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1.
Biomed Pharmacother ; 174: 116526, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38574621

RESUMO

Spinocerebellar ataxia type 1 (SCA1) is a debilitating neurodegenerative disorder of the cerebellum and brainstem. Memantine has been proposed as a potential treatment for SCA1. It blocks N-methyl-D-aspartate (NMDA) receptors on neurons, reduces excitotoxicity and decreases neurodegeneration in Alzheimer models. However, in cerebellar neurodegenerative diseases, the potential value of memantine is still unclear. We investigated the effects of memantine on motor performance and synaptic transmission in the cerebellum in a mouse model where mutant ataxin 1 is specifically targeted to glia. Lentiviral vectors (LVV) were used to express mutant ataxin 1 selectively in Bergmann glia (BG). In mice transduced with the mutant ataxin 1, chronic treatment with memantine improved motor activity during initial tests, presumably due to preserved BG and Purkinje cell (PC) morphology and numbers. However, mice were unable to improve their rota rod scores during next days of training. Memantine also compromised improvement in the rota rod scores in control mice upon repetitive training. These effects may be due to the effects of memantine on plasticity (LTD suppression) and NMDA receptor modulation. Some effects of chronically administered memantine persisted even after its wash-out from brain slices. Chronic memantine reduced morphological signs of neurodegeneration in the cerebellum of SCA1 model mice. This resulted in an apparent initial reduction of ataxic phenotype, but memantine also affected cerebellar plasticity and ultimately compromised motor learning. We speculate that that clinical application of memantine in SCA1 might be hampered by its ability to suppress NMDA-dependent plasticity in cerebellar cortex.


Assuntos
Modelos Animais de Doenças , Memantina , Fenótipo , Ataxias Espinocerebelares , Animais , Memantina/farmacologia , Ataxias Espinocerebelares/tratamento farmacológico , Ataxias Espinocerebelares/patologia , Camundongos , Ataxina-1/metabolismo , Ataxina-1/genética , Atividade Motora/efeitos dos fármacos , Cerebelo/efeitos dos fármacos , Cerebelo/patologia , Cerebelo/metabolismo , Células de Purkinje/efeitos dos fármacos , Células de Purkinje/patologia , Células de Purkinje/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Camundongos Transgênicos , Camundongos Endogâmicos C57BL , Neuroglia/efeitos dos fármacos , Neuroglia/patologia , Neuroglia/metabolismo , Masculino , Plasticidade Neuronal/efeitos dos fármacos
2.
Biomedicines ; 9(10)2021 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-34680569

RESUMO

One of the most challenging problems in the treatment of glioblastoma (GBM) is the highly infiltrative nature of the disease. Infiltrating cells that are non-resectable are left behind after debulking surgeries and become a source of regrowth and recurrence. To prevent tumor recurrence and increase patient survival, it is necessary to cleanse the adjacent tissue from GBM infiltrates. This requires an innovative local approach. One such approach is that of photodynamic therapy (PDT) which uses specific light-sensitizing agents called photosensitizers. Here, we show that tetramethylrhodamine methyl ester (TMRM), which has been used to asses mitochondrial potential, can be used as a photosensitizer to target GBM cells. Primary patient-derived GBM cell lines were used, including those specifically isolated from the infiltrative edge. PDT with TMRM using low-intensity green light induced mitochondrial damage, an irreversible drop in mitochondrial membrane potential and led to GBM cell death. Moreover, delayed photoactivation after TMRM loading selectively killed GBM cells but not cultured rat astrocytes. The efficacy of TMRM-PDT in certain GBM cell lines may be potentiated by adenylate cyclase activator NKH477. Together, these findings identify TMRM as a prototypical mitochondrially targeted photosensitizer with beneficial features which may be suitable for preclinical and clinical translation.

3.
Brain Sci ; 10(2)2020 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-32024010

RESUMO

: Glioblastoma multiforme (GBM) is the most malignant form of primary brain tumour with extremely poor prognosis. The current standard of care for newly diagnosed GBM includes maximal surgical resection followed by radiotherapy and adjuvant chemotherapy. The introduction of this protocol has improved overall survival, however recurrence is essentially inevitable. The key reason for that is that the surgical treatment fails to eradicate GBM cells completely, and adjacent parenchyma remains infiltrated by scattered GBM cells which become the source of recurrence. This stimulates interest to any supplementary methods which could help to destroy residual GBM cells and fight the infiltration. Photodynamic therapy (PDT) relies on photo-toxic effects induced by specific molecules (photosensitisers) upon absorption of photons from a light source. Such toxic effects are not specific to a particular molecular fingerprint of GBM, but rather depend on selective accumulation of the photosensitiser inside tumour cells or, perhaps their greater sensitivity to the effects, triggered by light. This gives hope that it might be possible to preferentially damage infiltrating GBM cells within the areas which cannot be surgically removed and further improve the chances of survival if an efficient photosensitiser and hardware for light delivery into the brain tissue are developed. So far, clinical trials with PDT were performed with one specific type of photosensitiser, protoporphyrin IX, which tends to accumulate in the cytoplasm of the GBM cells. In this review we discuss the idea that other types of molecules which build up in mitochondria could be explored as photosensitisers and used for PDT of these aggressive brain tumours.

4.
Brain Sci ; 9(4)2019 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-31013844

RESUMO

Astrogliosis is a pathological process that affects the density, morphology, and function of astrocytes. It is a common feature of brain trauma, autoimmune diseases, and neurodegeneration including spinocerebellar ataxia type 1 (SCA1), a poorly understood neurodegenerative disease. S100ß is a Ca2+ binding protein. In SCA1, excessive excretion of S100ß by reactive astrocytes and its uptake by Purkinje cells has been demonstrated previously. Under pathological conditions, excessive extracellular concentration of S100ß stimulates the production of proinflammatory cytokines and induces apoptosis. We modeled astrogliosis by S100ß injections into cerebellar cortex in mice. Injections of S100ß led to significant changes in Bergmann glia (BG) cortical organization and affected their processes. S100ß also changed morphology of the Purkinje cells (PCs), causing a significant reduction in the dendritic length. Moreover, the short-term synaptic plasticity and depolarization-induced suppression of synaptic transmission were disrupted after S100ß injections. We speculate that these effects are the result of Ca2+-chelating properties of S100ß protein. In summary, exogenous S100ß induced astrogliosis in cerebellum could lead to neuronal dysfunction, which resembles a natural neurodegenerative process. We suggest that astrocytes play an essential role in SCA1 pathology, and that astrocytic S100ß is an important contributor to this process.

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