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1.
Proc Natl Acad Sci U S A ; 120(2): e2216814120, 2023 01 10.
Artigo em Inglês | MEDLINE | ID: mdl-36603028

RESUMO

Spinal muscular atrophy (SMA) is a severe autosomal recessive neuromuscular disease affecting children and young adults, caused by mutations of the survival motor neuron 1 gene (SMN1). SMA is characterized by the degeneration of spinal alpha motor neurons (αMNs), associated with muscle paralysis and atrophy, as well as other peripheral alterations. Both growth hormone-releasing hormone (GHRH) and its potent agonistic analog, MR-409, exert protective effects on muscle atrophy, cardiomyopathies, ischemic stroke, and inflammation. In this study, we aimed to assess the protective role of MR-409 in SMNΔ7 mice, a widely used model of SMA. Daily subcutaneous treatment with MR-409 (1 or 2 mg/kg), from postnatal day 2 (P2) to euthanization (P12), increased body weight and improved motor behavior in SMA mice, particularly at the highest dose tested. In addition, MR-409 reduced atrophy and ameliorated trophism in quadriceps and gastrocnemius muscles, as determined by an increase in fiber size, as well as upregulation of myogenic genes and inhibition of proteolytic pathways. MR-409 also promoted the maturation of neuromuscular junctions, by reducing multi-innervated endplates and increasing those mono-innervated. Finally, treatment with MR-409 delayed αMN death and blunted neuroinflammation in the spinal cord of SMA mice. In conclusion, the present study demonstrates that MR-409 has protective effects in SMNΔ7 mice, suggesting that GHRH agonists are promising agents for the treatment of SMA, possibly in combination with SMN-dependent strategies.


Assuntos
Hormônio Liberador de Hormônio do Crescimento , Atrofia Muscular Espinal , Animais , Camundongos , Atrofia/metabolismo , Modelos Animais de Doenças , Hormônio Liberador de Hormônio do Crescimento/agonistas , Neurônios Motores/metabolismo , Atrofia Muscular Espinal/tratamento farmacológico , Atrofia Muscular Espinal/genética , Atrofia Muscular Espinal/metabolismo , Medula Espinal/metabolismo , Proteína 1 de Sobrevivência do Neurônio Motor/genética , Proteína 1 de Sobrevivência do Neurônio Motor/metabolismo
2.
J Neuroinflammation ; 20(1): 34, 2023 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-36782185

RESUMO

BACKGROUND: One intrastriatal administration of quinolinic acid (QA) in rats induces a lesion with features resembling those observed in Huntington's disease. Our aim is to evaluate the effects of the cysteinyl leukotriene receptor antagonist montelukast (MLK), which exhibited neuroprotection in different preclinical models of neurodegeneration, on QA-induced neuroinflammation and regional metabolic functions. METHODS: The right and left striatum of Sprague Dawley and athymic nude rats were injected with QA and vehicle (VEH), respectively. Starting from the day before QA injection, animals were treated with 1 or 10 mg/kg of MLK or VEH for 14 days. At 14 and 30 days post-lesion, animals were monitored with magnetic resonance imaging (MRI) and positron emission tomography (PET) using [18F]-VC701, a translocator protein (TSPO)-specific radiotracer. Striatal neuroinflammatory response was measured post-mortem in rats treated with 1 mg/kg of MLK by immunofluorescence. Rats treated with 10 mg/kg of MLK also underwent a [18F]-FDG PET study at baseline and 4 months after lesion. [18F]-FDG PET data were then used to assess metabolic connectivity between brain regions by applying a covariance analysis method. RESULTS: MLK treatment was not able to reduce the QA-induced increase in striatal TSPO PET signal and MRI lesion volume, where we only detected a trend towards reduction in animals treated with 10 mg/kg of MLK. Post-mortem immunofluorescence analysis revealed that MLK attenuated the increase in striatal markers of astrogliosis and activated microglia in the lesioned hemisphere. We also found a significant increase in a marker of anti-inflammatory activity (MannR) and a trend towards reduction in a marker of pro-inflammatory activity (iNOS) in the lesioned striatum of MLK-compared to VEH-treated rats. [18F]-FDG uptake was significantly reduced in the striatum and ipsilesional cortical regions of VEH-treated rats at 4 months after lesion. MLK administration preserved glucose metabolism in these cortical regions, but not in the striatum. Finally, MLK was able to counteract changes in metabolic connectivity and measures of network topology induced by QA, in both lesioned and non-lesioned hemispheres. CONCLUSIONS: Overall, MLK treatment produced a significant neuroprotective effect by reducing neuroinflammation assessed by immunofluorescence and preserving regional brain metabolism and metabolic connectivity from QA-induced neurotoxicity in cortical and subcortical regions.


Assuntos
Encefalite , Fármacos Neuroprotetores , Síndromes Neurotóxicas , Ratos , Animais , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Ratos Sprague-Dawley , Ácido Quinolínico/toxicidade , Ácido Quinolínico/metabolismo , Fluordesoxiglucose F18/metabolismo , Doenças Neuroinflamatórias , Corpo Estriado/metabolismo , Síndromes Neurotóxicas/patologia , Encefalite/patologia , Modelos Animais de Doenças
3.
Neuroimage ; 225: 117481, 2021 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-33122115

RESUMO

Brain disorders tend to impact on many different regions in a typical way: alterations do not spread randomly; rather, they seem to follow specific patterns of propagation that show a strong overlap between different pathologies. The insular cortex is one of the brain areas more involved in this phenomenon, as it seems to be altered by a wide range of brain diseases. On these grounds we thoroughly investigated the impact of brain disorders on the insular cortices analyzing the patterns of their structural co-alteration. We therefore investigated, applying a network analysis approach to meta-analytic data, 1) what pattern of gray matter alteration is associated with each of the insular cortex parcels; 2) whether or not this pattern correlates and overlaps with its functional meta-analytic connectivity; and, 3) the behavioral profile related to each insular co-alteration pattern. All the analyses were repeated considering two solutions: one with two clusters and another with three. Our study confirmed that the insular cortex is one of the most altered cerebral regions among the cortical areas, and exhibits a dense network of co-alteration including a prevalence of cortical rather than sub-cortical brain regions. Regions of the frontal lobe are the most involved, while occipital lobe is the less affected. Furthermore, the co-alteration and co-activation patterns greatly overlap each other. These findings provide significant evidence that alterations caused by brain disorders are likely to be distributed according to the logic of network architecture, in which brain hubs lie at the center of networks composed of co-altered areas. For the first time, we shed light on existing differences between insula sub-regions even in the pathoconnectivity domain.


Assuntos
Encefalopatias/fisiopatologia , Córtex Cerebral/fisiopatologia , Rede Nervosa/fisiopatologia , Encéfalo/fisiopatologia , Mapeamento Encefálico , Conectoma , Substância Cinzenta/fisiopatologia , Humanos , Imageamento por Ressonância Magnética , Rede Nervosa/fisiologia , Lobo Occipital/fisiopatologia
4.
Age Ageing ; 50(4): 1261-1267, 2021 06 28.
Artigo em Inglês | MEDLINE | ID: mdl-33480986

RESUMO

INTRODUCTION: Prevention of frailty is paramount in older adults. We evaluated the efficacy of a tailored multidomain intervention, monitored with the My Active and Healthy Aging platform, in reducing conversion from a prefrail status to overt frailty and preventing decline in quality of life. METHODS: We performed a multicentre, multicultural, randomised control study. The effects of multidomain interventions on frailty parameters, quality of life, physical, cognitive, psychosocial function, nutrition and sleep were evaluated in a group of 101 prefrail older subjects and compared with 100 prefrail controls, receiving general health advice. RESULTS: At the 12-month assessment, controls showed a decline in quality of life that was absent in the active group. In addition, active participants showed an increase in mood and nutrition function. No effect on remaining parameter was observed. DISCUSSION: Our study supports the use of personalised multidomain intervention, monitored with an information and communication technology platform, in preventing quality of life decline in older adults.


Assuntos
Fragilidade , Envelhecimento Saudável , Idoso , Fragilidade/diagnóstico , Fragilidade/prevenção & controle , Humanos , Estado Nutricional , Qualidade de Vida , Projetos de Pesquisa
5.
Int J Mol Sci ; 22(2)2021 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-33430035

RESUMO

Traumatic peripheral nerve lesions affect hundreds of thousands of patients every year; their consequences are life-altering and often devastating and cause alterations in movement and sensitivity. Spontaneous peripheral nerve recovery is often inadequate. In this context, nowadays, cell therapy represents one of the most innovative approaches in the field of nerve repair therapies. The purpose of this systematic review is to discuss the features of different types of mesenchymal stem cells (MSCs) relevant for peripheral nerve regeneration after nerve injury. The published literature was reviewed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A combination of the keywords "nerve regeneration", "stem cells", "peripheral nerve injury", "rat", and "human" were used. Additionally, a "MeSH" research was performed in PubMed using the terms "stem cells" and "nerve regeneration". The characteristics of the most widely used MSCs, their paracrine potential, targeted stimulation, and differentiation potentials into Schwann-like and neuronal-like cells are described in this paper. Considering their ability to support and stimulate axonal growth, their remarkable paracrine activity, their presumed differentiation potential, their extremely low immunogenicity, and their high survival rate after transplantation, ADSCs appear to be the most suitable and promising MSCs for the recovery of peripheral nerve lesion. Clinical considerations are finally reported.


Assuntos
Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/fisiologia , Regeneração Nervosa/fisiologia , Nervos Periféricos/fisiologia , Animais , Diferenciação Celular , Humanos , Regeneração Nervosa/genética , Ratos , Células de Schwann/fisiologia , Nervo Isquiático/crescimento & desenvolvimento
6.
Neurol Sci ; 41(2): 329-333, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31586289

RESUMO

BACKGROUND: Ultrasonography of the optic nerve sheath diameter (ONSD) is used for the non-invasive assessment of increased intracranial pressure (ICP). ONSD values are usually obtained by averaging the measurements of the two eyes, but asymmetric ONSD dilation is possible, leading to potentially inaccurate ICP estimation when using binocular averaging. In addition, few data are available about the asymmetry of the ONSD and the use of the maximum ONSD value between eyes for raised ICP detection. The aim of the study was to evaluate the interocular ONSD asymmetry in healthy subjects and patients with intracranial hypertension (IH) by ultrasonography and to investigate whether the maximum ONSD could be as useful as the binocular assessment. METHODS: Forty healthy subjects and 40 patients with IH (20 with idiopathic intracranial hypertension and 20 with intracerebral hemorrhage) who underwent transorbital sonography were retrospectively enrolled. The prevalence and degree of ONSD asymmetry were compared among groups; ONSD median binocular and maximum values were compared. RESULTS: Forty-two out of 80 subjects (52.5%) showed significant ONSD asymmetry, without significant differences in prevalence among groups (p = 0.28). The median asymmetry was higher in patients than in healthy subjects (0.45 mm vs 0.23 mm; p = 0.007), without significant differences between the two pathologies (p = 0.58). Both binocular and maximum ONSD measurements were significantly higher in patients with IH than in controls (p < 0.001). CONCLUSIONS: Interocular ONSD asymmetry occurs both in healthy subjects and, more consistently, in patients with IH. Both binocular and maximum ONSD may be useful markers for increased ICP detection.


Assuntos
Hipertensão Intracraniana/patologia , Pressão Intracraniana/fisiologia , Nervo Óptico/patologia , Pseudotumor Cerebral/patologia , Adulto , Idoso , Hemorragia Cerebral/patologia , Olho/patologia , Feminino , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade
7.
Proc Natl Acad Sci U S A ; 114(7): E1234-E1242, 2017 02 14.
Artigo em Inglês | MEDLINE | ID: mdl-28137879

RESUMO

Medium spiny neurons (MSNs) are a key population in the basal ganglia network, and their degeneration causes a severe neurodegenerative disorder, Huntington's disease. Understanding how ventral neuroepithelial progenitors differentiate into MSNs is critical for regenerative medicine to develop specific differentiation protocols using human pluripotent stem cells. Studies performed in murine models have identified some transcriptional determinants, including GS Homeobox 2 (Gsx2) and Early B-cell factor 1 (Ebf1). Here, we have generated human embryonic stem (hES) cell lines inducible for these transcription factors, with the aims of (i) studying their biological role in human neural progenitors and (ii) incorporating TF conditional expression in a developmental-based protocol for generating MSNs from hES cells. Using this approach, we found that Gsx2 delays cell-cycle exit and reduces Pax6 expression, whereas Ebf1 promotes neuronal differentiation. Moreover, we found that Gsx2 and Ebf1 combined overexpression in hES cells achieves high yields of MSNs, expressing Darpp32 and Ctip2, in vitro as well in vivo after transplantation. We show that hES-derived striatal progenitors can be transplanted in animal models and can differentiate and integrate into the host, extending fibers over a long distance.


Assuntos
Diferenciação Celular/genética , Proteínas de Homeodomínio/genética , Células-Tronco Embrionárias Humanas/metabolismo , Neurônios/metabolismo , Transativadores/genética , Animais , Ciclo Celular/genética , Linhagem Celular , Fosfoproteína 32 Regulada por cAMP e Dopamina/genética , Fosfoproteína 32 Regulada por cAMP e Dopamina/metabolismo , Expressão Gênica , Proteínas de Homeodomínio/metabolismo , Células-Tronco Embrionárias Humanas/transplante , Humanos , Camundongos Nus , Neurônios/citologia , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Transplante de Células-Tronco/métodos , Telencéfalo/citologia , Transativadores/metabolismo , Transplante Heterólogo , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo
8.
Int J Mol Sci ; 21(10)2020 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-32466216

RESUMO

Mitochondria play a central role in a plethora of processes related to the maintenance of cellular homeostasis and genomic integrity. They contribute to preserving the optimal functioning of cells and protecting them from potential DNA damage which could result in mutations and disease. However, perturbations of the system due to senescence or environmental factors induce alterations of the physiological balance and lead to the impairment of mitochondrial functions. After the description of the crucial roles of mitochondria for cell survival and activity, the core of this review focuses on the "mitochondrial switch" which occurs at the onset of neuronal degeneration. We dissect the pathways related to mitochondrial dysfunctions which are shared among the most frequent or disabling neurodegenerative diseases such as Alzheimer's, Parkinson's, and Huntington's, Amyotrophic Lateral Sclerosis, and Spinal Muscular Atrophy. Can mitochondrial dysfunctions (affecting their morphology and activities) represent the early event eliciting the shift towards pathological neurobiological processes? Can mitochondria represent a common target against neurodegeneration? We also review here the drugs that target mitochondria in neurodegenerative diseases.


Assuntos
Doença de Alzheimer/metabolismo , Esclerose Lateral Amiotrófica/metabolismo , Mitocôndrias/metabolismo , Atrofia Muscular Espinal/metabolismo , Doença de Parkinson/metabolismo , Doença de Alzheimer/tratamento farmacológico , Esclerose Lateral Amiotrófica/tratamento farmacológico , Animais , Antioxidantes/uso terapêutico , Humanos , Mitocôndrias/patologia , Atrofia Muscular Espinal/tratamento farmacológico , Fármacos Neuroprotetores/uso terapêutico , Biogênese de Organelas , Doença de Parkinson/tratamento farmacológico
9.
Int J Mol Sci ; 20(11)2019 05 31.
Artigo em Inglês | MEDLINE | ID: mdl-31159345

RESUMO

Spinal cord injury (SCI) constitutes an inestimable public health issue. The most crucial phase in the pathophysiological process of SCI concerns the well-known secondary injury, which is the uncontrolled and destructive cascade occurring later with aberrant molecular signaling, inflammation, vascular changes, and secondary cellular dysfunctions. The use of mesenchymal stem cells (MSCs) represents one of the most important and promising tested strategies. Their appeal, among the other sources and types of stem cells, increased because of their ease of isolation/preservation and their properties. Nevertheless, encouraging promise from preclinical studies was followed by weak and conflicting results in clinical trials. In this review, the therapeutic role of MSCs is discussed, together with their properties, application, limitations, and future perspectives.


Assuntos
Células-Tronco Mesenquimais/metabolismo , Traumatismos da Medula Espinal/etiologia , Traumatismos da Medula Espinal/metabolismo , Animais , Materiais Biocompatíveis , Biomarcadores , Terapia Baseada em Transplante de Células e Tecidos , Transplante de Células-Tronco de Sangue do Cordão Umbilical , Modelos Animais de Doenças , Humanos , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/citologia , Fatores de Crescimento Neural/metabolismo , Regeneração Nervosa , Medicina Regenerativa , Traumatismos da Medula Espinal/patologia , Traumatismos da Medula Espinal/terapia , Regeneração da Medula Espinal , Alicerces Teciduais , Pesquisa Translacional Biomédica
10.
Neural Plast ; 2016: 1938292, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26881093

RESUMO

Several functional connectivity approaches require the definition of a set of regions of interest (ROIs) that act as network nodes. Different methods have been developed to define these nodes and to derive their functional and effective connections, most of which are rather complex. Here we aim to propose a relatively simple "one-step" border detection and ROI estimation procedure employing the fuzzy c-mean clustering algorithm. To test this procedure and to explore insular connectivity beyond the two/three-region model currently proposed in the literature, we parcellated the insular cortex of 20 healthy right-handed volunteers scanned in a resting state. By employing a high-dimensional functional connectivity-based clustering process, we confirmed the two patterns of connectivity previously described. This method revealed a complex pattern of functional connectivity where the two previously detected insular clusters are subdivided into several other networks, some of which are not commonly associated with the insular cortex, such as the default mode network and parts of the dorsal attentional network. Furthermore, the detection of nodes was reliable, as demonstrated by the confirmative analysis performed on a replication group of subjects.


Assuntos
Mapeamento Encefálico/métodos , Córtex Cerebral/fisiologia , Lógica Fuzzy , Rede Nervosa/fisiologia , Adulto , Algoritmos , Análise por Conglomerados , Feminino , Humanos , Masculino , Adulto Jovem
11.
Cereb Cortex ; 24(8): 2178-88, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23529006

RESUMO

In primates, different cortical areas send axons of different diameters into comparable tracts, notably the corpus callosum (Tomasi S, Caminiti R, Innocenti GM. 2012. Areal differences in diameter and length of corticofugal projections. Cereb Cortex. 22:1463-1472). We now explored if an area also sends axons of different diameters to different targets. We find that the parietal area PEc sends thicker axons to area 4 and 6, and thinner ones to the cingulate region (area 24). Areas 4 and 9, each sends axons of different diameters to the nucleus caudatus, to different levels of the internal capsule, and to the thalamus. The internal capsule receives the thickest axon, followed by thalamus and nucleus caudatus. The 2 areas (4 and 9) differ in the diameter and length of axons to corresponding targets. We calculated how diameter determines conduction velocity of the axons and together with pathway length determines transmission delays between different brain sites. We propose that projections from and within the cerebral cortex consist of a complex system of lines of communication with different geometrical and time computing properties.


Assuntos
Axônios , Encéfalo/citologia , Animais , Axônios/fisiologia , Biotina/análogos & derivados , Encéfalo/fisiologia , Dextranos , Macaca , Microscopia Eletrônica , Modelos Neurológicos , Condução Nervosa , Vias Neurais/citologia , Vias Neurais/fisiologia , Técnicas de Rastreamento Neuroanatômico , Fotomicrografia
12.
Cytotherapy ; 16(8): 1059-72, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24794182

RESUMO

BACKGROUND AIMS: Mesenchymal stromal cells (MSCs), after intraparenchymal, intrathecal and endovenous administration, have been previously tested for cell therapy in amyotrophic lateral sclerosis in the SOD1 (superoxide dismutase 1) mouse. However, every administration route has specific pros and cons. METHODS: We administrated human MSCs (hMSCs) in the cisterna lumbaris, which is easily accessible and could be used in outpatient surgery, in the SOD1 G93A mouse, at the earliest onset of symptoms. Control animals received saline injections. Motor behavior was checked starting from 2 months of age until the mice were killed. Animals were killed 2 weeks after transplantation; lumbar motoneurons were stereologically counted, astrocytes and microglia were analyzed and quantified after immunohistochemistry and cytokine expression was assayed by means of real-time polymerase chain reaction. RESULTS: We provide evidence that this route of administration can exert strongly positive effects. Motoneuron death and motor decay were delayed, astrogliosis was reduced and microglial activation was modulated. In addition, hMSC transplantation prevented the downregulation of the anti-inflammatory interleukin-10, as well as that of vascular endothelial growth factor observed in saline-treated transgenic mice compared with wild type, and resulted in a dramatic increase in the expression of the anti-inflammatory interleukin-13. CONCLUSIONS: Our results suggest that hMSCs, when intracisternally administered, can exert their paracrine potential, influencing the inflammatory response of the host.


Assuntos
Esclerose Lateral Amiotrófica/terapia , Terapia Baseada em Transplante de Células e Tecidos , Inflamação/terapia , Transplante de Células-Tronco Mesenquimais , Esclerose Lateral Amiotrófica/patologia , Animais , Astrócitos/patologia , Modelos Animais de Doenças , Humanos , Inflamação/patologia , Células-Tronco Mesenquimais , Camundongos , Microglia/patologia , Terapia Ambiental , Neurônios Motores/metabolismo , Neurônios Motores/patologia
13.
Front Neuroanat ; 18: 1398400, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39045347

RESUMO

Peripheral nerve damage often leads to the onset of neuropathic pain (NeuP). This condition afflicts millions of people, significantly burdening healthcare systems and putting strain on families' financial well-being. Here, we will focus on the role of peripheral sensory neurons, specifically the Dorsal Root Ganglia neurons (DRG neurons) in the development of NeuP. After axotomy, DRG neurons activate regenerative signals of axons-soma communication to promote a gene program that activates an axonal branching and elongation processes. The results of a neuronal morphological cytoskeleton change are not always associated with functional recovery. Moreover, any axonal miss-targeting may contribute to NeuP development. In this review, we will explore the epidemiology of NeuP and its molecular causes at the level of the peripheral nervous system and the target organs, with major focus on the neuronal cross-talk between intrinsic and extrinsic factors. Specifically, we will describe how failures in the neuronal regenerative program can exacerbate NeuP.

14.
Aging Dis ; 15(2): 893-910, 2024 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-37548943

RESUMO

Sarcopenia is the primary cause of impaired motor performance in the elderly. The current prevailing approach to counteract such condition is increasing the muscle mass through inhibition of the myostatin system: however, this strategy only moderately improves muscular strength, not being able to sustain the innervation of the hypertrophic muscle per se, leading to a progressive worsening of motor performances. Thus, we proposed the administration of ActR-Fc-nLG3, a protein that combines the soluble activin receptor, a strong myostatin inhibitor, with the C-terminal agrin nLG3 domain. This compound has the potential of reinforcing neuro-muscular stability to the hypertrophic muscle. We previously demonstrated an enhancement of motor endurance and ACh receptor aggregation in young mice after ActR-Fc-nLG3 administration. Now we extended these observations by demonstrating that also in aged (2 years-old) mice, long-term administration of ActR-Fc-nLG3 increases in a sustained way both motor endurance and muscle strength, compared with ActR-Fc, a myostatin inhibitor, alone. Histological data demonstrate that the administration of this biological improves neuromuscular stability and fiber innervation maintenance, preventing muscle fiber atrophy and inducing only moderate hypertrophy. Moreover, at the postsynaptic site we observe an increased folding in the soleplate, a likely anatomical substrate for improved neurotransmission efficiency in the NMJ, that may lead to enhanced motor endurance. We suggest that ActR-Fc-nLG3 may become a valid option for treating sarcopenia and possibly other disorders of striatal muscles.


Assuntos
Miostatina , Sarcopenia , Humanos , Camundongos , Animais , Idoso , Pré-Escolar , Músculo Esquelético/metabolismo , Agrina/metabolismo , Sarcopenia/tratamento farmacológico , Junção Neuromuscular/metabolismo
15.
Ann Neurol ; 72(4): 610-24, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23109155

RESUMO

OBJECTIVE: Microvesicles (MVs) have been indicated as important mediators of intercellular communication and are emerging as new biomarkers of tissue damage. Our previous data indicate that reactive microglia/macrophages release MVs in vitro. The aim of the study was to evaluate whether MVs are released by microglia/macrophages in vivo and whether their number varies in brain inflammatory conditions, such as multiple sclerosis (MS). METHODS: Electron and fluorescence microscopy and flow cytometry were used to detect myeloid MVs in the cerebrospinal fluid (CSF) of healthy controls, MS patients, and rodents affected by experimental autoimmune encephalomyelitis (EAE), the animal model of MS. RESULTS: Myeloid MVs were detected in CSF of healthy controls. In relapsing and remitting EAE mice, the concentration of myeloid MVs in the CSF was significantly increased and closely associated with disease course. Analysis of MVs in the CSF of 28 relapsing patients and 28 patients with clinical isolated syndrome from 2 independent cohorts revealed higher levels of myeloid MVs than in 13 age-matched controls, indicating a clinical value of MVs as a companion tool to capture disease activity. Myeloid MVs were found to spread inflammatory signals both in vitro and in vivo at the site of administration; mice impaired in MV shedding were protected from EAE, suggesting a pathogenic role for MVs in the disease. Finally, FTY720, the first approved oral MS drug, significantly reduced the amount of MVs in the CSF of EAE-treated mice. INTERPRETATION: These findings identify myeloid MVs as a marker and therapeutic target of brain inflammation.


Assuntos
Biomarcadores/líquido cefalorraquidiano , Doenças do Sistema Nervoso Central/líquido cefalorraquidiano , Doenças do Sistema Nervoso Central/tratamento farmacológico , Inflamação/líquido cefalorraquidiano , Inflamação/tratamento farmacológico , Medula Espinal/metabolismo , Animais , Western Blotting , Sinalização do Cálcio/fisiologia , Comunicação Celular , Células Cultivadas , Encefalite/líquido cefalorraquidiano , Encefalite/patologia , Citometria de Fluxo , Lentivirus/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microscopia Eletrônica , Microscopia de Fluorescência , Esclerose Múltipla/patologia , Doença Autoimune do Sistema Nervoso Experimental/líquido cefalorraquidiano , Doença Autoimune do Sistema Nervoso Experimental/tratamento farmacológico , Neuroglia/metabolismo , Neuroglia/fisiologia , Ratos , Ratos Endogâmicos Lew , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase em Tempo Real , Esfingomielina Fosfodiesterase/genética , Esfingomielina Fosfodiesterase/fisiologia
16.
Mol Cell Neurosci ; 49(3): 300-10, 2012 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22206897

RESUMO

Kainic acid (KA) induced seizures provokes an extensive neuronal degeneration initiated by c-Jun N-terminal kinases (JNK) as central mediators of excitotoxicity. However, the actions of their individual isoforms in cellular organelles including mitochondria remain to be elucidated. Here, we have studied the activation of JNK1, JNK2 and JNK3 and their activators, mitogen-activated protein kinase kinase (MKK) 4/7, in brain mitochondria, cytosolic and nuclear fractions after KA seizures. In the mitochondrial fraction, KA significantly increased the presence of JNK1, JNK3 and MKK4 and stimulated their phosphorylation i.e. activation. The pro-apoptotic proteins, Bim and Bax were induced and, consequently, the ratio Bcl-2-Bax decreased. These changes were paralleled by the release of cytochrome c and cleavage of poly(ADP-ribose)-polymerase (PARP). The JNK peptide inhibitor, D-JNKI-1 (XG-102) reversed these pathological events in the mitochondria and almost completely abolished cytochrome c release and PARP cleavage. Importantly, JNK3, but not JNK1 or JNK2, was associated with Bim in mitochondria and D-JNKI-1 prevented the formation of this apoptotic complex. Apart from of the attenuation of c-Jun phosphorylation in the nucleus, D-JNKI-1 did not affect the level of JNK3 isoform in the nuclear and cytosolic fractions. These findings provide novel insights into the mode of action of individual JNK isoforms in cell organelles and points to the JNK3 pool in mitochondria as a target of the JNK inhibitor D-JNKI-1 to confer neuroprotection.


Assuntos
Encéfalo/metabolismo , Citocromos c/metabolismo , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Mitocôndrias/metabolismo , Peptídeos/farmacologia , Poli(ADP-Ribose) Polimerases/metabolismo , Animais , Apoptose/fisiologia , Citocromos c/efeitos dos fármacos , Modelos Animais de Doenças , Hipocampo/metabolismo , Proteínas Quinases JNK Ativadas por Mitógeno/fisiologia , Sistema de Sinalização das MAP Quinases/fisiologia , Masculino , Mitocôndrias/efeitos dos fármacos , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Fosforilação/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Proteína X Associada a bcl-2/metabolismo
17.
J Clin Med ; 12(4)2023 Feb 09.
Artigo em Inglês | MEDLINE | ID: mdl-36835913

RESUMO

Von Economo neurons (VENs) are rod, stick, or corkscrew cells mostly located in layer V of the frontoinsular and anterior cingulate cortices. VENs are projection neurons related to human-like social cognitive abilities. Post-mortem histological studies found VEN alterations in several neuropsychiatric disorders, including schizophrenia (SZ). This pilot study aimed to evaluate the role of VEN-containing areas in shaping patterns of resting-state brain activation in patients with SZ (n = 20) compared to healthy controls (HCs; n = 20). We performed a functional connectivity analysis seeded in the cortical areas with the highest density of VENs followed by fuzzy clustering. The alterations found in the SZ group were correlated with psychopathological, cognitive, and functioning variables. We found a frontotemporal network that was shared by four clusters overlapping with the salience, superior-frontal, orbitofrontal, and central executive networks. Differences between the HC and SZ groups emerged only in the salience network. The functional connectivity of the right anterior insula and ventral tegmental area within this network were negatively correlated with experiential negative symptoms and positively correlated with functioning. This study provides some evidence to show that in vivo, VEN-enriched cortical areas are associated with an altered resting-state brain activity in people with SZ.

18.
Neurotherapeutics ; 20(2): 524-545, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36717478

RESUMO

Spinal and bulbar muscular atrophy (SBMA) is characterized by motor neuron (MN) degeneration that leads to slowly progressive muscle weakness. It is considered a neuromuscular disease since muscle has a primary role in disease onset and progression. SBMA is caused by a CAG triplet repeat expansion in the androgen receptor (AR) gene. The translated poly-glutamine (polyQ) tract confers a toxic gain of function to the mutant AR altering its folding, causing its aggregation into intracellular inclusions, and impairing the autophagic flux. In an in vitro SBMA neuronal model, we previously showed that the antiandrogen bicalutamide and trehalose, a natural disaccharide stimulating autophagy, block ARpolyQ activation, reduce its nuclear translocation and toxicity and facilitate the autophagic degradation of cytoplasmic AR aggregates. Here, in a knock-in SBMA mouse model (KI AR113Q), we show that bicalutamide and trehalose ameliorated SBMA pathology. Bicalutamide reversed the formation of the AR insoluble forms in KI AR113Q muscle, preventing autophagic flux blockage. We demonstrated that apoptosis is activated in KI AR113Q muscle, and that both compounds prevented its activation. We detected a decrease of mtDNA and an increase of OXPHOS enzymes, already at early symptomatic stages; these alterations were reverted by trehalose. Overall, bicalutamide and/or trehalose led to a partial recovery of muscle morphology and function, and improved SBMA mouse motor behavior, inducing an extension of their survival. Thus, bicalutamide and trehalose, by counteracting ARpolyQ toxicity in skeletal muscle, are valuable candidates for future clinical trials in SBMA patients.


Assuntos
Atrofia Bulboespinal Ligada ao X , Atrofia Muscular Espinal , Camundongos , Animais , Atrofia Bulboespinal Ligada ao X/tratamento farmacológico , Atrofia Bulboespinal Ligada ao X/genética , Trealose/farmacologia , Trealose/uso terapêutico , Receptores Androgênicos/genética , Anilidas/farmacologia , Camundongos Transgênicos
19.
Neuroimage ; 62(1): 343-55, 2012 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-22521480

RESUMO

The human insula has been parcellated on the basis of resting state functional connectivity and diffusion tensor imaging. Little is known about the organization of the insula when involved in active tasks. We explored this issue using a novel meta-analytic clustering approach. We queried the BrainMap database asking for papers involving normal subjects that recorded activations in the insular cortex, retrieving 1305 papers, involving 22,872 subjects and a total of 2957 foci. Data were analyzed with several different methodologies, some of which expressly designed for this work. We used meta-analytic connectivity modeling and meta-analytic clustering of data obtained from the BrainMap database. We performed cluster analysis to subdivide the insula in areas with homogeneous connectivity, and density analysis of the activated foci using Voronoi tessellation. Our results confirm and extend previous findings obtained investigating the resting state connectivity of the anterior-posterior and left-right insulae. They indicate, for the first time, that some blocks of the anterior insula play the role of hubs between the anterior and the posterior insulae, as confirmed by their activation in several different paradigms. This finding supports the view that the network to which the anterior insula belongs is related to saliency detection. The insulae of both sides can be parcellated in two clusters, the anterior and the posterior: the anterior is characterized by an attentional pattern of connectivity with frontal, cingulate, parietal, cerebellar and anterior insular highly connected areas, whereas the posterior is characterized by a more local connectivity pattern with connections to sensorimotor, temporal and posterior cingulate areas. This antero-posterior subdivision, better characterized on the right side, results sharper with the connectivity based clusterization than with the behavioral based clusterization. The circuits belonging to the anterior insula are very homogeneous and their blocks in multidimensional scaling of MACM-based profiles are in central position, whereas those belonging to the posterior insula, especially on the left, are located at the periphery and sparse, thus suggesting that the posterior circuits bear a more heterogeneous connectivity. The anterior cluster is mostly activated by cognition, whereas the posterior is mostly activated by interoception, perception and emotion.


Assuntos
Córtex Cerebral/fisiologia , Modelos Anatômicos , Modelos Neurológicos , Rede Nervosa/fisiologia , Simulação por Computador , Humanos , Vias Neurais/fisiologia
20.
Mol Pain ; 8: 39, 2012 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-22616849

RESUMO

BACKGROUND: Current tools for analgesia are often only partially successful, thus investigations of new targets for pain therapy stimulate great interest. Consequent to peripheral nerve injury, c-Jun N-terminal kinase (JNK) activity in cells of the dorsal root ganglia (DRGs) and spinal cord is involved in triggering neuropathic pain. However, the relative contribution of distinct JNK isoforms is unclear. Using knockout mice for single isoforms, and blockade of JNK activity by a peptide inhibitor, we have used behavioral tests to analyze the contribution of JNK in the development of neuropathic pain after unilateral sciatic nerve transection. In addition, immunohistochemical labelling for the growth associated protein (GAP)-43 and Calcitonin Gene Related Peptide (CGRP) in DRGs was used to relate injury related compensatory growth to altered sensory function. RESULTS: Peripheral nerve injury produced pain-related behavior on the ipsilateral hindpaw, accompanied by an increase in the percentage of GAP43-immunoreactive (IR) neurons and a decrease in the percentage of CGRP-IR neurons in the lumbar DRGs. The JNK inhibitor, D-JNKI-1, successfully modulated the effects of the sciatic nerve transection. The onset of neuropathic pain was not prevented by the deletion of a single JNK isoform, leading us to conclude that all JNK isoforms collectively contribute to maintain neuropathy. Autotomy behavior, typically induced by sciatic nerve axotomy, was absent in both the JNK1 and JNK3 knockout mice. CONCLUSIONS: JNK signaling plays an important role in regulating pain threshold: the inhibition of all of the JNK isoforms prevents the onset of neuropathic pain, while the deletion of a single splice JNK isoform mitigates established sensory abnormalities. JNK inactivation also has an effect on axonal sprouting following peripheral nerve injury.


Assuntos
Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Neuralgia/metabolismo , Nervo Isquiático/lesões , Animais , Proteína GAP-43/metabolismo , Gânglios Espinais/metabolismo , Isoenzimas/antagonistas & inibidores , Isoenzimas/metabolismo , Proteínas Quinases JNK Ativadas por Mitógeno/antagonistas & inibidores , Masculino , Camundongos , Camundongos Knockout , Neurônios/metabolismo , Peptídeos/farmacologia , Nervo Isquiático/metabolismo
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