National Neurological Institute
National Neurological Institute
Feligioni M.,EBRI European Brain Research Institute |
Mango D.,EBRI European Brain Research Institute |
Piccinin S.,EBRI European Brain Research Institute |
Imbriani P.,University of Rome Tor Vergata |
And 9 more authors.
Synapse | Year: 2016
Homozygous or heterozygous mutations in the PTEN-induced kinase 1 (PINK1) gene have been linked to early-onset Parkinson's disease (PD). Several neurophysiological studies have demonstrated alterations in striatal synaptic plasticity along with impaired dopamine release in PINK1-deficient mice. Using electrophysiological methods, here we show that PINK1 loss of function causes a progressive increase of spontaneous glutamate-mediated synaptic events in the hippocampus, without influencing long-term potentiation. Moreover, fluorescence analysis reveals increased neurotrasmitter release although our biochemical results failed to detect which presynaptic proteins might be engaged. This study provides a novel role for PINK1 beyond the physiology of nigrostriatal dopaminergic circuit. Specifically, PINK1 might contribute to preserve synaptic function and glutamatergic homeostasis in the hippocampus, a brain region underlying cognition. The subtle changes in excitatory transmission here observed might be a pathogenic precursor to excitotoxic neurodegeneration and cognitive decline often observed in PD. Using electrophysiological and fluorescence techniques, we demonstrate that lack of PINK1 causes increased excitatory transmission and neurotransmitter release in the hippocampus, which might lead to the cognitive decline often observed in Parkinson's disease. Synapse 70:223-230, 2016. Using electrophysiological and fluorescence techniques, we demonstrate that lack of PINK1 causes increased excitatory transmission and neurotransmitter release in the hippocampus, which might lead to the cognitive decline often observed in Parkinson's disease. © 2016 Wiley Periodicals, Inc.
PubMed | University of Aarhus, National Neurological Institute, University of Insubria and University of Piemonte Orientale
Type: | Journal: Scientific reports | Year: 2016
Parkinsons disease (PD) is characterized by loss of dopaminergic neurons in substantia nigra pars compacta, -synuclein (-syn)-rich intraneuronal inclusions (Lewy bodies), and microglial activation. Emerging evidence suggests that CD4+ T lymphocytes contribute to neuroinflammation in PD. Since the mainstay of PD treatment is dopaminergic substitution therapy and dopamine is an established transmitter connecting nervous and immune systems, we examined CD4+ T naive and memory lymphocytes in PD patients and in healthy subjects (HS), with specific regard to dopaminergic receptor (DR) expression. In addition, the in vitro effects of -syn were assessed on CD4+ T naive and memory cells. Results showed extensive association between DR expression in T lymphocytes and motor dysfunction, as assessed by UPDRS Part III score. In total and CD4+ T naive cells expression of D
Krauss G.L.,Johns Hopkins University |
Perucca E.,National Neurological Institute |
Perucca E.,University of Pavia |
Ben-Menachem E.,Sahlgrenska Academy |
And 9 more authors.
Epilepsia | Year: 2014
Objective To evaluate safety, tolerability, seizure frequency, and regional variations in treatment responses with the AMPA antagonist, perampanel, in a large extension study during up to 3 years of treatment. Methods Patients ≥12 years old with partial-onset seizures despite treatment with 1-3 antiepileptic drugs at baseline completed a perampanel phase III trial and entered extension study 307 (NCT00735397). Patients were titrated to 12 mg/day (or their individual maximum tolerated dose) during the blinded conversion period, followed by open-label maintenance. Exposure, safety (adverse events [AEs], vital signs, weight, electrocardiography [ECG], laboratory values) and seizure outcomes were analyzed; key measures were assessed by geographic regions. Results Among 1,216 patients, median exposure was 1.5 years (range 1 week to 3.3 years), with >300 patients treated for >2 years. Treatment retention was 58.5% at cutoff. AEs reported in ≥10% of patients were dizziness, somnolence, headache, fatigue, irritability, and weight increase. Only dizziness and irritability caused discontinuation in >1% of patients (3.9% and 1.3%, respectively). The only serious AEs reported in >1% of patients were epilepsy-related (convulsion, 3.0%; status epilepticus, 1.1%). No clinically relevant changes in vital signs, ECG or laboratory parameters were seen. After titration/conversion, responder rate and median percentage change from baseline in seizure frequency were stable: 46% for both measures at 9 months (in 980 patients with ≥9 months' exposure) and 58% and 60%, respectively, at 2 years (in the 337 patients with 2 years' exposure). Median percentage reduction in frequency of secondarily generalized (SG) seizures ranged from 77% at 9 months (N = 422) to 90% at 2 years (N = 141). Among the 694 patients with maintenance data ≥1 year, 5.3% were seizure-free for the entire year. Significance No new safety signals emerged during up to 3 years of perampanel exposure in 39 countries. Seizure responses remained stable, with marked reductions, particularly in SG seizures. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here. © 2014 The Authors. Epilepsia published by Wiley Periodicals, Inc. on behalf of International League Against Epilepsy.
PubMed | National Neurological Institute and University of Milan
Type: | Journal: Ecancermedicalscience | Year: 2015
During the last 20 years, numerous studies have highlighted the need to consider Quality of Life (QoL) issues in the treatment of brain cancer. However, gaps in scientific knowledge are still present as we have poor data surrounding the whole experience in patients and regarding their needs. The present study was aimed at evaluating QoL in brain cancer patients and correlated aspects. In particular, we aimed to assess QoL, mood state, and emotional issues in order to describe the patients experience to find out the critical aspects involved.We obtained data from 85 patients during chemotherapy treatment at the National Neurological Institute C. Besta of Milan, Italy. We used standardised questionnaires to assess different aspects of patients QoL. In particular, the functional assessment of cancer therapy-brain (FACT-Br) and the Hamilton scale were used. We also performed a semi-structured ad hoc interview in order to collect -narrative data about patients experience.Our data depict a difficult adjustment process to the illness, even though positive elements emerged. Indeed, patients reported a satisfying self-perceived QoL, although specific concerns are still present. Further, even if many patients report depressive symptoms, only a minority have a severe condition.Brain cancer may heavily affect patients QoL and well being. However, some element of the context may improve the -adjustment to the disease. In particular, we found that most patients found psychosocial resources to cope with cancer and that spiritual well being also seems to play a key role. These issues deserve further studies in order to obtain significant clinical recommendations.
Lodi R.,University of Bologna |
Tonon C.,University of Bologna |
Valentino M.L.,University of Bologna |
Manners D.,University of Bologna |
And 12 more authors.
Archives of Neurology | Year: 2011
Objective: To assess whether impaired energy metabolism in skeletal muscle is a hallmark feature of patients with dominant optic atrophy due to several different mutations in the OPA1 gene. Design: We used phosphorus 31 magnetic resonance spectroscopy to assess calf muscle oxidative metabolism in subjects with molecularly defined dominant optic atrophy carrying different mutations in the OPA1 gene. In a subset of patients, we also evaluated serum lactate levels after exercise and muscle biopsy results for histology and mitochondrial DNA analysis. Setting: University neuromuscular and neurogenetics and magnetic resonance imaging units. Patients: Eighteen patients with dominant optic atrophy were enrolled from 8 unrelated families, 7 of which carried an OPA1 mutation predicted to induce haplo-insufficiency and 1 with a missense mutation in exon 27. Fifteen patients had documented optic atrophy. Main Outcome Measures: Presence of skeletal muscle mitochondrial oxidative phosphorylation dysfunction as assessed by phosphorus 31 magnetic resonance spectroscopy, serum lactate levels, and histological and mitochondrial DNA analysis. Results: Phosphorus 31 magnetic resonance spectroscopy showed reduced phosphorylation potential in the calf muscle at rest in patients with an OPA1 mutation (-24% from normal mean; P = .003) as well as a reduced maximum rate of mitochondrial adenosine triphosphate synthesis (-36%; P<.001; ranging from -28% to -49% in association with different mutations). In 4 of 10 patients (40%), the serum lactate level after exercise was elevated. Only 2 of 5 muscle biopsies, from the 2 patients with a missense mutation, showed slight myopathic changes. Low levels of mitochondrial DNA multiple deletions were found in all muscle biopsies. Conclusions: Defective oxidative phosphorylation in skeletal muscle is a subclinical feature of patients with OPA1-related dominant optic atrophy, indicating a systemic expression of the OPA1 defect, similar to that previously reported for Leber hereditary optic neuropathy due to complex I dysfunction. This defect of oxidative phosphorylation does not appear to depend on the low amounts of mitochondrial DNA multiple deletions detected in muscle biopsies. ©2011 American Medical Association. All rights reserved.
Grazzi L.,National Neurological Institute |
Chiapparini L.,National Neurological Institute |
Ferraro S.,National Neurological Institute |
Usai S.,National Neurological Institute |
And 4 more authors.
Headache | Year: 2010
Background. - Chronic migraine with symptomatic medication overuse (CMwMO) is a common and often debilitating clinical condition. Withdrawal of the offending drug(s) is considered the first step in management. Functional magnetic resonance imaging (fMRI) may be a useful technique for obtaining information on particular neuronal changes in the pain network involved in this condition. Objective. - To identify specific fMRI patterns in patients suffering from CMwMO before and after withdrawal intervention. Methods. - We collected fMRI data from a group of patients suffering from CMwMO, evaluating those patients prior to and 6 months following withdrawal. We applied stimuli at sites far removed from where the headaches were experienced. Moreover, pre-intervention fMRI data from the headache patients were compared with those obtained from headache-free and otherwise healthy controls. Results. - Before withdrawal, the right supramarginal gyrus, the right inferior and superior parietal cortex were hypoactive. Activity recovered to almost normal 6 months after withdrawal of the offending medications. Conclusions. - The hypoactivation we detected in the lateral pain system indicate that there exists a modification of the pain network in CMwMO and that these changes are reversible with therapy. © 2010 American Headache Society.
Fattore C.,National Neurological Institute |
Perucca E.,National Neurological Institute |
Perucca E.,University of Pavia
Drugs | Year: 2011
Despite the introduction of many second-generation antiepileptic drugs (AEDs) in the last 2 decades, the proportion of individuals with pharmacoresistant epilepsy has not been reduced substantially compared with the late 1960s. All currently available AEDs also have limitations in terms of adverse effects and susceptibility to be involved in clinically important drug-drug interactions. Therefore, the search for potentially more effective and better tolerated agents is continuing. This article reviews the pharmacological and clinical profile of the latest compounds to receive marketing authorization.Since the beginning of 2008, three novel AEDs, lacosamide, eslicarbazepine acetate and retigabine (also known as ezogabine), have become commercially available in Europe, with lacosamide and retigabine also being licensed in the US. All three agents are indicated for the adjunctive treatment of focal seizures in adults.Eslicarbazepine acetate is a produg for eslicarbazepine, which acts by blocking voltage-dependent sodium channels. Lacosamide enhances the slow inactivation phase of voltage-dependent sodium channels, and retigabine potentiates neuronal M-currents by opening Kv 7.27.5 potassium channels.All three agents, which are well absorbed from the gastrointestinal tract, exhibit linear pharmacokinetics. Lacosamide is also available as an intravenous formulation intended as replacement therapy for patients temporarily unable to take oral medications. All three drugs are eliminated partly unchanged in urine and partly by biotransformation through glucuronide conjugation (eslicarbazepine, retigabine), N-acetylation (retigabine) and oxidative demethylation (lacosamide). The half-life is in the order of 820 hours for eslicarbazepine, 1216 hours for lacosamide and 610 hours for retigabine. Based on the limited information available to date, the ability of these agents to cause pharmacokinetic drug interactions appears to be relatively modest, although eslicarbazepine can cause a significant decrease in the blood levels of ethinylestradiol, levonorgestrel and simvastatin.The approved effective dose ranges are 200400mgday in two divided doses for lacosamide, 8001200mgday once daily for eslicarbazepine acetate, and 6001200mgday in three divided doses for retigabine. In phase III, randomized, double-blind, adjunctive therapy trials, responder rates (proportion of patients with ≥50 reduction in seizure frequency vs baseline) at the highest approved dose were comparable for the three drugs (eslicarbazepine acetate: 3743 vs 1320 for placebo; lacosamide: 3841 vs 1826 for placebo; retigabine: 3344 vs 1618 for placebo). The adverse events most commonly reported with active treatment compared with placebo included dizziness, diplopia and nausea for lacosamide; dizziness, somnolence and nausea for eslicarbazepine acetate; and dizziness, somnolence and fatigue for retigabine.The role of these agents in the treatment algorithm will be increasingly defined as clinical experience accumulates. At present, their use is largely restricted to the adjunctive treatment of focal seizures, with or without secondary generalization, in adults with epilepsy who failed to achieve seizure freedom after having tried two or more first-line agents. © 2011 Adis Data Information BV. All rights reserved.
Ambrosi G.,National Neurological Institute |
Ambrosi G.,University of Pavia |
Cerri S.,National Neurological Institute |
Blandini F.,National Neurological Institute
Journal of Neural Transmission | Year: 2014
Increased levels of extracellular glutamate and hyperactivation of glutamatergic receptors in the basal ganglia trigger a critical cascade of events involving both intracellular pathways and cell-to-cell interactions that affect cell viability and promote neuronal death. The ensemble of these glutamate-triggered events is responsible for excitotoxicity, a phenomenon involved in several pathological conditions affecting the central nervous system, including a neurodegenerative disease such as Parkinson’s disease (PD). PD is an age-related disorder caused by the degeneration of dopaminergic neurons within the substantia nigra pars compacta, with a miscellaneous pathogenic background. Glutamate-mediated excitotoxicity may be involved in a lethal vicious cycle, which critically contributes to the exacerbation of nigrostriatal degeneration in PD. Since excitotoxicity is a glutamate-receptormediated phenomenon, growing interest and work have been dedicated to the research for modulators of glutamate neurotransmission that might enable new therapeutic interventions to slow down the neurodegenerative process and ameliorate PD motor symptoms. © Springer-Verlag Wien 2013.
Zanotti S.,Foundation Irccs Neurological Institute C Besta |
Gibertini S.,Foundation Irccs Neurological Institute C Besta |
Savadori P.,Foundation Irccs Neurological Institute C Besta |
Mantegazza R.,Foundation Irccs Neurological Institute C Besta |
And 2 more authors.
Cell and Tissue Research | Year: 2013
Severe muscle fibrosis is the endpoint of many chronic myopathies. Identification of factors that regulate fibrosis is important for understanding its pathogenesis and for developing anti-fibrotic treatments that prevent muscle destruction. We have developed an in vitro model for screening potential anti-fibrotic agents. The model consists of three-dimensional clusters (nodules) of fibroblasts derived from Duchenne muscular dystrophy (DMD) muscle. The primary fibroblasts spontaneously and quickly form nodules resembling fibrotic foci (cells plus extracellular matrix) when grown on a solid substrate. We tested the anti-fibrotic action of suramin, decorin, and spironolactone (all with established anti-fibrotic activity) on the model. All three agents significantly reduced nodule number, and spironolactone and suramin significantly reduced nodule diameter. Nodule secretion of soluble collagen was also significantly reduced by decorin and spironolactone treatment, whereas suramin had no significant effect. Collagen I and fibronectin protein expression was significantly reduced in the culture medium of control and DMD fibroblasts by spironolactone treatment, but not by decorin and suramin treatment. Finally, in DMD fibroblast monolayers, collagen deposition was significantly reduced by all three agents. Spironolactone significantly reduced collagen I and fibronectin transcript levels, whereas decorin reduced only fibronectin. Our in vitro model of fibrogenesis has thus revealed differing anti-fibrotic effects in the three anti-fibrotic agents tested. It therefore appears as a useful and sensitive system for the testing of anti-fibrotic drugs and could be adapted for the high-throughput screening of new anti-fibrotic molecules. © 2013 Springer-Verlag Berlin Heidelberg.
PubMed | University of Rome La Sapienza, University of Rome Tor Vergata, National Neurological Institute and EBRI European Brain Research Institute
Type: Journal Article | Journal: Synapse (New York, N.Y.) | Year: 2016
Homozygous or heterozygous mutations in the PTEN-induced kinase 1 (PINK1) gene have been linked to early-onset Parkinsons disease (PD). Several neurophysiological studies have demonstrated alterations in striatal synaptic plasticity along with impaired dopamine release in PINK1-deficient mice. Using electrophysiological methods, here we show that PINK1 loss of function causes a progressive increase of spontaneous glutamate-mediated synaptic events in the hippocampus, without influencing long-term potentiation. Moreover, fluorescence analysis reveals increased neurotrasmitter release although our biochemical results failed to detect which presynaptic proteins might be engaged. This study provides a novel role for PINK1 beyond the physiology of nigrostriatal dopaminergic circuit. Specifically, PINK1 might contribute to preserve synaptic function and glutamatergic homeostasis in the hippocampus, a brain region underlying cognition. The subtle changes in excitatory transmission here observed might be a pathogenic precursor to excitotoxic neurodegeneration and cognitive decline often observed in PD. Using electrophysiological and fluorescence techniques, we demonstrate that lack of PINK1 causes increased excitatory transmission and neurotransmitter release in the hippocampus, which might lead to the cognitive decline often observed in Parkinsons disease.