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1.
Cell Rep ; 43(7): 114386, 2024 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-38909362

RESUMO

The dentate gyrus plays a key role in the discrimination of memories by segregating and storing similar episodes. Whether hilar mossy cells, which constitute a major excitatory principal cell type in the mammalian hippocampus, contribute to this decorrelation function has remained largely unclear. Using two-photon calcium imaging of head-fixed mice performing a spatial virtual reality task, we show that mossy cell populations robustly discriminate between familiar and novel environments. The degree of discrimination depends on the extent of visual cue differences between contexts. A context decoder revealed that successful environmental classification is explained mainly by activity difference scores of mossy cells. By decoding mouse position, we reveal that in addition to place cells, the coordinated activity among active mossy cells markedly contributes to the encoding of space. Thus, by decorrelating context information according to the degree of environmental differences, mossy cell populations support pattern separation processes within the dentate gyrus.

2.
Neurol Ther ; 13(2): 415-435, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38329615

RESUMO

BACKGROUND: Galcanezumab is approved in the European Union (EU) as migraine prophylaxis in adults with at least four migraine days per month. The aim of this retrospective observational study was to evaluate the long-term effectiveness of galcanezumab on migraine-related burdens and its impact on the use of healthcare resources for migraine prophylaxis in an Italian setting. METHODS: This retrospective study was conducted in patients with migraine who initiated treatment with galcanezumab for migraine prevention between September 2019 and December 2020. Patient data for monthly migraine days (MMDs) and MMDs with acute medication intake were obtained by medical chart reviews. Information on patient-reported outcomes (using the Migraine Disability Assessment [MIDAS] questionnaire and Headache Impact Test 6 [HIT-6] questionnaire) and on the use of healthcare resources were also collected. The time points of interest were 1, 3, 6, 9, 12 months after the initiation of galcanezumab, and the most recent time point available during follow-up. RESULTS: A total of 207 patients were enrolled in the study. Starting from month 3 after treatment initiation, more than half of the patients presented at least a 50% reduction in MMDs, and approximately one-third of non-responders at month 3 became responders at month 6. From month 3 to month 12, MMDs decreased on average by 10 days. Headache impact and disability, as well as migraine-associated health resource utilization decreased significantly during the treatment period. A positive significant association among the three dimensions of clinical burden (MMDs, MIDAS and days of acute medication intake) was also observed. CONCLUSION: The results of this Italian real-world study confirmed that galcanezumab has a rapid onset of effect and provides a long-term response among patients over different migraine-related burdens. The use of healthcare resources was also remarkably reduced.

3.
Clin Neuropharmacol ; 46(6): 220-228, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37962309

RESUMO

OBJECTIVES: Randomized controlled trials (RCTs) have established the efficacy of galcanezumab, an antibody binding calcitonin gene-related peptide (CGRP) ligand, in the preventive treatment of migraine. The objective was to summarize real-world data evaluating galcanezumab in the preventive treatment of migraine, to complement RCT results with evidence observed in clinical practice. METHODS: A literature search was conducted to identify real-world studies evaluating galcanezumab in the treatment for patients with migraine. RESULTS: Twenty-five studies were identified; some only evaluated galcanezumab, and others used pooled data from multiple anti-CGRP antibodies. The studies recruited diverse patient populations, including patients who had failed multiple prior preventive therapies. Treatment was associated with significant reductions from baseline in monthly migraine days and monthly headache days by 4.3 to 12.9 and 3.1 to 13.9, respectively. These values were numerically greater than those reported in most galcanezumab RCTs. Significant decreases from baseline were evident within the first month of treatment, and efficacy was maintained throughout the follow-up periods, ranging from 3 to 12 months. Galcanezumab was also associated with improvements in other efficacy end points, including decreased headache pain intensity, reduction in analgesic use, and improvements in daily functioning and quality of life. Functionality scores, as assessed by the Migraine Disability Assessment Scale questionnaire, decreased by 27 to 75 points from baseline at 3 to 12 months. Galcanezumab was associated with a low discontinuation rate and higher rates of persistence compared with standard migraine preventive treatments. CONCLUSIONS: The results provide complementary data that galcanezumab is effective across the diverse patient populations observed in routine clinical practice.


Assuntos
Transtornos de Enxaqueca , Humanos , Peptídeo Relacionado com Gene de Calcitonina , Cefaleia , Transtornos de Enxaqueca/tratamento farmacológico , Transtornos de Enxaqueca/prevenção & controle , Resultado do Tratamento
4.
Front Cell Dev Biol ; 10: 875468, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36568982

RESUMO

GTPases of the Rho family are components of signaling pathways linking extracellular signals to the control of cytoskeleton dynamics. Among these, RAC1 plays key roles during brain development, ranging from neuronal migration to neuritogenesis, synaptogenesis, and plasticity. RAC1 activity is positively and negatively controlled by guanine nucleotide exchange factors (GEFs), guanosine nucleotide dissociation inhibitors (GDIs), and GTPase-activating proteins (GAPs), but the specific role of each regulator in vivo is poorly known. ARHGAP15 is a RAC1-specific GAP expressed during development in a fraction of migrating cortical interneurons (CINs) and in the majority of adult CINs. During development, loss of ARHGAP15 causes altered directionality of the leading process of tangentially migrating CINs, along with altered morphology in vitro. Likewise, time-lapse imaging of embryonic CINs revealed a poorly coordinated directional control during radial migration, possibly due to a hyper-exploratory behavior. In the adult cortex, the observed defects lead to subtle alteration in the distribution of CALB2-, SST-, and VIP-positive interneurons. Adult Arhgap15-knock-out mice also show reduced CINs intrinsic excitability, spontaneous subclinical seizures, and increased susceptibility to the pro-epileptic drug pilocarpine. These results indicate that ARHGAP15 imposes a fine negative regulation on RAC1 that is required for morphological maturation and directional control during CIN migration, with consequences on their laminar distribution and inhibitory function.

5.
Am J Cancer Res ; 10(12): 4308-4324, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33415001

RESUMO

The p140Cap adaptor protein, encoded by the SRCIN1 gene, negatively controls tumor progression, as demonstrated in the subgroup of HER2-amplified breast cancers and in neuroblastoma patients, where high p140Cap expression predicts a decreased probability of developing metastasis, with a significantly prolonged survival. In NeuT mice, a preclinical model or Her2-positive breast cancer, we previously reported that p140Cap counteracts Her2-dependent breast cancer progression, associating with the specific Rac1 Guanine Nucleotide Exchange Factor, Tiam1, and limiting the activation of both Tiam1 and Rac1. Here, we show that in TUBO breast cancer cells derived from the NeuT tumors, p140Cap expression causes Tiam1 redistribution along the apicobasal junctional axis. Furthermore, p140Cap and Tiam1 interact with E-cadherin, a member of the adherence junction, with a concomitant increase of E-cadherin at the cell membrane. We characterized biochemically the interaction between p140Cap and Tiam1, showing that the amino terminal region of p140Cap (1-287 amino acids) is sufficient to associate with full length Tiam1, and with the truncated catalytic domain of Tiam1, with a concomitant decrease of the Tiam1 activity. Moreover, in a large cohort of Her2 positive breast cancer, high levels of SRCIN1 expression positively correlates with increased survival in patients with high TIAM1 expression. Overall, our findings sustain a protective role of p140Cap in Her2 positive breast cancer, where p140Cap can associate with Tiam1 and negatively regulate the Tiam1/Rac1 axis.

6.
Neuroimage ; 54(2): 787-93, 2011 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-20888921

RESUMO

Obstructive sleep apnea (OSA) is accompanied by neurocognitive impairment, likely mediated by injury to various brain regions. We evaluated brain morphological changes in patients with OSA and their relationship to neuropsychological and oximetric data. Sixteen patients affected by moderate-severe OSA (age: 55.8±6.7 years, 13 males) and fourteen control subjects (age: 57.6±5.1 years, 9 males) underwent 3.0 Tesla brain magnetic resonance imaging (MRI) and neuropsychological testing evaluating short- and long-term memory, executive functions, language, attention, praxia and non-verbal learning. Volumetric segmentation of cortical and subcortical structures and voxel-based morphometry (VBM) were performed. Patients and controls differed significantly in Rey Auditory-Verbal Learning test (immediate and delayed recall), Stroop test and Digit span backward scores. Volumes of cortical gray matter (GM), right hippocampus, right and left caudate were smaller in patients compared to controls, with also brain parenchymal fraction (a normalized measure of cerebral atrophy) approaching statistical significance. Differences remained significant after controlling for comorbidities (hypertension, diabetes, smoking, hypercholesterolemia). VBM analysis showed regions of decreased GM volume in right and left hippocampus and within more lateral temporal areas in patients with OSA. Our findings indicate that the significant cognitive impairment seen in patients with moderate-severe OSA is associated with brain tissue damage in regions involved in several cognitive tasks. We conclude that OSA can increase brain susceptibility to the effects of aging and other clinical and pathological occurrences.


Assuntos
Transtornos Cognitivos/etiologia , Transtornos Cognitivos/patologia , Apneia Obstrutiva do Sono/complicações , Apneia Obstrutiva do Sono/patologia , Encéfalo/patologia , Encéfalo/fisiopatologia , Transtornos Cognitivos/fisiopatologia , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Apneia Obstrutiva do Sono/fisiopatologia
7.
Epilepsia ; 51(5): 768-72, 2010 May.
Artigo em Inglês | MEDLINE | ID: mdl-19817812

RESUMO

PURPOSE: The endocannabinoid system is involved in excitatory/inhibitory balance mechanisms within the central nervous system (CNS). Growing evidence shows that its perturbation leads to development of epileptic seizures in experimental models, thus indicating that endocannabinoids play an intrinsic protective role in suppressing pathologic neuronal excitability. Experimental data also demonstrate that the endocannabinoid anandamide (AEA) can antagonize epileptic discharges in hippocampal tissue. The objective of our study was to measure endocannabinoids levels in the cerebrospinal fluid (CSF) of drug-naive patients affected by temporal lobe epilepsy (TLE). METHODS: We measured the levels of both AEA and the other endocannabinoid, 2-arachidonoylglycerol (2-AG), in the CSF of drug-naive patients with TLE. RESULTS: A significant reduction of AEA was found in the CSF of patients with compared with healthy controls (epileptic patients = 2.55 +/- 1.78 pmol/ml; healthy controls = 11.65 +/- 7.53 pmol/ml; n = 9 for both groups, p < 0.01). 2-AG levels, however, were not affected (epileptic patients = 209.5 +/- 146.56; healthy controls = 159.6 +/- 110.2) (n = 6 for both groups, p = 0.48). DISCUSSION: Our findings seem to be consistent with experimental evidence demonstrating a significant prevention of epileptic seizures induced by endocannabinoids in models of epilepsy. Furthermore, they support the hypothesis that AEA may be involved in its pathogenesis, suggesting a hypothetical primary impairment of the endocannabinoid system in untreated TLE. The actual role of this in vivo dysregulation still remains unclear.


Assuntos
Ácidos Araquidônicos/líquido cefalorraquidiano , Moduladores de Receptores de Canabinoides/líquido cefalorraquidiano , Endocanabinoides , Epilepsia do Lobo Temporal/líquido cefalorraquidiano , Epilepsia do Lobo Temporal/fisiopatologia , Alcamidas Poli-Insaturadas/líquido cefalorraquidiano , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Ácidos Araquidônicos/fisiologia , Moduladores de Receptores de Canabinoides/análise , Moduladores de Receptores de Canabinoides/fisiologia , Modelos Animais de Doenças , Epilepsia/líquido cefalorraquidiano , Epilepsia/fisiopatologia , Epilepsia/prevenção & controle , Epilepsia do Lobo Temporal/prevenção & controle , Feminino , Glicerídeos/líquido cefalorraquidiano , Glicerídeos/fisiologia , Hipocampo/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Receptor CB1 de Canabinoide/fisiologia , Receptor CB2 de Canabinoide/fisiologia
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