Riluzole protects Huntington disease patients from brain glucose hypometabolism and grey matter volume loss and increases production of neurotrophins

Squitieri, Ferdinando; Orobello, Sara; Cannella, Milena; Martino, Tiziana; Romanelli, Pantaleo; Giovacchini, Giampiero; Frati, Luigi; Mansi, Luigi; Ciarmiello, Andrea

doi:10.1007/s00259-009-1103-3

Cited by 57 publications

(48 citation statements)

References 30 publications

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“…These striatal hypometabolic patterns have important implications in regard of the potential usefulness of 18 F-FDG PET/CT, not just focusing on following disease progression, but also monitoring the potential effects of candidate diseasemodifying therapies, even if focused on premanifest subjects [27,28]. In this line, a recent study demonstrated a linear correlation between progressive striatal hypometabolism and severity of UHDRS scores in subjects treated with placebo compared to subjects treated with disease-modifying therapies (riluzole) [34]. In subjects treated with disease-modifying therapies, the metabolism was preserved, different from patients treated with placebo, suggesting that disease-modifying therapies may protect from the progressive hypometabolism in HD subjects.…”

Section: Discussionmentioning

confidence: 99%

Striatal hypometabolism in premanifest and manifest Huntington’s disease patients

López-Mora

Camacho

Pérez‐Pérez

et al. 2016

Eur J Nucl Med Mol Imaging

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F-FDG PET/CT might be a helpful tool to identify patterns of glucose metabolism in the striatum across the stages of HD and might be relevant in assessing the clinical status of gene-expanded HD carriers due to the fact that dysfunctional glucose metabolism begins at early preHD stages of the disease. F-FDG PET/CT appears as a promising method to monitor the response to disease-modifying therapies even if applied in premanifest subjects.

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Section: Discussionmentioning

confidence: 99%

Striatal hypometabolism in premanifest and manifest Huntington’s disease patients

López-Mora

Camacho

Pérez‐Pérez

et al. 2016

Eur J Nucl Med Mol Imaging

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“…However, other non-invasively strategies have been reported to increase BDNF in the HD brains such as drug administration [61,69,70]. Thus, combination therapy with the pGFAP-BDNF construct and administration of a drug such as ampakines [69] could be crucial to fully recover the HD phenotype.…”

Section: Discussionmentioning

confidence: 99%

Conditional BDNF release under pathological conditions improves Huntington's disease pathology by delaying neuronal dysfunction

Giralt

Carretón

Lao-Peregrin

et al. 2011

Mol Neurodegeneration

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BackgroundBrain-Derived Neurotrophic Factor (BDNF) is the main candidate for neuroprotective therapy for Huntington's disease (HD), but its conditional administration is one of its most challenging problems.ResultsHere we used transgenic mice that over-express BDNF under the control of the Glial Fibrillary Acidic Protein (GFAP) promoter (pGFAP-BDNF mice) to test whether up-regulation and release of BDNF, dependent on astrogliosis, could be protective in HD. Thus, we cross-mated pGFAP-BDNF mice with R6/2 mice to generate a double-mutant mouse with mutant huntingtin protein and with a conditional over-expression of BDNF, only under pathological conditions. In these R6/2:pGFAP-BDNF animals, the decrease in striatal BDNF levels induced by mutant huntingtin was prevented in comparison to R6/2 animals at 12 weeks of age. The recovery of the neurotrophin levels in R6/2:pGFAP-BDNF mice correlated with an improvement in several motor coordination tasks and with a significant delay in anxiety and clasping alterations. Therefore, we next examined a possible improvement in cortico-striatal connectivity in R62:pGFAP-BDNF mice. Interestingly, we found that the over-expression of BDNF prevented the decrease of cortico-striatal presynaptic (VGLUT1) and postsynaptic (PSD-95) markers in the R6/2:pGFAP-BDNF striatum. Electrophysiological studies also showed that basal synaptic transmission and synaptic fatigue both improved in R6/2:pGAP-BDNF mice.ConclusionsThese results indicate that the conditional administration of BDNF under the GFAP promoter could become a therapeutic strategy for HD due to its positive effects on synaptic plasticity.

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“…RI, 9 ME 10 and MB 8 were used to treat HD-NPCs and determine if viability and cytotoxicity can be improved. After 24 hours treatment, no significant improvement in viability and cytotoxicity were observed in WT-NPCs and HD-NPCs (Fig.…”

Section: Resultsmentioning

confidence: 99%

Induced Pluripotent HD Monkey Stem Cells Derived Neural Cells for Drug Discovery

et al. 2017

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Huntington’s disease (HD) is a neurodegenerative disease caused by an expansion of CAG trinucleotide repeat (polyglutamine; polyQ) in the huntingtin (HTT) gene which leads to the formation of mutant HTT (mHTT) protein aggregates. In the nervous system, an accumulation of mHTT protein results in glutamate-mediated excitotoxicity, proteosome instability and apoptosis. Although HD pathogenesis has been extensively studied, effective treatment of HD has yet to be developed. Therapeutic discovery research in HD has been reported using yeast, cells derived from transgenic animal models and HD patients and induced pluripotent stem cell (iPSCs) from patients. A transgenic nonhuman primate model of HD (HD monkey) shows neuropathological, behavioral and molecular changes similar to an HD patient. Additionally, neural progenitor cell (NPC) derived from HD monkeys can be maintained in culture and differentiated to neural cells with distinct HD cellular phenotypes including the formation of mHTT aggregates, intranuclear inclusions and increased susceptibility to oxidative stress. Here, we evaluated the potential application of HD monkey NPCs (HD-NPCs) and neural cells (HD-NCs) as an in vitro model for HD drug discovery research.

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Riluzole protects Huntington disease patients from brain glucose hypometabolism and grey matter volume loss and increases production of neurotrophins

Abstract: The linear correlation between decreased metabolic FDG uptake and worsening clinical scores in the placebo-treated patients suggests that FDG-PET may be a valuable procedure to assess brain markers of HD.

Cited by 57 publications

References 30 publications

Striatal hypometabolism in premanifest and manifest Huntington’s disease patients

Striatal hypometabolism in premanifest and manifest Huntington’s disease patients

Conditional BDNF release under pathological conditions improves Huntington's disease pathology by delaying neuronal dysfunction

Induced Pluripotent HD Monkey Stem Cells Derived Neural Cells for Drug Discovery

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