sunyer

(Image caption: The study proves that fingolimod influences BDNF receptors and re-establishes their normal balance, by increasing TrkB and reducing p75NTR simultaneously. Credit: A. Miguez)

Researchers discovered new applications of the drug fingolimod to improve cognitive deficits in Huntington’s disease

Fingolimod, a drug used to treat multiple sclerosis, restores hippocampal synaptic plasticity and improves memory function. This is the main conclusion of a study developed by researchers at the University of Barcelona (UB) and the August Pi i Sunyer Biomedical Research Institute (IDIBAPS) in a mouse model of Huntington disease (HD). The study has been published in the journal Human Molecular Genetics and highlighted by the journal Nature Reviews Neurology.

“Preclinical results show an improvement of cognitive deficits in Huntington’s disease. Given the safety profile of the drug and the fact that it can also rescue motor deficits in HD mice, the study suggests that fingolimod can be an effective drug to treat Huntington’s disease. We believe it would be worthy to carry out clinical trials in the mid-term”, affirms Professor Jordi Alberch, head of the Consolidated Research Group on Pathophysiology of Neurodegenerative Diseases of the UB, IDIBAPS researcher and leader of the study.

Huntington’s disease is a progressive and irreversible neurodegenerative disorder caused by a mutation of the gene that codifies the protein huntingtin (HTT). In western countries, it affects between five and seven subjects out of 100,000. It is a rare hereditary disease which mainly affects basal ganglia and causes severe motor, cognitive and psychiatric disturbances. Remarkable advances have been done in basic research on Huntington’s disease; however, an effective treatment has not been found yet.

Drugs with new applications

The Consolidated Research Group on Pathophysiology of Neurodegenerative Diseases of the UB, affiliated with the Centre for Networked Biomedical Research on Neurodegenerative Diseases (CIBERNED), has studied the signalling pathways of brain-derived neurotrophic factor (BDNF) with receptors TrkB and p75NTR, a key factor in synaptic plasticity regulation, cognitive function and memory. In a previous study, the UB-IDIBAPS research team found that cognitive and synaptic deficits of Huntington’s disease patients linked to an imbalance between these two receptors.

The study proves that fingolimod influences BDNF receptors and re-establishes their normal balance, by increasing TrkB and reducing p75NTR simultaneously. From a cellular point of view, it attenuates over-activation of astrocytes and reduces neuroinflammation, ultimately leading to a better preservation of dendritic spines and memory function.

In order to reliably assess the utility of the drug in the chronic treatment of Huntington’s disease in a preclinical model, the drug was delivered to HD mice during 3 months, starting at presymptomatic stages. It was observed that memory deficits improved significantly in the long term and that mice performed better in spatial recognition tests.

“Findings constitute a significant step forward in understanding how fingolimod acts on brain cells; it has been proved that it can be an effective drug to treat diseases affecting the hippocampus, like Huntington’s disease and Alzheimer’s disease”, points out Andrés Miguez, researcher in the UB-IDIBAPS research group and first author of the paper. “Findings also open the door for studying cognitive function improvement in multiple sclerosis patients treated with fingolimod; this is an issue that has not been examined in detail yet even if it is estimated to occur in more than 50% of patients”, concludes Miguez.  

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The Esteve Pharmacy is a medieval pharmacy and museum located in the town of Llívia, in the comarca of Cerdanya, Catalonia, Spain. Llívia is a Spanish exclave within the French region of Pyrénées-Orientales. The Esteve Pharmacy, founded at the beginning of the 15th century,is one of the oldest pharmacies in Europe and keeps a collection of albarellos from the 16th and 17th centuries, glass from the 19th century, Renaissance boxes with portraits of saints and personages, a library, laboratory instruments, antique drugs and preparations, old prescription books, and a Baroque “cordialer” cupboard made by Josep Sunyer during the period when the Esteve family managed the pharmacy for up to seven generations. It is one of the most important collections of its kind in Europe.

In 1942, Lleó Antoni Esteve closed the pharmacy and moved to Puigcerdà. In 1958 the pharmacy was transferred to the Llívia town, and the Province of Girona Diputació purchased it in 1965.

Al nucli històric de Llívia, a la comarca de la Cerdanya, es troba el museu de la farmàcia Esteve de Llívia, una farmàcia d'origen medieval, probablement la més antiga de les que s'han conservat a Europa. Fundada possiblement a començament del segle XV, guarda una col·lecció de caixes renaixentistes amb retrats de sants i personatges; albarels (pots) del segle XVI i XVIII; un cordialer barroc tallat per Josep Sunyer en l'època en què la família Esteve es féu càrrec de la farmàcia i que mantindrà durant set generacions.

A la farmàcia es conserven bocals de vidre del segle XIX, així com una biblioteca, instruments de laboratori, drogues antigues, preparats, receptaris, etc. És, per tot això, un dels conjunts més importants d'Europa.

El 1942, Lleó Antoni Esteve va tancar la farmàcia i s'instal·là a Puigcerdà. El 1958 es va confiar la seva custòdia a l'Ajuntament de Llívia, i la Diputació de Girona la va comprar el 1965. Es va traslladar el contingut a la Torre Bernat de So i d'allà al nou edifici construït al costat de l'Ajuntament

I much prefer the nonsense of Picabia or any one of the silly Dadaist to the easygoing ways of my compatriots in Paris, stealing from Renoi (whose only value now is a classic) or producing a watered-down mixture of Sunyer and Matisse
—  Miró
Un fármaco contra la esclerosis múltiple podría tener aplicación en la enfermedad de Huntington

MADRID, 17 (EUROPA PRESS)

Investigadores de la Universidad de Barcelona (UB) y el Instituto de Investigaciones Biomédicas August Pi i Sunyer (IDIBAPS) han descubierto nuevas aplicaciones del medicamento ‘Fingolimod’ para mejorar los déficits cognitivos de la enfermedad de Huntington trabajando con ratones.

Se trata de un fármaco de uso común en el tratamiento de la esclerosis múltiple, y que también restituye la plasticidad sináptica del hipocampo y mejora las funciones de la memoria, según el estudio publicado en la revista 'Human Molecular Genetics’, destacado en 'Nature Reviews Neurology’ y recogido por la plataforma Sinc.

“Los resultados preclínicos muestran una mejora de los factores cognitivos en la enfermedad de Huntington. Teniendo en cuenta que el medicamento ya ha superado los test de seguridad, este trabajo destaca el 'Fingolimod’ como un medicamento prometedor para tratar la enfermedad de Huntington”, ha comentado el catedrático del Departamento de Biología Celular, Inmunología y Neurociencias de la UB y director de esta investigación, Jordi Alberch.

La patología de Huntington es un trastorno neurodegenerativo progresivo e irreversible originado por la mutación en el gen que codifica para la proteína huntingtina. Además, es enfermedad rara de carácter hereditario que en los países occidentales tiene una incidencia de cinco a siete afectados por cada 100.000 personas.

Afecta especialmente a los ganglios basales y causa alteraciones motoras, déficits cognitivos y desórdenes psiquiátricos. Sobre la enfermedad de Huntington se han logrado avances muy significativos en investigación básica, pero todavía no hay tratamientos efectivos.

El Grupo de Investigación Consolidado de Fisiopatología de Enfermedades Neurodegenerativas de la UB, vinculado al Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), ha estudiado durante años la vía de señalización del factor neurotrófico derivado del cerebro (BDNF) con los receptores TrkB y p75NTR, una vía considerada clave en la regulación de la plasticidad sináptica, el aprendizaje y la memoria.

Además, el equipo de la UB-IDIBAPS también constató en un trabajo anterior que los déficits cognitivos y sinápticos de los enfermos de Huntington están estrechamente relacionados con un desequilibrio en estos dos receptores.

NIVELES EN LOS RECEPTORES DE BDNF

En concreto, en este nuevo trabajo se muestra de qué manera el 'Fingolimod’ influye en los niveles de los receptores de BDNF: restablece su equilibrio normal haciendo aumentar el TrkB y disminuir el p75NTR de manera simultánea.

De hecho, desde el punto de vista celular, atenúa la sobreactivación de los astrocitos y reduce el efecto inflamatorio en la membrana de las neuronas del hipocampo, lo que contribuye a preservar las espinas dendríticas y la función de la memoria.

Para determinar la validez de este medicamento en el tratamiento crónico de la enfermedad de Huntington en modelos preclínicos, se administró durante tres meses a ratones que tenían la enfermedad en estadios iniciales. Como resultado se mostró que los ratones tratados mostraban una disminución significativa de los déficits de memoria a largo plazo y hacían mejor las pruebas de reconocimiento espacial.

“Los resultados constituyen un paso importante para entender cómo actúa el 'Fingolimod’ sobre las células del cerebro; se comprueba que puede ser un fármaco adecuado en enfermedades en las que se ve afectado el hipocampo, como la enfermedad de Huntington o la de Alzheimer. "También se abre la puerta al estudio para mejorar la función cognitiva en enfermos de esclerosis múltiple tratados con este medicamento, un campo poco estudiado hasta ahora a pesar de que afecta a cerca del 50 por ciento de los enfermos”, ha zanjado el investigador del mismo grupo UB-IDIBAPS y primer firmante del trabajo, Andrés Miguez.

New suggestive genetic loci and biological pathways for attention function in adult attention-deficit/hyperactivity disorder.

PubMed: Related Articles

New suggestive genetic loci and biological pathways for attention function in adult attention-deficit/hyperactivity disorder.

Am J Med Genet B Neuropsychiatr Genet. 2015 Jul 14;

Authors: Alemany S, Ribasés M, Vilor-Tejedor N, Bustamante M, Sánchez-Mora C, Bosch R, Richarte V, Cormand B, Casas M, Ramos-Quiroga JA, Sunyer JS

Abstract
Attention deficit is one of the core symptoms of the attention-deficit/hyperactivity disorder (ADHD). However, the specific genetic variants that may be associated with attention function in adult ADHD remain largely unknown. The present study aimed to identifying SNPs associated with attention function in adult ADHD and tested whether these associations were enriched for specific biological pathways. Commissions, hit-reaction time (HRT), the standard error of HRT (HRTSE), and intraindividual coefficient variability (ICV) of the Conners Continuous Performance Test (CPT-II) were assessed in 479 unmedicated adult ADHD individuals. A Genome-Wide Association Study (GWAS) was conducted for each outcome and, subsequently, gene set enrichment analyses were performed. Although no SNPs reached genome-wide significance (P  http://dlvr.it/BXzG8s

Sleep Disorders in Parkinsonian and Nonparkinsonian LRRK2 Mutation Carriers.

PubMed: Sleep Disorders in Parkinsonian and Nonparkinsonian LRRK2 Mutation Carriers.

PLoS One. 2015;10(7):e0132368

Authors: Pont-Sunyer C, Iranzo A, Gaig C, Fernández-Arcos A, Vilas D, Valldeoriola F, Compta Y, Fernández-Santiago R, Fernández M, Bayés A, Calopa M, Casquero P, de Fàbregues O, Jaumà S, Puente V, Salamero M, José Martí M, Santamaría J, Tolosa E

Abstract
OBJECTIVE: In idiopathic Parkinson disease (IPD) sleep disorders are common and may antedate the onset of parkinsonism. Based on the clinical similarities between IPD and Parkinson disease associated with LRRK2 gene mutations (LRRK2-PD), we aimed to characterize sleep in parkinsonian and nonmanifesting LRRK2 mutation carriers (NMC).
METHODS: A comprehensive interview conducted by sleep specialists, validated sleep scales and questionnaires, and video-polysomnography followed by multiple sleep latency test (MSLT) assessed sleep in 18 LRRK2-PD (17 carrying G2019S and one R1441G mutations), 17 NMC (11 G2019S, three R1441G, three R1441C), 14 non-manifesting non-carriers (NMNC) and 19 unrelated IPD.
RESULTS: Sleep complaints were frequent in LRRK2-PD patients; 78% reported poor sleep quality, 33% sleep onset insomnia, 56% sleep fragmentation and 39% early awakening. Sleep onset insomnia correlated with depressive symptoms and poor sleep quality. In LRRK2-PD, excessive daytime sleepiness (EDS) was a complaint in 33% patients and short sleep latencies on the MSLT, which are indicative of objective EDS, were found in 71%. Sleep attacks occurred in three LRRK2-PD patients and a narcoleptic phenotype was not observed. REM sleep behavior disorder (RBD) was diagnosed in three LRRK2-PD. EDS and RBD were always reported to start after the onset of parkinsonism in LRRK2-PD. In NMC, EDS was rarely reported and RBD was absent. When compared to IPD, sleep onset insomnia was more significantly frequent, EDS was similar, and RBD was less significantly frequent and less severe in LRRK2-PD. In NMC, RBD was not detected and sleep complaints were much less frequent than in LRRK2-PD. No differences were observed in sleep between NMC and NMNC.
CONCLUSIONS: Sleep complaints are frequent in LRRK2-PDand show a pattern that when compared to IPD is characterized by more frequent sleep onset insomnia, similar EDS and less prominent RBD. Unlike in IPD, RBD and EDS seem to be not markers of the prodromal stage of LRRK2-PD.

PMID: 26177462 [PubMed - as supplied by publisher] http://dlvr.it/BXmztx