Efecto del compuesto N-2,6-dicloro-aralquil-2-Aminoindano en la conducta estereotipada de ratas. Acción dopaminérgica selectiva central sobre los ganglios basales más que en las estructuras límbicas / Effect of the compound N-2,6-dichloro-aralkyl-2-aminoindane on the stereotyped behavior of rats. Selective action on the central dopaminergic system in the basal ganglia over limbic structures

Resumen La dopamina 1, está implicada en trastornos neurodegenerativos que afectan al sistema nervioso central (SNC) tales como la enfermedad de Parkinson, entre otros. Aunque no se dispone aún de ningún fármaco capaz de prevenir, detener o curar la progresión de estas enfermedades, son numerosos los compuestos que han sido diseñados, sintetizados y evaluados farmacológicamente, que han aportado las generalizaciones farmacofóricas del receptor dopaminérgico, necesarias para la búsqueda de un fármaco capaz de mejorar o curar estas patologías. Los derivados 2-aminoindano-N-aralquílicos han mostrado tener actividad selectiva en el sistema dopaminérgico central, de modo tal que los compuestos clorhidratos de N-[(2,4-diclorofenil)-1-metil- etil]-2-aminoindano 2 y N-[(3,4-diclorofenil)-1-metil-etil]-2-aminoindano 3 demostraron tener actividad agonística mediada por mecanismos dopaminérgicos centrales. Con el propósito de contribuir en la búsqueda de nuevos fármacos que permitan restablecer la homeostasis de la transmisión dopaminérgica en la enfermedad de Parkinson, el compuesto N-2,6-dicloro-aralquil-2-aminoindano 4 fue diseñado a través de estrategias de la química medicinal, que contienen las aproximaciones farmacofóricas de los profármacos. La evaluación farmacológica del compuesto 4, en la conducta estereotipada en ratas macho de la cepa Sprague Dawley, demostró tener actividad agonística a través de la activación de los mecanismos dopaminérgicos centrales y mostró mayor selectividad en las respuestas de conductas estereotipadas propias de los ganglios basales sobre las respuestas conductuales propias de las estructuras límbicas.

Abstract Dopamine 1 is involved in neurodegenerative disorders affecting the central nervous system (CNS), such as Parkinson's disease. Despite the absence of some available drugs capable of preventing, stopping or curing the progression of such diseases, there are numerous compounds designed, synthesized, and pharmacologically tested which give rise to pharmacophoric generalizations about the dopaminergic receptor required for the search of a drug able to improve or cure those pathologies. N-aralkyl-2-aminoindane derivatives have shown selective activity in the central dopaminergic system. Both the N-[(2,4-dichlorophenyl)-1-methyl-ethyl]-2-aminoindane hydrochloride 2 and N-[(3,4-dichlorophenyl)-1-methyl-ethyl]-2-aminoindane hydrochloride 3 showed an agonistic activity mediated by central dopaminergic mechanisms. To contribute to the search of new drugs able to re-establish homeostasis in the dopaminergic transmission in Parkinson's disease, the compound N-2,6- dichloro-aralkyl-2-aminoindane 4 was designed through medicinal chemistry strategies that contain pharmacophoric approximations of prodrugs. The pharmacological evaluation of compound 4 in the stereotyped behavior of male Sprague Dawley rats showed agonistic activity through the activation of central dopaminergic mechanisms and a higher selectivity in the responses of stereo- typed behavior characteristic of the basal ganglia over the typical responses from limbic structures.

Oligodendrocyte dysfunction in cerebral ischemia and neurodegenerative disorders:the effect of CysLT receptor antagonists / 中国药理学与毒理学杂志

Ischemic stroke is an acute and serious cerebrovascular accident.Neurodegenerative disorders are characterized by progressive degeneration of neu-rons in the central nervous system(CNS),resulting in severe disability and death.Myelin is essential for the health and function of neuronal axons.Oligodendrocytes,the myelinating cells of CNS,are vulnerable to ischemia and neurodegenerative disorders.G protein-coupled receptor 17(GPR17)is a dual receptor activated by uracil nucleotides/cysteinyl leukotrienes(CysLTs).Abnormal GPR17 activation contributes to oligodendrocyte dysfunc-tion and axonal damage.Gelosa et al.reported that CysLT1 receptor antagonist montelukast increased the recruitment and proliferation of oligodendrocyte precursor cells(OPCs)at the acute phase after ischemic stroke.Similarly,a study showed that montelukast stimulated neural progenitor proliferation and hippocampal neuro-genesis of aged rats through inhibition of GPR17.These results were supported by several studies on neurode-generative diseases.The authors showed that pharmaco-logical blockade of GPR17 with CysLT1 or CysLT2 recep-tor antagonists(montelukast or HAMI3379)improved oli-godendrocyte function and fiber connectivity,highlighting GPR17 as a potential therapeutic target in oligodendro-cyte protection and remyelination.Recently,growing evi-dence has revealed a significant interaction between mi-croglia and oligodendrocytes in CNS injury and disease.It was reported that M2 microglia promoted,while M1 microglia inhibited oligodendrogenesis,OPCs maturation and remyelination.Microglia-mediated neuroinflamma-tion,considered as an important pathological event,neg-atively affected OPCs fate and function in experimental neurological disorders.This was further corroborated by later studies.It was recently reported that montelukast enhanced OPCs differentiation and maturation by upreg-ulating the number of M2 microglia at chronic phase of brain ischemia.In line with the above results,inhibition of microglial inflammation by montelukast was shown to be responsible for neurite outgrowth.Although the exact mechanisms were not fully clarified,these results indi-cate that montelukast may indirectly promote OPCs dif-ferentiation and remyelination by a microglia-dependent manner.It has been widely accepted that CysLT1,CysLT2 and GPR17 receptors are localized in various cell types and their expression are upregulated after brain damage.Therefore,it is likely that CysLT receptor antagonists confer neuroprotection by targeting different receptors and multiple cell functions.Many studies have reported that CysLT receptor antagonists promote protec-tion of oligodendrocytes by inhibiting GPR17.Moreover,they may improve OPCs differentiation and neuronal sur-vival by regulating CysLTs-mediated microglial activation.Altogether,these data open novel perspectives in the treatment of cerebral ischemia and neurodegenerative diseases.

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)

Regulation of epigenetic state by non-histone chromatin proteins and transcription factors: Implications in disease

Besides the fundamental components of the chromatin, DNA and octameric histone, the non-histone chromatinproteins and non-coding RNA play a critical role in the organization of functional chromatin domains. Thenon-histone chromatin proteins therefore regulate the transcriptional outcome in both physiological andpathophysiological state as well. They also help to maintain the epigenetic state of the genome indirectly.Several transcription factors and histone interacting factors also contribute in the maintenance of the epigeneticstates, especially acetylation by the induction of autoacetylation ability of p300/CBP. Alterations of KATactivity have been found to be causally related to disease manifestation, and thus could be potential therapeutictarget.

Neuromodulatory effects of ethyl acetate fraction of Zingiber officinale Roscoe extract in rats with lead-induced oxidative stress / 中西医结合学报

OBJECTIVE@#This study investigated the ameliorative potential of Zingiber officinale Roscoe extract against lead-induced brain damage in rats.@*METHODS@#Thirty male rats were divided into 5 groups of 6 rats each. Lead-acetate toxicity was induced by intraperitoneal injection (10 mg/kg body weight (b.w.)) in Groups B-E. Group A (control) and Group B (lead-acetate) were left untreated; vitamin C (200 mg/kg b.w.) was administered to Group C; ethyl acetate fraction from Z. officinale extract (200 and 100 mg/kg b.w.) was administered to Group D and E by oral gavage once daily for 7 days. Changes in the content of some key marker enzymes such as acetylcholinesterase (AChE), butyrylcholinesterase (BChE), monoamine oxidase (MAO), epinephrine, dopamine, Na/K-ATPase, catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (GPx) as well as malonaldehyde (MDA) levels were determined in serum.@*RESULTS@#Exposure to lead acetate resulted in a significant decrease (P < 0.05) in the activities of BChE, AChE, Na/K-ATPase, SOD, CAT and GPx with a corresponding increase in the levels of MDA, xanthine oxidase, epinephrine, dopamine and MAO relative to the control group. Levels of all disrupted parameters were alleviated by co-administration of Z. officinale fraction and by the standard drug, vitamin C.@*CONCLUSION@#These results suggest that ethyl acetate fraction of Z. officinale extract attenuates lead-induced brain damage and might have therapeutic potential as a supplement that can be applied in lead poisoning.

Peroxisome Proliferator-Activated Receptor-Review

Peroxisomes are subcellular organelles found in most plant and animal cells that perform diverse metabolic functions including hydrogen peroxide (H2O2)-based respiration, β-oxidation of fatty acids (FAs), and cholesterol metabolism. Peroxisomes are found in most eukaryotic cells, and their essential role has been emphasized by the discoveries of several human disorders caused by the lack of peroxisomes. Peroxisomes are unique for their ability to proliferate in response to several structurally different chemicals, which are designated "peroxisome proliferators (PPs)," in rodent liver cells. Peroxisome proliferator-activated receptors (PPARs) proteins belong to the superfamily of a phylogenetically related protein termed nuclear hormone factor. Activation of PPAR-? reduces triglyceride level and is involved in regulation of energy homeostasis. Activation of PPAR-? causes insulin sensitization and enhances glucose metabolism, whereas activation of PPAR-?/? enhances fatty acids metabolism. Thus, PPAR family of nuclear receptors plays a major regulatory role in energy homeostasis and metabolic function. Since intervention of PPAR agonist can provide therapeutic targets for a range of diseases such as dyslipidemia, diabetes, obesity, inflammation, a neurodegenerative disorder, and cancer, this review was carried out to update existing knowledge on these nuclear receptors

Three siblings with neuronal ceroid lipofuscinosis type 7 and 2 novel mutations in their MFSD8 gene / 中华实用儿科临床杂志

Objective The neuronal ceroid lipofuscinosis (CLN are a group of severe lysosomal storage diseases.The patients present with clinically and genetically heterogeneous neurodegenerative disorders.This study aims to investigate the clinical characteristics and the gene mutations of a rare Chinese family with 3 siblings affected by CLN7.Methods The proband,a 5-year-old girl,visited us because of intermittently seizures and mental retardation for 2 years and a half in December,2015.Clinical investigation,brain magnetic resonance imaging(MRI),biochemical and the gene analysis were performed for the etiological study.Results The proband had seizures at the age of 2 and a half years,with the progressive motor deterioration,speech disturbance,mental regression and vision loss.Her brain MRI showed diffusive cerebral atrophy.The blood aminoacids,acylcarnitine and urine organic acid profiles were normal.Lysosomal palmitoyl protein thioesterase and tripeptidyl peptidase activities of peripheral leukocytes were normal.A compound heterozygous mutation of c.1351-1G ＞ A and c.300T ＞ G was detected on her MFSD8 gene,supporting the diagnosis of CLN7.Both of the 2 mutations were novel.Each of her parents carried one of the mutations.Two brothers of the proband had similar clinical process.Her elder brother died at the age of 7 due to severe encephalopathy of unknown etiology.The younger brother showed dyskinesia from the age of 2 years and seizures from the age of 4 years.A compound heterozygous mutation on MFSD8 gene,c.1351-1G ＞ A and c.300T ＞ G,was found from the younger brother,as same as the proband.Conclusions CLN7 is a rare disorder of CLN.In this study,the diagnosis of the 3 siblings with similar clinical process were much delayed.Gene analysis was key for the diagnosis.Two novel mutations were found on MFSD8 of the family.There is still no effective treatment for neurol ceroid lipofuscinosis.The prognosis is poor.Based on the mutation diagnosis,prenatal diagnosis for the next sibling is possible to the prevention of the disease.

Calcium homeostasis modulator 1 ( CALHM1 ) polymorphisms in cattle

The calcium homeostasis modulator 1 gene (CALHM1), which is located on chromosome 10 in humans and on chromosome 26 in cattle, is a transmembrane glycoprotein that controls the cytosolic calcium concentrations. Altered calcium homeostasis has been associated with several neurodegenerative disorders, including Alzheimer's disease (AD). In a recent study, single nucleotide polymorphisms (SNPs) of CALHM1 have been associated with sporadic Creutzfeldt-Jakob disease (CJD). The protein sequence of human CALHM1 shows 93% homology with bovine CALHM1. Although SNPs of human CALHM1 have been correlated with human prion disease, polymorphisms of the bovine CALHM1 gene have not been reported in cattle thus far. To investigate polymorphisms of the bovine CALHM1 gene in Korean native cattle, we analyzed the open reading frame (ORF) of this gene in 175 Hanwoo and 141 Holstein cattle. We observed five SNPs: c.219C>T (rs380966453), c.357C>T (rs385969338), and c.869A>G (rs516301908) within the ORF region of two exons; and c.552+92A>G (rs481706737) and c.553-3A>C (rs448524869) in the intron of bovine CALHM1. Among the three SNPs that are in the ORF region of bovine CALHM1, the genotype and allele frequencies of the c.869A>G (p.His290Arg) and c.219C>T (p.Asn73Asn) SNPs were significantly different between Hanwoo and Holstein cattle (P<0.0001). Haplotype analysis showed that haplotypes ht2, ht3 and ht5 were also significantly different in these two cattle breeds. This study provides the first genetic analysis of the bovine CALHM1 gene in cattle.(AU)

Potential Therapeutic Targets of the Endocannabinoid System in Common Neurodegenerative Disorders and Organic Acidemias

Abstract The cannabinoid chemistry is currently being addressed in preclinical approaches as a viable therapeutic alternative for the management of a wide range of signs, symptoms, and some biochemical hallmarks of many neurological pathologies (such as neuroinflammation and neurodegeneration). This clinical orientation is grounded on the consistent promissory profile that cannabinoid compounds have shown, and the great necessity of feasible options to undergo such disorders. Even though at early research stages, metabolic disorders are starting to rise as potential targets of cannabinoid alternatives; approaches in this term could, in turn, aim to modulate the endocannabinoid response for therapeutic purposes. This review recalls the pathologic scenarios endured in the course of neurological diseases of high occurrence and the most typical metabolic disorders, while discussing the neuroprotective mechanisms of cannabinoid agonists in the central nervous system, and the potential targets of the endocannabinoid system and metabolic disorders.

Biología molecular de la enfermedad de Alzheimer / Molecular biology of Alzheimer's disease

Resumen:La enfermedad de Alzheimer (EA) es una enfermedad neurodegenerativa asociada con una disminución cognitiva y es la forma más común de demencia en los ancianos. Un gran número de factores se asocian con un riesgo aumentado de EA, no obstante, la edad representa, por mucho, el riesgo individual más grande en la etiología de la EA. La variante genética más fuerte para la EA típica de inicio tardío es la apolipoproteína E (APOE). Mutaciones raras en tres genes han sido implicadas en la enfermedad familiar de inicio temprano: APP, PSEN1 y PSEN2. Las placas amiloides extracelulares y los ovillos neurofibrilares intraneurales (NFT) son las dos lesiones características de esta enfermedad fatal. La proteína tau está involucrada en el ensamblaje y estabilización de los microtúbulos.La fosforilación anormal de tau, una característica prominente del cerebro con EA, decrece su habilidad de unión a los microtúbulos, pudiendo desestabilizar los microtúbulos y causar daño celular. Un grupo heterogéneo de péptidos Aβ monoméricos de entre 37 a 43 aminoácidos se genera a partir de la proteína precursora amiloide transmembrana (APP) por el corte mediado por las secretasas β y ץ. El monómero tiene una alta tendencia a autoagregarse formando agregados grandes y fibrillas. In vivoexiste una sopa de oligómeros de Aβ consistiendo de una gran variedad de formas intercambiables rápidamente, que difieren en tamaño, conformación, desorden intrínseco y toxicidad. Evidencia creciente sugiere que las formas más dañinas de los péptidos del amiloide β son los oligómeros solubles y que los depósitos amorfos e insolubles o fibrilares representan una forma inactivada menos peligrosa del péptido. Varios mecanismos han sido propuestos para explicar las anormalidades en la EA, incluyendo la toxicidad por Aβ, deficiencias del transporte axónico y el estrés oxidativo.

Abstract:Alzheimer disease (AD is a progressive neurodegenerative disease associated with cognitive decline and is the most common form of dementia in the enderly. A large number of factors has been associated with increased risk of AD, however, age represents, by far, the single greatest risk factor in the etiology of AD. The strongest common genetic variant for typical late-onset AD is apoliprotein E (APOE). Rare mutations in three genes have been implicated in familial early-onset disease: APP, PSEN1, and PSEN2.Extracellular amyloid plaques and intraneuronal neurofibrillary tangles (NFT) are two major hallmark lesions of this fatal pathology.Tau protein is involved in microtubule assembly and stabilization. Abnormal phosphorylation of tau, a prominent feature of AD brain, decreases its microtubule binding ability, which may destabilize microtubules and results in cellular damage.A heterogeneous pool of monomeric Aβ peptide varying in length from 37 to 43 amino acids is generated from the transmembrane amyloid precursor protein (APP) by β- and ץ-secretase-mediated cleavage. The Aβ monomer has a high tendency to self-assemble into large aggregates and fibrils.A diverse "Aβ oligomeric soup" exists, consisting of a large variety of rapidly exchangeable polymorphs that differ in size, conformation, intrinsic disorder, and toxicity.Growing evidence suggests that the most detrimental forms of amyloid β peptides are the soluble oligomers and that the insoluble amorphous or fibrillar deposits represent a less harmful inactivated form of the peptide.Several mechanisms have been proposed to account for abnormalities in AD, including Aβ toxicity, axonal transport deficiencies, and oxidative stress.

Thalamic superoxide and peroxide handling capacity (SPHC): An experimental study with aluminum, ethanol and tocopherol in rats.

Superoxide and peroxide handling capacity (SPHC) is an important determinant of oxidative stress. Neurotoxic impacts of aluminum are associated with oxidant imbalance. Here, we studied the influence of aluminum on oxidative stress parameters, antioxidative enzymes and SPHC of thalamic area on pro-oxidant (ethanol) and antioxidant (-tocopherol) exposure. Two sets of male Wistar rats were divided into 8 groups (6 each) and exposed to aluminum (10 mg/Kg body wt.), ethanol (0.6 g/Kg body wt.) and -tocopherol (5 IU/day) for 4 wk, each having respective control group. Levels of reduced glutathione (GSH), lipid peroxidation (TBARS) along with activities of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and glutathione reductase (GR) of thalamic area were estimated for each group. Glutathione-independent superoxide peroxide handling capacity (GI-SPHC) and glutathione-dependent superoxide peroxide handling capacity (GD-SPHC) were calculated from the GPx, CAT and SOD values. Concomitant exposure to aluminum and ethanol demonstrated significant increase in SOD activity and significant decrease in GPx activity compared to the control group, while lone aluminum-exposed rats showed raised GR activity, without alterations in GPx and SOD activities. However, significant reduction of both GI- and GD- SPHC were found in ethanol-exposed groups. -Tocopherol supplementation could resist most of the alterations. In addition, current antioxidant exposure reduced the inherent GD-SPHC, and thus, made thalamic area more vulnerable to oxidant threat. The present study corroborates the thalamic susceptibility to aluminum-augmented oxidant imbalance and suggests cautious use of antioxidant supplementation against neurodegenerative disorders.

Simulation of Peroxiredoxin II and Brain-type Creatine Kinase protein-protein interaction using the on-line docking server ClusPro 2.0.

Importance of dedicated web servers and specialized software for simulations of protein-protein interactions is well established. The purpose of our study was to examine the protein-protein interaction that occurred under physiological and stress conditions between peroxiredoxin II and the creatine kinase brain-type using protein-docking server ClusPro 2.0. To predict the particular site of amino acid docking, computer software analyzes various protein conformations and chooses the most profitable energy state, therefore selecting a number of possible combinations that would fit the correct profile. By co-immunoprecipitation assay, we demonstrated that two molecules Prx II and CKBB have interacted with further attenuation of this specific binding by pretreatment with selected stress factors. In previous study, we showed that the enzymatic activity of CKBB was recovered by different concentration ratios of Prx II. The specific binding models were generated by ClusPro 2.0 protein docking server and studied using PyMol software. It was shown that a number of amino acid residues including Lys 11, Arg 13, Ala 204, Arg 209for creatine kinase, and Asp 181, Glu 192, Lys 196, Glu 162, Gln 163 for Prx II have participated in the complex formation throughout the first ten conformations.

Microquimerismos en la enfermedadde Alzheimer y la demencia frontotemporal / Microchimerism in Alzheimer’s disease and frontotemporal dementia

Resumen: las enfermedades neurodegenerativas constituyen un problema global de salud pública que tiende a incrementarse. En la búsqueda de alternativas terapéuticas frente a estas afecciones aparecen los microquimerismos fetomaternales (células fetales en estados inmaduros de diferenciaciónadquiridas durante el embarazo) que, al tratarse de células madre, suponen una opción terapéutica similar a la terapia celular. Estudios recientes han demostrado el papel protector de los microquimerismos en la enfermedad de Alzheimer y la esclerosis múltiple; sin embargo, al tratarse de células provenientes de otro organismo surge la posibilidad de que induzcan una respuesta inmune que lleve a la aparición o potenciación de los procesos inflamatorios propios de las enfermedadesneurodegenerativas. De acuerdo con lo anterior, diversos estudios han sugerido un papel de los microquimerismos en el desarrollo de enfermedades autoinmunes. El esclarecimiento de las características, funciones, vías de ingreso, localización e interacciones de los microquimerismos con el sistema inmune del organismo hospedero es relevante en la medida en que pueden guiar el desarrollode tratamientos frente a este tipo de enfermedades. En esta revisión se describen algunos de estos aspectos relevantes.

Abstract: neurodegenerative diseases represent a major and increasing public health problem around the world. In the search for therapeutic alternatives against these conditions, feto-maternal microchimerisms (immature fetal cells acquired during pregnancy) appear as a possible therapeutic option similar to stem cell therapy. In fact, several studies have found that the microchimerisms play a protective role against Alzheimer´s disease and multiple sclerosis. Nonetheless, given the fact that the microchimerisms are ®foreign cells¼, they could induce an immune response, leading to the apparition or exacerbation of the inflammatory responses characteristic of neurodegenerative diseases.According to this, several studies have suggested a role for microchimerisms in the development of autoimmune diseases. The elucidation of characteristics, functions, ways of acquisition, paths of entry, localization, and interactions between microchimerisms and the immune system of the host can serve as a guide towards the development of a treatement against these disease. In this review, some of these important aspects are described.

Higher risk of complications in odynophagia-associated dysphagia in amyotrophic lateral sclerosis / Disfagia associada a odinofagia na esclerose lateral amiotrofica pode sugerir maior risco para complicacoes pulmonares e nutricionais

Objective This investigation aimed to identify associated factors with dysphagia severity in amyotrophic lateral sclerosis (ALS). Method We performed a cross-sectional study of 49 patients with ALS. All patients underwent fiberoptic endoscopy evaluation of swallowing and answered a verbal questionnaire about swallowing complaints. The patients were divided into groups according to dysphagia severity. Results Among the factors analyzed, only odynophagia was associated with moderate or severe dysphagia. Conclusion Odynophagia was associated with moderate and severe dysphagia in ALS and suggests a high risk of pulmonary and nutritional complications. .

Objetivo Identificar fatores associados com a gravidade da disfagia na esclerose lateral amiotrófica (ELA). Método Estudo transversal incluindo 49 sujeitos com esclerose lateral amiotrófica. Todos foram submetidos à videoendoscopia da deglutição e responderam a um questionário sobre queixas de deglutição. Foram divididos em grupos de acordo com a gravidade da disfagia. Resultados Dentre os fatores estudados, apenas a odinofagia foi significantemente associada à disfagia moderada ou grave. Conclusão A odinofagia foi associada à disfagia moderada ou grave na ELA e sua presença sugere maior risco para complicações pulmonares e nutricionais. .

Application of Iron Related Magnetic Resonance Imaging in the Neurological Disorders / 대한임상신경생리학회지

Iron is an important element for brain oxygen transport, myelination, DNA synthesis and neurotransmission. However, excessive iron can generate reactive oxygen species and contribute neurotoxicity. Although brain iron deposition is the natural process with normal aging, excessive iron accumulation is also observed in various neurological disorders such as neurodegeneration with brain iron accumulation, Parkinson's disease, Alzheimer's disease, multiple sclerosis, Friedreich ataxia, and others. Magnetic resonance image (MRI) is a useful method for detecting iron deposits in the brain. It can be a powerful tool for diagnosis and monitoring, while furthering our understanding of the role of iron in the pathophysiology of a disease. In this review, we will introduce the mechanism of iron toxicity and the basics of several iron-related MRI techniques. Also, we will summarize the previous results concerning the clinical application of such MR imagings in various neurological disorders.

Rol del eje tirotrópico en enfermedades neurodegenerativas / Thyrotropic Axis Role in Neurodegenerative Disorders

Las hormonas tiroideas actúan como reguladores primarios del metabolismo intermediario en todos los tejidos del organismo; tienen funciones de gran trascendencia a nivel del sistema nervioso, donde ejercen acciones potencialmente neuroprotectoras. Los niveles de las hormonas tiroideas están sujetos a una estrecha regulación en el sistema nervioso y se sugiere que incluso ligeras desviaciones del rango de normalidad pueden estar asociadas a enfermedades neurodegenerativas. En esta revisión se resumieron los hallazgos existentes en torno al papel de las hormonas tiroideas en la fisiología normal y patológica del sistema nervioso, con énfasis en enfermedades neurodegenerativas y los mecanismos moleculares implicados. Las evidencias indican un rol significativo para las hormonas tiroideas en varias enfermedades neurodegenerativas, si bien es necesaria la realización de estudios prospectivos de mayor envergadura para precisar su función y evaluar su utilidad como bio-marcadores y dianas terapéuticas.

Thyroid hormones are primary regulators of intermediate metabolism in all body tissues. Particularly, they have very important functions at the level of nervous system, even having potentially neuro-protective effects. Usually, thyroid hormone levels are under a very close regulation in the nervous system and, because of that, small deviations from the normality range can be associated to neurodegenerative conditions. In this review, evidences about the roles of thyroid hormones in normal and pathological physiology of the nervous system are summarized, with an emphasis in neurodegenerative disorders and the molecular mechanisms involved. Findings suggest a significant role for thyroid hormones in several neurodegenerative diseases, although larger prospective studies are needed to clarify their function and to assess their usefulness as biomarkers and therapeutic targets.

Sleep pattern and learning in knockdown mice with reduced cholinergic neurotransmission

Impaired cholinergic neurotransmission can affect memory formation and influence sleep-wake cycles (SWC). In the present study, we describe the SWC in mice with a deficient vesicular acetylcholine transporter (VAChT) system, previously characterized as presenting reduced acetylcholine release and cognitive and behavioral dysfunctions. Continuous, chronic ECoG and EMG recordings were used to evaluate the SWC pattern during light and dark phases in VAChT knockdown heterozygous (VAChT-KDHET, n=7) and wild-type (WT, n=7) mice. SWC were evaluated for sleep efficiency, total amount and mean duration of slow-wave, intermediate and paradoxical sleep, as well as the number of awakenings from sleep. After recording SWC, contextual fear-conditioning tests were used as an acetylcholine-dependent learning paradigm. The results showed that sleep efficiency in VAChT-KDHET animals was similar to that of WT mice, but that the SWC was more fragmented. Fragmentation was characterized by an increase in the number of awakenings, mainly during intermediate sleep. VAChT-KDHET animals performed poorly in the contextual fear-conditioning paradigm (mean freezing time: 34.4±3.1 and 44.5±3.3 s for WT and VAChT-KDHET animals, respectively), which was followed by a 45% reduction in the number of paradoxical sleep episodes after the training session. Taken together, the results show that reduced cholinergic transmission led to sleep fragmentation and learning impairment. We discuss the results on the basis of cholinergic plasticity and its relevance to sleep homeostasis. We suggest that VAChT-KDHET mice could be a useful model to test cholinergic drugs used to treat sleep dysfunction in neurodegenerative disorders.

Copper interactions with DNA of chromatin and its role in neurodegenerative disorders / 药物分析学报

In this study, we have demonstrated the conformational changes to DNA induced by abnormal interactions of copper using circular dichroism, in combination with UV-absorbance and fluorescence spectroscopy. Results confirm that binding of copper to bases of DNA in chromatin is concentration dependent. Binding efficiency of Cu2+ions to DNA is increased in proportion to the degree of unwinding of the double helix induced by denaturation. Altered B-DNA conformation will alter the integrity of DNA which may affect the normal process of DNA replication and transcription. Copper induced DNA damage in the brain may cause neurotoxicity and the neuronal cell death and is implicated in Alzheimer's disease and other neurological disorders.

Amyloidogenic Protein of alpha-Synuclein / 한양의대학술지

Amyloidogenesis is the key pathological phenomenon commonly observed in various neurodegenerative disorders. alpha-Synuclein is the major constituent of Lewy bodies as a common pathological signature of Lewy body diseases (LBDs) including Parkinson's disease (PD), PD with dementia (PDD), and Dementia with Lewy bodies (DLB). As proteins unfold, they would result in producing either ordered or disordered aggregates unless they are folded back to the native state by molecular chaperones or removed via proteolytic degradation. alpha-Synuclein known as a natively unfolded protein has self-assembled into the ordered protein aggregates of amyloid fibrils which comprise the radiating filaments found in Lewy bodies. Amyloid fibrils are generated via either a template-dependent or template-independent mechanism. The prevalent nucleation-dependent fibrillation accelerates the assembly process in the presence of seeds such as prefibrillar species. As a template-independent process, we have recently proposed the double-concerted fibrillation mechanism in which the oligomeric species of alpha-synuclein act as a growing unit to form the mature fibrils. Despite insufficient understanding of the toxic causes of alpha-synuclein, the oligomeric species have been suggested to be responsible for the cellular degeneration by influencing membrane stability while leaving the amyloid fibrils as a detoxification end product. Alternatively, the transition process from the oligomers to the fibrils has been proposed to affect cell viability. It is, therefore, expected to develop prophylactic and therapeutic strategies toward the synucleinopathies by studying cellular function of alpha-synuclein, molecular mechanism of its assembly into the amyloid fibrils, and their effects on cellular biogenesis. By studying cellular function of alpha-synuclein, its molecular mechanism of assembly into amyloid fibrils and their effects on cellular biogenesis, progress of prophylactic and therapeutic strategies toward synucleinopathy can be seen.

Doença de Parkinson / Parkinson disease

Em 1817 James Parkinson descrevia pela primeira vez a síndrome parkinsoniana ou a paralisia agitante. Não poderia jamais imaginar que em 2010, após tantos anos de sua descrição e, apesar do enorme desenvolvimento de conhecimentos sobre a doença que havia relatado, ainda não existiria um marcador biológico que pudesse ser utilizado para o seu diagnóstico. E assim é: ainda não contamos com recursos laboratoriais ou de imagens que nos forneça o diagnóstico da doença de Parkinson.Com o envelhecimento da população, conquista de nosso século, espera-se um crescimento quase dramático da frequência de algumas patologias que atingem mais a população acima dos 60 anos. A doença descrita por Parkinson é uma das neurodegenerativas mais comuns nessa faixa etária. A evolução da doença, a gravidade e progressão dos sintomas variam de paciente para paciente. Tremor de repouso, bradicinesia, rigidez e anormalidades posturais estão entre os sinais e sintomas mais frequentes.Levodopa é ainda o padrão-ouro do tratamento sintomático das manifestações da doença. Muitos outros fármacos e diferentes estratégias terapêuticas foram avaliados para o controle ou melhora das complicações motoras da doença e, embora parcialmente eficazes, devem ser usados para proporcionar uma melhora da qualidade de vida do paciente.