1,721,207 research outputs found
The neurochemistry of morphine addiction in the neocortex.
No full textDifferent strategies have been used in an attempt to understand the neurobiology of opioid addiction. Here, Michele Simonato initially discusses the identification of key anatomical areas involved in the phenomenon and proposes an explanation of opioid addiction based on the theory of complexity. The variable importance of direct and indirect effects in phenotypically different neuronal populations cam imply differences in the adaptive changes that occur with chronic morphine exposure. Opioid addiction is therefore proposed as a complex multicellular event, where individual neurones differentially adapt both on the basis of the signals they receive and of their second messengers and genetic programmes
Innovative gene therapies for epilepsy treatment (EPIXCHANGE)
No full textA significant part of the costs of neurological diseases on society is associated with epilepsy. About 30-40% of the patients are refractory to pharmacological treatments, which are mostly symptomatic and often have side effects. In few cases surgical intervention is considered and no treatments interfering with or preventing the development of epilepsy are currently available. In this context, EPIXCHANGE aims at exploring, providing the basis for clinical application and implementing in the industrial arena new and unconventional strategies for the therapy of partial epilepsy advancing the state-of-the-art in the field. To achieve this, a strategic partnership will be created, including two internationally recognized academic institutions (UniFE, ULund) and two SMEs (NsGene, Bioviron) developing encapsulated cell biodelivery (ECB) based and amplicon-based therapeutic products. ECBs will be transferred to the academic partners, while knowledge and technology on animal models, viral vectors and BDNF-producing cells will be transferred to the SME.
This partnership will implement a joint research programme, which will enable to exploit the complementary competencies and technologies available at each participant site and will increase the knowledge-sharing and technology transfer, as well as the mutual understanding and penetration of the different cultural settings and skills required for both academic and industrial sectors, thus improving partners’ RTD capability and competitiveness.
This will be combined with transfer of knowledge on complementary skills. Experienced researchers will be also recruited to bring top level experience in techniques that are not present in the consortium. Annual workshops will be organized to benefit the transfer of knowledge programme and the dissemination of results both within the consortium and towards the scientific community
Gene therapy for epilepsy
No full textGene therapy may represent an effective alternative to standard pharmacological approaches for certain forms of epilepsy. Currently, the best candidates for this therapeutic approach appear to be epilepsies characterized by a focal lesion. Gene therapy has been attempted to produce antiepileptogenic (prevention of development of epilepsy in subject at risk after having received an epileptogenic insult), antiseizure (reduction of frequency and/or severity of seizures), and disease-modifying (alteration of the natural history of the disease) effects. An example of gene therapy aimed at producing antiepileptogenic effects is a combination therapy based on the supplementation of the neurotrophic factors brain-derived neurotrophic factor (BDNF) and fibroblast growth factor 2 (FGF-2). Antiseizure effects have been obtained by increasing the strength of inhibitory signals (by supplementing specific GABAA receptor subunits or inhibitory neuropeptides like galanin or neuropeptide Y) or by reducing the strength of excitatory signals (by knocking downNMDA receptor subunits). This review summarizes the results obtained to date using gene therapy in epilepsy models and discusses the challenges and the opportunities that this approach can offer for the treatment of human epilepsies
Fisiologia e fisiopatologia di BDNF: verso lo sviluppo di nuove strategie terapeutiche per alcune delle principali malattie neuro-psichiatriche
No full textLa neurotrofina BDNF (Brain-Derived Neurotrophic Factor) esercita molteplici effetti sul sistema nervoso centrale: non solo è in grado di aumentare la sopravvivenza dei neuroni adulti e di favorire la differenziazione neuronale delle cellule progenitrici neurali, ma è anche implicata in modificazioni plastiche di tipo strutturale (per esempio nella genesi dei dendriti) e sinaptico (per esempio nel potenziamento delle sinapsi eccitatorie). In ragione di questi effetti, la modulazione del sistema BDNF è stata proposta come un nuovo approccio terapeutico per molte malattie neurologiche e neuropsichiatriche. Questa strategia, tuttavia, si è rivelata difficile da realizzare, per almeno due ordini di problemi. In primo luogo, BDNF può esercitare effetti differenti, e talvolta addirittura opposti, in dipendenza da diversi fattori: lo splicing alternativo del suo mRNA, il processamento della forma pro- verso quella matura, la specifica struttura cellulare su cui agisce, il sottotipo recettoriale (ad alta o bassa affinità), la via di trasduzione del segnale attivata. Comprendere in dettaglio la biologia di BDNF e trovare il modo per interferire selettivamente con effetti specifici della neurotrofina sarà essenziale per sviluppare efficaci strategie terapeutiche, prive di effetti collaterali indesiderati (o addirittura paradossali). In secondo luogo, BDNF è di natura peptidica e dovrebbe essere veicolato specificatamente nell'area cerebrale affetta da una determinata patologia al fine di evitare effetti indesiderati. Questa considerazione evidenzia il problema del delivery: devono essere sviluppate strategie per veicolare BDNF e far sì che la sua azione terapeutica si eserciti in modo selettivo nell'area dove è necessaria.
Lo scopo principale di questo progetto è di contribuire alla soluzione di questi problemi, identificando nuove strategie terapeutiche e testando la loro applicazione alle principali malattie neurologiche. Il progetto coinvolge 8 gruppi di ricerca molto attivi nei settori delle neurotrofine e della trasmissione sinaptica, con un particolare interesse ai meccanismi molecolari e cellulari dei disordini neurologici, con un track record collaudato ed una storia consolidata di collaborazione scientifica. I diversi partner si scambieranno reagenti, protocolli sperimentali e know-how, linee cellulari e modelli di topi transgenici.
Le dieci principali linee di ricerca saranno organizzati in work-packages:
1) analisi delle varianti di splicing dell'mRNA di BDNF e loro regolazione farmacologica;
2) meccanismi degli effetti di BDNF sulla maturazione e sull'integrazione funzionale dei neuroni neo-generati nel cervello adulto;
3) ruolo delle sinapsine (SYN, una famiglia di fosfoproteine associate alle vescicole sinaptiche) e di BDNF sulla neurogenesi ippocampale;
4) studi strutturali e funzionali di BDNF e proBDNF e loro interazioni con TrkB, p75NTR e sortilin;
5) manipolazioni transgeniche di BDNF nel pesce short-lived nothobranchius furzeri;
6) effetto terapeutico di BDNF in modelli murini della sindrome di Rett e studio degli effetti di un BDNF mutante, privo della potenziale attività epilettogena;
7) ruolo neuroprotettivo di BDNF nella malattia di Alzheimer;
8) analisi epigenetica di un modello animale di patologie neuropsichiatriche umane che possiedono il polimorfismo val66met;
9) sviluppo del sistema GABAergico in topi privi del fattore di trascrizione Engrailed2 (topi EN2-/-, un modello per i disturbi dello spettro autistico) e ruolo di BDNF
in questo processo;
10) implicazione di BDNF in epilessie focali e sviluppo di strategie di rilascio selettivo della neurotrofina nella zona epilettogena.
La proposta ha un forte razionale scientifico, un solido background sperimentale dei gruppi partecipanti (sia generale che specifico su BDNF) e, infine, utilizza tecnologie sperimentali “state of the art”. I risultati potranno fornire informazioni utili per lo sviluppo di nuovi approcci terapeutici per il trattamento di disturbi neurologici e psichiatrici
Sistemi di gestione energeticamente efficiente dei forni combinati ad uso professionale.
Full text linkL'attività di ricerca è stata finalizzata allo sviluppo di strategie d'uso efficacie di forni combinati ad uso professionale. Nella fattispecie, si è cercato di ridurre i consumi d'esercizio e le tempistiche di funzionamento, pur mantenendo ottimale la qualità di cottura. Il risultato è stata l'individuazione di un set di regole d'utilizzo, implementate nel sistema di controllo elettronico dei forni
Neurotrophic factors and status epilepticus
No full textBecause of their strong effects on cell survival and on synaptic function, neurotrophic factors (NTFs) have been hypothesized to be involved in some aspects of status epilepticus (SE) and in its possible consequences. This hypothesis has been explored mainly for 2 NTFs, namely fibroblast growth factor 2 (FGF-2) and brain-derived neurotrophic factor (BDNF). This article focuses on these 2 NTFs. I first summarize their biologic features and then describe existing evidence supporting their implication in SE and its outcomes. Available data support a direct implication of FGF-2 and BDNF in SE and in its consequences. However, these NTFs have been found to exert some contrasting effects, for example, to favor seizures but protect from cell damage. A better understanding of the mechanisms of FGF-2 and BDNF biosynthesis and signaling will be therefore instrumental for the development of therapeutic strategies that are not compromised by paradoxical side effects
Epilepsy an Update on Disease Mechanisms: The Potential Role of MicroRNAs
No full textSo far, research on epilepsy mechanisms has been designed mainly using animal models and tracking down molecular mechanisms underlying seizures in that model. While this approach is clearly valuable, it can be questioned if it is the best possible. One attractive alternative approach may stem from the consideration of epilepsy as a complex disease of a very complex organ, the brain. This short review summarizes data from analyses of the alterations in expression of microRNAs and their target messenger RNAs in a specific brain subregion, the dentate gyrus of the hippocampus, in three experimental models of lesional epilepsy. The findings are discussed within the conceptual framework of complex systems
Fibroblast Growth Factor-2 (FGF-2).
No full textEpileptogenesis and epilepsy progression are associated with rearrangements of neuronal circuits mediated by such processes as sprouting, neuronal cell death, and neurogenesis. These processes lead to hyperexcitability, spontaneous seizures, and/or worsening of seizure severity/frequency. Neurotrophic factors, and the Fibroblast Growth Factor-2 (FGF-2) in particular, are mediators for these reorganizational processes, and thus may play a role in epileptic phenomena. In this article, we will summarize and discuss the data supporting this hypothesis. Experimental evidence demonstrates that: 1) Seizures increase FGF-2 mRNA and protein levels in specific brain areas, and up-regulate the expression of the FGF-2 high-affinity receptor, FGFR-1; 2) Acute injection of FGF-2 causes seizures, while chronic infusion of low dose FGF-2 does not affect kainate-induced seizures but reduces hippocampal damage; 3) Kainate-induced seizure severity is not altered in FGF-2 knock-out mice, but is increased in FGF-2 over-expressing mice. Thus, FGF-2 may be implicated in seizure susceptibility and in seizure-induced plasticity, exerting two different, and apparently contrasting effects - favoring ictogenesis but reducing seizure-induced cell death. Dissecting out the mechanisms underlying these effects will be critical in pursuing the goal of controlling seizures and their deleterious consequences through modulation of the FGF-2 system
Gene networks and microRNAs: Promises and challenges for treating epilepsies and their comorbidities
No full textNeurobiology research has used an essentially reductionist approach for many years, dissecting out the brain in more simple elements. Recent technical advances, like systems biology, have made now possible to embrace a more holistic vision and try to tackle the complexity of the system. In this short review, we describe how these approaches, in particular analyses or gene networks and of microRNAs, may be useful for epilepsy research. We will describe and discuss recent studies that illustrate how these research approaches can lead to the identification of therapeutic targets and pharmacological strategies to prevent or treat some forms of epilepsy. We aim to show that studying epilepsy and its comorbidities within a complex system framework is a promising integration to the traditional reductionist approaches, and that it will become more and more important in the future for developing new therapies
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