RESUMO
Gangliosidoses (GM1 and GM2 gangliosidosis) are rare, autosomal recessive progressive neurodegenerative lysosomal storage disorders caused by defects in the degradation of glycosphingolipids. We aimed to investigate clinical, biochemical and molecular genetic spectrum of Turkish patients with infantile gangliosidoses and examined the potential role of serum aspartate transaminase levels as a biomarker. We confirmed the diagnosis of GM1 and GM2 gangliosidosis based on clinical findings with specific enzyme and/or molecular analyses. We retrospectively reviewed serum aspartate transaminase levels of patients with other biochemical parameters. Serum aspartate transaminase level was elevated in all GM1 and GM2 gangliosidosis patients in whom the test was performed, along with normal alanine transaminase. Aspartate transaminase can be a biochemical diagnostic clue for infantile gangliosidoses. It might be a simple but important biomarker for diagnosis, follow up, prognosis and monitoring of the response for the future therapies in these patients.
Assuntos
Aspartato Aminotransferases/metabolismo , Biomarcadores/análise , Gangliosidoses/tratamento farmacológico , Doença de Sandhoff/tratamento farmacológico , Aspartato Aminotransferases/efeitos dos fármacos , Feminino , Gangliosidoses GM2/tratamento farmacológico , Gangliosidose GM1/tratamento farmacológico , Humanos , Masculino , Estudos RetrospectivosRESUMO
As part of a program towards the development of specific inhibitors of human lysosomal beta-hexosaminidase for use as chemical chaperones in therapy of G(M2) gangliosidosis related diseases, the synthesis of 2-acetamidomethyl derivatives of isofagomine has been undertaken. Key event in this synthesis is the conversion of a C-2 substituted gluconolactone derivative into the corresponding lactam, followed by reduction to the corresponding amine. The 1-N-imino-2 acetamidomethyl derivative 5 proved to be a rather selective inhibitor with a K(i) of 2.4 microM for homogenate of human spleen lysosomal beta-hexosaminidase.
Assuntos
Desenho de Fármacos , Lisossomos/enzimologia , Piperidinas/síntese química , Piperidinas/farmacologia , beta-N-Acetil-Hexosaminidases/antagonistas & inibidores , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Gangliosidoses/tratamento farmacológico , Humanos , Imino Piranoses , Concentração Inibidora 50 , Cinética , Baço/enzimologia , Baço/ultraestrutura , Relação Estrutura-AtividadeRESUMO
Mouse models of the GM2 gangliosidoses [Tay-Sachs, late onset Tay-Sachs (LOTS), Sandhoff] and GM1 gangliosidosis have been studied to determine whether there is a common neuro-inflammatory component to these disorders. During the disease course, we have: (i) examined the expression of a number of inflammatory markers in the CNS, including MHC class II, CD68, CD11b (CR3), 7/4, F4/80, nitrotyrosine, CD4 and CD8; (ii) profiled cytokine production [tumour necrosis factor alpha (TNF alpha), transforming growth factor (TGF beta 1) and interleukin 1 beta (IL1 beta)]; and (iii) studied blood-brain barrier (BBB) integrity. The kinetics of apoptosis and the expression of Fas and TNF-R1 were also assessed. In all symptomatic mouse models, a progressive increase in local microglial activation/expansion and infiltration of inflammatory cells was noted. Altered BBB permeability was evident in Sandhoff and GM1 mice, but absent in LOTS mice. Progressive CNS inflammation coincided with the onset of clinical signs in these mouse models. Substrate reduction therapy in the Sandhoff mouse model slowed the rate of accumulation of glycosphingolipids in the CNS, thus delaying the onset of the inflammatory process and disease pathogenesis. These data suggest that inflammation may play an important role in the pathogenesis of the gangliosidoses.
Assuntos
Antígenos CD/metabolismo , Citocinas/metabolismo , Gangliosidoses/etiologia , Genes MHC da Classe II/fisiologia , 1-Desoxinojirimicina/análogos & derivados , 1-Desoxinojirimicina/uso terapêutico , Animais , Apoptose , Biomarcadores/análise , Barreira Hematoencefálica , Inibidores Enzimáticos/uso terapêutico , Gangliosidoses/tratamento farmacológico , Gangliosidoses/patologia , Gangliosidoses GM2/tratamento farmacológico , Gangliosidoses GM2/etiologia , Gangliosidoses GM2/patologia , Gangliosidose GM1/tratamento farmacológico , Gangliosidose GM1/etiologia , Gangliosidose GM1/patologia , Imuno-Histoquímica , Inflamação/patologia , Camundongos , Doença de Sandhoff/tratamento farmacológico , Doença de Sandhoff/etiologia , Doença de Sandhoff/patologia , Doença de Tay-Sachs/tratamento farmacológico , Doença de Tay-Sachs/etiologia , Doença de Tay-Sachs/patologiaRESUMO
We have developed a series of inhibitors of glucosylceramide synthase that are structurally based on the parent compound D-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (PDMP). These inhibitors provide useful tools for manipulating glycosphingolipid levels in cells and for elucidating questions associated with sphingolipid signaling. Recently, two highly active glucosylceramide synthase inhibitors, D-threo-3', 4'-ethylenedioxy-1-phenyl-2-palmitoylamino-3- pyrrolidino-1-propanol and D-threo-4'-hydroxy-1-phenyl-2-palmitoylamino-3- pyrrolidino-1-propanol, were designed, synthesized, and studied. These inhibitors markedly reduced glycosphingolipid levels in MDCK cells without any accumulation of intracellular ceramide and associated growth inhibition. Subsequently, each inhibitor was evaluated for its ability to lower glycolipid levels in virally transformed lymphoblasts from a patient with alpha-galactosidase A deficiency. Both compounds significantly reduced neutral glycosphingolipid levels in the lymphoblasts without any morphological changes and growth inhibition. Furthermore, the inhibitors were applied to a mouse knockout model of Fabry disease. Inhibitor treatment blocked accumulation of globotriaosylceramide (Gb3) in the kidney, liver and heart of mice. In contrast to another glucosylceramide synthase inhibitor, N-butyldeoxynojirimycin, this treatment was not associated with any significant change in body weight or organ weight and without immunodepletion. These results suggest that these newest PDMP homologues are promising as therapeutic agents for the treatment of glycosphingolipid storage disorders.
Assuntos
Inibidores Enzimáticos/uso terapêutico , Gangliosidoses/tratamento farmacológico , Glicoesfingolipídeos/metabolismo , Morfolinas/uso terapêutico , Animais , Glicoesfingolipídeos/biossíntese , Humanos , CamundongosRESUMO
Normal human skin fibroblasts secrete most of their hexosaminidase (Hex) into the medium upon incubation with 10(-4) imipramine, while preincubation with 2.5 X 10(-9) M dexamethasone prevents this effect. These results support the hypotheses that 1) treatment of psychotic Hex A deficient patients with amphiphilic antidepressants (such as imipramine) aggravates the patients' disease through depletion of their residual cellular Hex A, and 2) concomitant medication with dexamethasone may mitigate this drug-induced deleterious effect.