Effect of myricetin on cognitive impairments in the transgenic Drosophila model of Parkinson’s Disease

Parkinson’s Disease (PD) is a progressive neurodegenerative disorder involving the loss of dopaminergic neurons. Despite the availability of many drugs to ease the life of PD patients, there is no permanent cure until now. Now-a-days, there has been a considerable attention towards the use of herbal products to treat PD patients worldwide due to less side effects. In this context, here we investigated myricetin, a common plant derived flavonoid, on the cognitive impairments exhibited by the transgenic Drosophila expressing human ?-synuclein in the neurons. The PD flies were allowed to feed on the diet having 10, 20 and 40 ?M of myricetin for 24 days and then assayed for cognitive impairments. The exposure of myricetin showed a dose dependent significant delay in the cognitive impairments. Molecular docking studies showed the positive interaction between myricetin and ?-synuclein. The results suggest a protective effect of myricetin against the cognitive impairments.

Homocysteine Induced Neurological Dysfunctions: A Link to Neurodegenerative Disorders

Excessive level of Homocysteine (Hcy) is considered a neurotoxin since it has a very deleterious effect on the nervous system. It is a sulfur-containing amino acid that is reversibly formed and secreted during metabolism. Preclinically and clinically, Hcy exhibits several neurological mechanisms that have been reported in the pathogenesis of Alzheimer’s disease, stroke, Parkinson’s disease, multiple sclerosis, epilepsy, neuronal cell death, and amyotrophic lateral sclerosis. Homocysteine may promote Alzheimer’s disease by more than one mechanism, including oxidative stress, neuronal cell damage, tau phosphorylation, enhancement of beta-amyloid aggregation, and hyperactivation of NMDA receptor. Moreover, it increases the production of chemokines by stimulation of nuclear factor-kappa B. It is well known that the use of levodopa diminishes the symptoms of Parkinson’s disease but also lead to an elevation in the level of homocysteine. In this review, we highlight the associate relationship between hyperhomocysteinemia and neurological disorders by discussing its neurodegenerative effects.

Síntomas no motores en pacientes con enfermedad de Parkinson / Non motor symptoms in patients with Parkinson´s disease

Se realizó un estudio prospectivo de 44 pacientes con enfermedad de Parkinson, atendidos en la consulta de Trastornos del Movimiento del Hospital Provincial Docente Clinicoquirúrgico Saturnino Lora Torres de Santiago de Cuba, desde agosto de 2013 hasta julio de 2015, con vistas a determinar la frecuencia de aparición de síntomas no motores. Entre los más frecuentes figuraron los siguientes: depresión (72,7 por ciento), nicturia (68,2 por ciento), ansiedad (54,6 por ciento), síndrome de piernas inquietas (50,0 por ciento), estreñimiento (47,7 por ciento) e insomnio (40,9 por ciento), por citar algunos. Cabe destacar que 95,5 por ciento de los afectados presentó algún síntoma y el promedio por paciente fue de 7,45, con menor aparición durante el primer año de la enfermedad

A prospective study of 44 patients with Parkinson´s disease assisted in the service for movement disorders of Saturnino Lora Torres Teaching Clinical Surgical Provincial Hospital in Santiago de Cuba, was carried out from August, 2013 to July, 2015, aimed at determining the emergence frequency of non motors symptoms. Among the most frequent symptoms there were: depression (72.7 percent), nicturia (68.2 percent), anxiety (54.6 percent), restless legs syndrome (50.0 percent), constipation (47.7 percent) and insomnia (40.9 percent), just to mention some of them. It is necessary to highlight that 95.5 percent of the affected patients presented some symptom and the average for patient was 7.45, with less emergence during the first year of the disease

Presentación atípica de la enfermedad de Alexander infantil sin macrocefalia / An atypical presentation of Infantile Alexander disease lacking macrocephaly

Resumen: Introducción: La enfermedad de Alexander consiste en una forma de leucodistrofia poco frecuente que afecta principalmente a los astrocitos; tiene un patrón de herencia autosómica recesiva y es causada por mutaciones en el gen GFAP, localizado en el cromosoma 17q21. Puede presentarse a cualquier edad y la forma infantil se caracteriza por macrocefalia, crisis convulsivas, retraso motor y cognitivo grave y espasticidad o ataxia progresivas. Caso clínico: Paciente de sexo femenino de 8 meses evaluada por retraso psicomotor y crisis convulsivas motoras focales no provocadas. En la exploración física, con perímetro cefálico normal, respuesta motora incrementada ante estímulos táctiles y al ruido, signos piramidales y ausencia de visceromegalias. Se observó hipodensidad generalizada de la sustancia blanca en la resonancia magnética y punción lumbar con hiperproteinorraquia. Se descartó enfermedad de Krabbe mediante ensayo enzimático y secuenciación del gen GALC. En la reevaluación del caso, las alteraciones en la neuroimagen hicieron sospechar de enfermedad de Alexander, y la secuenciación del gen GFAP reportó una mutación en el exón 4 c.716G > A, lo que ocasionó un cambio de arginina por histidina en la posición 239 de la proteína (p.Arg239His). Conclusiones: Los signos radiológicos en la resonancia fueron determinantes para el diagnóstico, que posteriormente se confirmó con estudio molecular. Es importante considerar que ciertas mutaciones no se asocian con macrocefalia, lo cual puede ocasionar retraso en el diagnóstico.

Abstract: Background: Alexander disease is a rare form of leukodystrophy that involves mainly astrocytes; it is inherited in an autosomal recessive manner and occurs by mutations in the GFAP gene, located on chromosome 17q21. It can occur at any age and its infantile form is characterized by macrocephaly, seizures, severe motor and cognitive delay, and progressive spasticity or ataxia. Case report: An 8-month-old female was evaluated with a history of neurodevelopmental delay and unprovoked focal motor seizures. Physical examination showed normal head circumference, increased motor responses to tactile and noise stimuli, pyramidal signs and no visceromegalies. Widespread hypodense white matter was found on magnetic resonance and lumbar puncture showed hyperproteinorrachia. Krabbe disease was ruled out by enzymatic assay and gene sequencing of GALC. In the reassessment of the case, abnormalities in neuroimaging lead to suspicion of Alexander disease, and GFAP gene sequencing reported a pathogenic mutation in exon 4 c.716G > A, which caused a change of arginine to histidine at position 239 of the protein (p.Arg239His). Conclusions: The radiographic signs observed in the resonance were decisive for the diagnosis, later confirmed by molecular study. It is important to consider that certain mutations are not associated with macrocephaly, which may cause delay in diagnosis.

Beneficial effect of diosgenin as a stimulator of NGF on the brain with neuronal damage induced by Aβ-42 accumulation and neurotoxicant injection / 한국실험동물학회지

To investigate the beneficial effects of diosgenin (DG) on the multiple types of brain damage induced by Aβ-42 peptides and neurotoxicants, alterations in the specific aspects of brain functions were measured in trimethyltin (TMT)-injected transgenic 2576 (TG) mice that had been pretreated with DG for 21 days. Multiple types of damage were successfully induced by Aβ-42 accumulation and TMT injection into the brains of TG mice. However, DG treatment significantly reduced the number of Aβ-stained plaques and dead cells in the granule cells layer of the dentate gyrus. Significant suppression of acetylcholinesterase (AChE) activity and Bax/Bcl-2 expression was also observed in the DG treated TG mice (TG+DG group) when compared with those of the vehicle (VC) treated TG mice (TG+VC group). Additionally, the concentration of nerve growth factor (NGF) was dramatically enhanced in TG+DG group, although it was lower in the TG+VC group than the non-transgenic (nTG) group. Furthermore, the decreased phosphorylation of downstream members in the TrkA high affinity receptor signaling pathway in the TG+VC group was significantly recovered in the TG+DG group. A similar pattern was observed in p75NTR expression and JNK phosphorylation in the NGF low affinity receptor signaling pathway. Moreover, superoxide dismutase (SOD) activity was enhanced in the TG+DG group, while the level of malondialdehyde (MDA), a marker of lipid peroxidation, was lower in the TG+DG group than the TG+VC group. These results suggest that DG could exert a wide range of beneficial activities for multiple types of brain damage through stimulation of NGF biosynthesis.

Development on neurodegenerative disorder modeling with induced pluripotent stem cells / 中国药理学通报

Remarkable advances in cellular reprogramming have made it possible to investigate relevant cell populations derived from induced pluripotent stem cells ( iPSCs ) of patients. Be-cause many diseases have its specific genetic information, using the cells to convert into iPSCs can build up a set of genetic pro-file of diseases. The iPSCs which contain the genetic contribution of the donor can be expanded and differentiated into cells of the affected lineages to show aberrant phenotypes in culture. To date, over fifty such disease models have been reported, and while the field is young and hurdles remain, we can foresee the huge potential of it in drug screening. Recent studies using iP-SCs to model various neurogenetic disorders are summarized. Compared to the traditional methods, we analyze the future de-velopment of iPSC based disease models and its past application on high-throughput screening ( HTS) and high-content screening ( HCS) .

DNA triplex structures in neurodegenerative disorder, Friedreich’s ataxia.

It is now established that a small fraction of genomic DNA does adopt the non-canonical B-DNA structure or ‘unusual’ DNA structure. The unusual DNA structures like DNA-hairpin, cruciform, Z-DNA, triplex and tetraplex are represented as hotspots of chromosomal breaks, homologous recombination and gross chromosomal rearrangements since they are prone to the structural alterations. Friedreich’s ataxia (FRDA), the autosomal recessive degenerative disorder of nervous and muscles tissue, is caused by the massive expansion of (GAA) repeats that occur in the first intron of Frataxin gene X25 on chromosome 9q13-q21.1. The purine strand of the DNA in the expanded (GAA) repeat region folds back to form the (R∙R*Y) type of triplex, which further inhibits the frataxin gene expression, and this clearly suggests that the shape of DNA is the determining factor in the cellular function. FRDA is the only disease known so far to be associated with DNA triplex. Structural characterization of GAA-containing DNA triplexes using some simple biophysical methods like UV melting, UV absorption, circular dichroic spectroscopy and electrophoretic mobility shift assay are discussed. Further, the clinical aspects and genetic analysis of FRDA patients who carry (GAA) repeat expansions are presented. The potential of some small molecules that do not favour the DNA triplex formation as therapeutics for FRDA are also briefly discussed.

Elevated ferric, calcium and magnesium ions in the brain induce protein aggregation in brain mitochondria / El aumento de iones férricos, calcio y magnesio en el cerebro induce la agregación de proteínas en las mitocondrias del cerebro

OBJECTIVE: Alzheimer s disease and Parkinson s disease are two of several neurodegenerative disorders that affect the elderly. Although their aetiology remains uncertain, studies suggest that elevated aluminium or other metal ions in the brain directly influence the development of the histological abnormalities normally associated with these diseases; other investigations suggest that metal-ion-induced-dysfunction of mitochondria might be a critical factor. METHODS: In this study, the impact of elevated aluminum (Al3+), ferric (Fe3+), calcium (Ca2+) and magnesium (Mg2+) ions on brain histology and on the protein composition of brain mitochondria were evaluated. Rabbits were injected intra-cerebrally with 1.4% solutions of either aluminium chloride (AlCl3), ferric chloride (FeCl2), calcium chloride (CaCl2) or magnesium chloride (MgCl2) and sacrificed 10 days later. RESULTS: Histological analysis revealed that Al3+ but not the other ions induced neurofibrillary degeneration within the midbrain and medulla. Alternatively, SDS-PAGE revealed that Fe3+, Ca2+ and Mg2+ but not Al3+ induced alterations to the distribution of brain mitochondrial proteins. Both Fe3+ and Ca2+ triggered decreased concentration of three low molecular weight proteins (~7-14 kd) but Ca precipitated their total absence. Both ions led to increased concentration of a high molecular weight protein (~ 110 kd). In contrast, Mg2+ led to the total absence of the protein of lowest molecular weight (~7 kd) and increased concentration of a ~36 kd protein. CONCLUSION: These results suggest that elevation of some metal ions in the brain induces protein aggregation with the nature of the aggregation being highly ion dependent. The results also point toward major differences between the histopathological effect of Al3+ and other ions.

OBJETIVO: La enfermedad de Alzheimer y la enfermedad de Parkinson son dos de los varios trastornos neurodegenerativos que afectan al anciano. Aunque su etiologia sigue siendo incierta, los estudios sugieren que el aumento de los iones de aluminio, influyen directamente sobre el desarrollo de las anormalidades histológicas asociadas normalmente con estas enfermedades. Otras investigaciones sugieren que la disfunción de las mitocondrias, inducida por iones metálicos, pudiera ser un factor critico. MÉTODOS: Este estudio evalúa el impacto del aumento de los iones de aluminio (Al3+), los iones férricos (Fe3+), y los iones de calcio (Ca2+) y magnesio (Mg2+) sobre la histologia del cerebro y la composición proteica de las mitocondrias del cerebro. Un número de conejos recibieron inyecciones intracerebrales de soluciones al 1.4% de soluciones de cloruro de aluminio (AlCl3), cloruro ferroso (FeCl3), cloruro de calcio (CaCl2), o cloruro de magnesio (MgCl2), y fueron sacrificados después de 10 días. RESULTADOS: El análisis histológico reveló que el Al3+ indujo una degeneración neurofibrilar dentro del mesencéfalo y la médula, Sin embargo, esto no ocurrió con los otros iones. Alternativamente, la técnica de electroforesis SDS-PAGE reveló que los iones Fe3+, Ca2+ y Mg2+, a diferencia del ión Al3+, inducían alteraciones de la distribución de las proteínas mitocondriales cerebrales. Tanto el Fe3+ como el Ca2+ desencadenaron una disminución de la concentración de tres proteínas de bajo peso molecular (~7-14 kd) pero Ca2+ precipitó su ausencia total. Ambos iones condujeron a un aumento de una proteína de peso molecular alto (~ 110 kd). En cambio, Mg2+ llevó a la ausencia total de la proteína de más bajo peso molecular (~7 kd) y al aumento de la concentración de una proteína de ~36 kd. CONCLUSIÓN: Estos resultados parecen sugerir que la elevación de algunos iones de metal en el cerebro induce la agregación de la proteína, siendo la naturaleza de la agregación altamente dependiente de los iones. Los resultados también apuntan a grandes diferencias entre el efecto histopatológico del Al3+ y otros iones.

Role of PPAR, a Nuclear Hormone Receptor in Neuroprotection.

Peroxisome proliferator-activated receptors (PPARs) belong to the nuclear receptor superfamily. PPAR-alpha is involved in wound healing, stimulation of lipid and folic acid catabolism, inflammation control, inhibition of ureagenesis and peroxisome proliferation. The PPAR/ is involved wound healing, cell proliferation, embryo implantation, adipocyte differentiation, myelination alteration and apoptosis. The PPAR is involved in fat, lipid and calorie utilization, sugar control, inflammation control and macrophage (MQ) matutation. Homocysteine (Hcy) binds to nuclear peroxisome proliferator activated receptor. Increase in PPAR expression decreases the level of nitrotyrosine and increases endothelial nitric oxide concentration, decreases metalloproteinase activity and expression as well as elastinolysis and reverses Hcy-mediated vascular dysfunction. The PPAR initially recognized as a regulator of adipocyte development has become a potential therapeutic target for the treatment of diverse disorders. In addition, the activation of PPAR receptor ameliorates neurodegenerative disease. This review focuses on the recent knowledge of PPAR in neuroprotection and deals with the mechanism of neuroprotection of central nervous system disorder by PPAR.

Insights into Alzheimer disease pathogenesis from studies in transgenic animal models

Alzheimer disease is the most common cause of dementia among the elderly, accounting for ~60-70 percent of all cases of dementia. The neuropathological hallmarks of Alzheimer disease are senile plaques (mainly containing p-amyloid peptide derived from amyloid precursor protein) and neurofibrillary tangles (containing hyperphosphorylated Tau protein), along with neuronal loss. At present there is no effective treatment for Alzheimer disease. Given the prevalence and poor prognosis of the disease, the development of animal models has been a research priority to understand pathogenic mechanisms and to test therapeutic strategies. Most cases of Alzheimer disease occur sporadically in people over 65 years old, and are not genetically inherited. Roughly 5 percent of patients with Alzheimer disease have familial Alzheimer disease-that is, related to a genetic predisposition, including mutations in the amyloid precursor protein, presenilin 1, and presenilin 2 genes. The discovery of genes for familial Alzheimer disease has allowed transgenic models to be generated through the overexpression of the amyloid precursor protein and/or presenilins harboring one or several mutations found in familial Alzheimer disease. Although none of these models fully replicates the human disease, they have provided valuable insights into disease mechanisms as well as opportunities to test therapeutic approaches. This review describes the main transgenic mouse models of Alzheimer disease which have been adopted in Alzheimer disease research, and discusses the insights into Alzheimer disease pathogenesis from studies in such models. In summary, the Alzheimer disease mouse models have been the key to understanding the roles of soluble b-amyloid oligomers in disease pathogenesis, as well as of the relationship between p-amyloid and Tau pathologies.

The Diagnosis and Management for REM Sleep Behavior Disorder

Rapid eye movement sleep behavior disorder (RBD) is characterized by violent behaviors during sleep, related to loss of REM sleep atonia and enactment of dreams. In this article, clinical characteristics, diagnosis and management of RBD will be reviewed. In the next section, recent studies on relationships between associated neurodegenerative disorders and RBD will be discussed. Clinical implications of idiopathic RBD to potential neurologic disorders, especially synucleinopathy will be presented.

The Clinical use of quantitative EEG in cognitive disorders / A utilização clínica do EEG quantitativo nos transtornos cognitivos

Abstract: The primary diagnosis of most cognitive disorders is clinically based, but the EEG plays a role in evaluating, classifying and following some of these disorders. There is an ongoing debate over routine use of qEEG. Although many findings regarding the clinical use of quantitative EEG are awaiting validation by independent investigators while confirmatory clinical follow-up studies are also needed, qEEG can be cautiously used by a skilled neurophysiologist in cognitive dysfunctions to improve the analysis of background activity, slow/fast focal activity, subtle asymmetries, spikes and waves, as well as in longitudinal follow-ups.

Resumo: O uso clínico do EEG Quantitativo nas doenças cognitivas. O diagnóstico das doenças cognitivas geralmente é clínico mas o EEG é importante como exame auxiliar na avaliação, diagnóstico e classificação de algumas delas. O debate atual refere-se ao uso clínico do EEGq. Embora muitos achados no EEGq ainda aguardem validação, o EEGq pode ser usado cautelosamente em situações específicas e por um neurofisiologista experiente. Nas doenças cognitivas ele pode contribuir na análise da atividade de base, em atividades focais lentas ou rápidas, assimetrias sutís, pontas e ondas e no acompanhamento longitudinal dos pacientes.