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Publications (90) View all
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Article: Progress in gene therapy for neurological disorders.
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ABSTRACT: Diseases of the nervous system have devastating effects and are widely distributed among the population, being especially prevalent in the elderly. These diseases are often caused by inherited genetic mutations that result in abnormal nervous system development, neurodegeneration, or impaired neuronal function. Other causes of neurological diseases include genetic and epigenetic changes induced by environmental insults, injury, disease-related events or inflammatory processes. Standard medical and surgical practice has not proved effective in curing or treating these diseases, and appropriate pharmaceuticals do not exist or are insufficient to slow disease progression. Gene therapy is emerging as a powerful approach with potential to treat and even cure some of the most common diseases of the nervous system. Gene therapy for neurological diseases has been made possible through progress in understanding the underlying disease mechanisms, particularly those involving sensory neurons, and also by improvement of gene vector design, therapeutic gene selection, and methods of delivery. Progress in the field has renewed our optimism for gene therapy as a treatment modality that can be used by neurologists, ophthalmologists and neurosurgeons. In this Review, we describe the promising gene therapy strategies that have the potential to treat patients with neurological diseases and discuss prospects for future development of gene therapy.Nature Reviews Neurology 04/2013; · 12.46 Impact Factor -
Article: Nociceptin/Orphanin FQ Receptor Agonists Attenuate L-DOPA-Induced Dyskinesias.
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ABSTRACT: In the present study we investigated whether the neuropeptide nociceptin/orphanin FQ (N/OFQ), previously implicated in the pathogenesis of Parkinson's disease, also affects l-DOPA-induced dyskinesia. In striatal slices of naive rodents, N/OFQ (0.1-1 μm) prevented the increase of ERK phosphorylation and the loss of depotentiation of synaptic plasticity induced by the D1 receptor agonist SKF38393 in spiny neurons. In vivo, exogenous N/OFQ (0.03-1 nmol, i.c.v.) or a synthetic N/OFQ receptor agonist given systemically (0.01-1 mg/Kg) attenuated dyskinesias expression in 6-hydroxydopamine hemilesioned rats primed with l-DOPA, without causing primary hypolocomotive effects. Conversely, N/OFQ receptor antagonists worsened dyskinesia expression. In vivo microdialysis revealed that N/OFQ prevented dyskinesias simultaneously with its neurochemical correlates such as the surge of nigral GABA and glutamate, and the reduction of thalamic GABA. Regional microinjections revealed that N/OFQ attenuated dyskinesias more potently and effectively when microinjected in striatum than substantia nigra (SN) reticulata, whereas N/OFQ receptor antagonists were ineffective in striatum but worsened dyskinesias when given in SN. Quantitative autoradiography showed an increase in N/OFQ receptor binding in striatum and a reduction in SN of both unprimed and dyskinetic 6-hydroxydopamine rats, consistent with opposite adaptive changes of N/OFQ transmission. Finally, the N/OFQ receptor synthetic agonist also reduced dyskinesia expression in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated dyskinetic macaques without affecting the global parkinsonian score. We conclude that N/OFQ receptor agonists may represent a novel strategy to counteract l-DOPA-induced dyskinesias. Their action is possibly mediated by upregulated striatal N/OFQ receptors opposing the D1 receptor-mediated overactivation of the striatonigral direct pathway.Journal of Neuroscience 11/2012; 32(46):16106-16119. · 7.11 Impact Factor -
Article: Loss of cortical GABA terminals in Unverricht-Lundborg disease.
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ABSTRACT: Unverricht-Lundborg disease (ULD) is the most common progressive myoclonic epilepsy. Its etiology has been identified in a defect of a protease inhibitor, cystatin B (CSTB), but the mechanism(s) by which this defect translates in the clinical manifestations of the disease are still obscure. We tested the hypothesis that ULD is accompanied by a loss of cortical GABA inhibition in a murine model (the CSTB knockout mouse) and in a human case. Cortical GABA signaling has been investigated measuring VGAT immunohistochemistry (a histological marker of the density of GABA terminals), GABA release from synaptosomes and paired-pulse stimulation. In CSTB knockout mice, a progressive decrease in neocortex thickness was found, associated with a prevalent loss of GABA interneurons. A marked reduction in VGAT labeling was found in the cortex of both CSTB knockout mice and an ULD patient. This implicates a reduction in GABA synaptic transmission, which was confirmed in the mouse model as reduction in GABA release from isolated nerve terminals and as loss of electrophysiologically measured GABA inhibition. The alterations in VGAT immunolabeling progressed in time, paralleling the worsening of myoclonus. These results provide direct evidence that loss of cortical GABA input occurs in a relevant animal model and in a case of human ULD, leading to a condition of latent hyperexcitability that favors myoclonus and seizures. These findings contribute to the understanding of the pathogenic mechanism of ULD and of the neurobiological basis of the effect of currently employed drugs.Neurobiology of Disease 04/2012; 47(2):216-24. · 5.40 Impact Factor -
Article: By-stander effect on brain tissue of mesoangioblasts producing neurotrophins.
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ABSTRACT: Neurotrophic factors (NTFs) are involved in the regulation of neuronal survival and function and, thus, may be used to treat neurological diseases associated with neuronal death. A major hurdle for their clinical application is the delivery mode. We describe here a new strategy, based on the use of progenitor cells called mesoangioblasts (MABs). MABs can be isolated from post-natal mesoderm tissues and, because of a high adhesin-dependent migratory capacity, can reach perivascular targets especially in damaged areas. We generated genetically modified MABs producing Nerve Growth Factor (MABs-NGF) or Brain-Derived Neurotrophic Factor (MABs-BDNF) and assessed their by-stander effects in vitro using PC12 cells, primary cultures and organotypic cultures of adult hippocampal slices. MABs-NGF-conditioned medium induced differentiation of PC12 cells, while MABs-BDNF-conditioned medium increased viability of cultured neurons and slices. Slices cultured with MABs-BDNF medium also better retained their morphology and functional connections, and all these effects were abolished by the TrkB kinase blocker K252a or the BDNF scavenger TrkB-IgG. Interestingly, the amount of BDNF released by MABs-BDNF produced greater effects than an identical amount of recombinant BDNF, suggesting that other NTFs produced by MABs synergize with BDNF. Thus, MABs can be an effective vehicle for NTF delivery, promoting differentiation, survival and functionality of neurons. In summary, MABs hold distinct advantages over other, currently evaluated, approaches for NTF delivery in the CNS, including synergy of MAB-produced NTF with the neurotrophins. Since MABs may be capable of homing into damaged brain areas, they represent a conceptually novel, promising therapeutic approach to treat neurodegenerative diseases.Cell Transplantation 04/2012; · 5.13 Impact Factor -
Article: Evaluation of cell damage in organotypic hippocampal slice culture from adult mouse: a potential model system to study neuroprotection.
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ABSTRACT: The use of organotypic hippocampal slice culture (OHSC) has become a powerful tool for studying cell damage in different neuropathological states, since it reproduces the basic morphological and functional properties of hippocampal neuronal network. However, the conventional OHSCs are established from postnatal animals rather than adult. Here we reevaluated the features of cell death in adult OHSC in detail and found potential utility for the study of neuroprotection. Organotypic culture of hippocampal slices from adult mice under conventional conditions led to a time-dependent and reproducible cell death. Around 6days in vitro (DIV), slices lost 50% of the cells, based on LDH release assessment. The cell death was greater than 90% after DIV 15. The cell loss was linearly correlated (r=0.944, P<0.01) with the time in culture. The electrophysiological responses to the stimulus in the cultured adult slices were accordingly reduced. The cell degeneration during adult OHSC might be utilized as a tool for studying neuroprotective effects in drug development. To illustrate this potential use, adult OHSCs were challenged with brain-derived neurotrophic factor (BDNF). We found that the continuous supplementation of 300ng/ml BDNF promoted cell survival of adult OHSC. Using immunohistochemistry and Western blot analyses of neuronal markers, we also demonstrated the pro-survival effects of BDNF on neurons in the adult OHSC system. It is suggested that OHSCs from adult mice might provide an alternative model system for neuronal degeneration, suitable for studying physiological factors and pharmacological compounds contributing to neuronal survival.Brain research 02/2011; 1385:68-76. · 2.46 Impact Factor
