta de DHA podría tener propiedades protectoras contraías enfermedades neurodegenerativas. Estas observaciones se sustentan por estudios in vivo que demuestran que las dietas ricas en DHA, limitan las lesiones sinápticas y disminuyen los defectos cognitivos inducidos por el péptido beta-amiloide. Aunque las bases moleculares de estos efectos neuroprotectores aún siguen siendo desconocidas, se han propuesto varios mecanismos, tales como: la regulación de la expresión de genes potencialmente protectores, la activación de vías antiinflamatorias, la modulación de las propiedades funcionales de las membranas neuronales, junto con cambios en las características estructurales y físico-químicas de las mismas. Este trabajo revisa y discute el fundamento molecular de estas hipótesis sobre el rol del DHA en la protección de la EA.

Food as medicine: potential therapeutic tendencies of plant derived polyphenolic compounds.

The last two decades have witnessed a major drift in the interests of the scientific community towards explaining better means to containing the health risks of the human race. The century old chemotherapies against various disorders have never been a success, albeit not a total failure. Such therapies have a major drawback of side effects that give rise to unseen disorders that emerge as a new challenge. In this regard, the concept of foodstuffs as natural medicines is very attractive. Epidemiological studies suggest that the vegeteranian food habit is associated with reduced risk of cancer, cardiovascular and neurodegenerative disorders. Consistent with this hypothesis is the fact that the incidence of these disorders is least in Asian populations where fruits, vegetables and spices are the major elements in the human diet. Recent research has shown that plant-derived polyphenolic compounds are promising nutraceuticals for control of various disorders such as cardiovascular,neurological and neoplastic disease. The richness of the polyphenolic contents of green tea and red wine has made them popular choice for associated anticancer and cardiovascular health benefits. The present article is a brief review of the promises plant polyphenols, bioactive components of our food, hold for the future.

Uma nova puericultura para crianças que vão viver 100 anos ou mais / A new child care for children who will live more than 100 years

O aumento da esperança de vida, decorrente dos avanços médico-científicos e sobretudo da melhoria das condições socioeconômicas das populações, tem sido, sem dúvida, uma das grandes conquistas de noso tempo. Em países desenvolvidos, como a França e o Japão, já se prevê uma vida de 100 anos para as primeiras décadas do século XXII, ou seja, parte significativa das crianças que nascem hoje poderá ser centenária...

Protective role of estrogen in the neurodegenerative disorders.

Estrogen is an anabolic hormone of gonadal cells and it also modulates the growth and differentiation of non-gonadal cells like neuron/glia and protects them against the injury. The anabolic or protective actions of estrogen on the neuronal cells are mediated by the modulation of intracellular factors such as insulin like growth factor (IGF-I), tyrosine kinase A (Trk A), nerve growth factors (NGF) etc. It also modulates the action of neurotrophins which in turn regulate the synaptogenesis, synaptic plasticity and synaptic functions. By these actions estrogen prevents or slows down the neurodegenerative process.