RESUMO
BACKGROUND: Despite the success of recently introduced immunomodulatory therapies, multiple sclerosis and its ophthalmic manifestation as optic neuritis lead to irreversible axonal degeneration. Hence, it would be desirable to apply a neuroprotective therapy in parallel. RESULTS AND DISCUSSION: We identified erythropoietin as an available and approved drug exerting neuroprotective effects in addition to its hematopoetic action. After several successful preclinical experiments, the pilot trial VISION PROTECT has shown that 33,000 IU erythropoietin, given intravenously on 3 consecutive days, preserves the retinal nerve fibre layer to a significant extent. This therapy will now be evaluated in a full scale and adequately powered trial to challenge this hypothesis. The TONE trial (Treatment of Optic Neuritis with Erythropoietin, NCT01962571) is a multicentric, prospective, double-blinded, clinical trial evaluating the same therapeutic regimen primarily with regard to thickness of the retinal nerve fibre layer and low contrast visual acuity.
Assuntos
Guias como Assunto , Esclerose Múltipla/diagnóstico , Esclerose Múltipla/terapia , Neurologia/normas , Oftalmologia/normas , Neurite Óptica/diagnóstico , Neurite Óptica/terapia , Algoritmos , Diagnóstico Diferencial , Humanos , Esclerose Múltipla/complicações , Neurite Óptica/etiologiaRESUMO
A clinically isolated syndrome (CIS) is a term which describes the first clinical onset of a potential multiple sclerosis (MS). It ought to be defined as an MS stage rather than a separate disease entity; however, with respect to the diagnostic work-up, differential diagnoses to be considered, prognostic factors for the development of a clinically confirmed MS and initiation of an immunomodulatory therapy, there are some important considerations supported by recent studies. These considerations as well as the current guidelines are critically discussed in this review article. Additionally, recommendations are given regarding the management of radiologically isolated syndrome (RIS) an imaging-based diagnosis of a potential preclinical stage of MS.
Assuntos
Doenças Desmielinizantes/diagnóstico , Esclerose Múltipla/diagnóstico , Adulto , Encéfalo/patologia , Doenças Desmielinizantes/tratamento farmacológico , Diagnóstico Diferencial , Acetato de Glatiramer , Fidelidade a Diretrizes , Humanos , Interferon beta/uso terapêutico , Imageamento por Ressonância Magnética , Metilprednisolona/uso terapêutico , Esclerose Múltipla/tratamento farmacológico , Exame Neurológico , Neurite Óptica/diagnóstico , Neurite Óptica/tratamento farmacológico , Peptídeos/uso terapêutico , Prognóstico , Pulsoterapia , Medula Espinal/patologia , Adulto JovemRESUMO
Mesenchymal stem cells (MSC) promote functional recovery in experimental models of central nervous system (CNS) pathology and are currently being tested in clinical trials for stroke, multiple sclerosis and CNS injury. Their beneficial effects are attributed to the activation of endogenous CNS protection and repair processes as well as immune regulation but their mechanisms of action are poorly understood. Here we investigated the neuroprotective effects of mouse MSC in rodent MSC-neuron co-cultures and mice using models of glutamate excitotoxicity. A 24h pre-culture of mouse primary cortical neurons with MSC protected them against glutamate (NMDA) receptor-induced death and conditioned medium from MSC (MSC CM) was sufficient for this effect. Protection by MSC CM was associated with reduced mRNA levels of genes encoding NMDA receptor subunits, and increased levels for genes associated with non-neuronal and stem cell types, as shown by RT-PCR and cDNA microarray analyses. Changes in gene expression were not associated with alterations in cell lineage representation within the cultures. Further, MSC CM-mediated neuroprotection in rat retinal ganglion cells was associated with reduced glutamate-induced calcium influx. The adoptive transfer of EGFP(+)MSC in a mouse kainic acid epilepsy model also provided neuroprotection against glutamate excitotoxicity in vivo, as shown by reduced neuron damage and glial cell activation in the hippocampus. These results show that MSC mediate direct neuroprotection by reducing neuronal sensitivity to glutamate receptor ligands and altering gene expression, and suggest a link between the therapeutic effects of MSC and the activation of cell plasticity in the damaged CNS.
Assuntos
Ácido Caínico/toxicidade , Transplante de Células-Tronco Mesenquimais/métodos , Doenças Neurodegenerativas/terapia , Animais , Células Cultivadas , Técnicas de Cocultura , Modelos Animais de Doenças , Feminino , Ácido Glutâmico/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Doenças Neurodegenerativas/induzido quimicamente , Doenças Neurodegenerativas/fisiopatologia , Neurônios/citologia , Neurônios/fisiologia , GravidezRESUMO
Antiretroviral therapy is limited by the development of human immunodeficiency virus (HIV) resistance mutations. Although resistance testing is recommended during therapy failure, little is known about the optimal time points for testing or its impact on treatment. In this study, we investigated HIV polymorphisms and mutations and assessed their influence on the outcome of highly active antiretroviral therapy (HAART). We focused on viral load and CD4+ cell counts as the most important parameters for therapy response. Resistance mutations were present in 19% of all patients prior to antiretroviral treatment. Mutations causing direct antiretroviral drug resistance were observed in 10%. Analyzing therapy response, we found a significant correlation between resistance mutations and impaired CD4+ cell recovery six months after the initiation of antiretroviral treatment. Lower CD4+ cell counts were also observed in a subgroup of patients infected with a virus presenting mutations that directly lowered drug susceptibility.
Assuntos
Fármacos Anti-HIV/administração & dosagem , Terapia Antirretroviral de Alta Atividade/métodos , Linfócitos T CD4-Positivos/imunologia , Farmacorresistência Viral , Infecções por HIV/virologia , HIV/efeitos dos fármacos , Mutação de Sentido Incorreto , Adulto , Idoso , Fármacos Anti-HIV/farmacologia , Contagem de Linfócito CD4 , Estudos de Coortes , Feminino , Genótipo , HIV/genética , HIV/isolamento & purificação , Infecções por HIV/tratamento farmacológico , Infecções por HIV/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético , Estudos Prospectivos , RNA Viral/genética , Carga Viral , Proteínas Virais/genéticaRESUMO
In multiple sclerosis (MS), long-term disability is primarily caused by axonal and neuronal damage. We demonstrated in a previous study that neuronal apoptosis occurs early during experimental autoimmune encephalomyelitis, a common animal model of MS. In the present study, we show that, in rats suffering from myelin oligodendrocyte glycoprotein (MOG)-induced optic neuritis, systemic application of erythropoietin (Epo) significantly increased survival and function of retinal ganglion cells (RGCs), the neurons that form the axons of the optic nerve. We identified three independent intracellular signaling pathways involved in Epo-induced neuroprotection in vivo: Protein levels of phospho-Akt, phospho-MAPK 1 and 2, and Bcl-2 were increased under Epo application. Using a combined treatment of Epo together with a selective inhibitor of phosphatidylinositol 3-kinase (PI3-K) prevented upregulation of phospho-Akt and consecutive RGC rescue. We conclude that in MOG-EAE the PI3-K/Akt pathway has an important influence on RGC survival under systemic treatment with Epo.
Assuntos
Eritropoetina/farmacologia , Esclerose Múltipla/tratamento farmacológico , Glicoproteína Associada a Mielina/farmacologia , Fármacos Neuroprotetores/farmacologia , Células Ganglionares da Retina/efeitos dos fármacos , Transdução de Sinais/fisiologia , Animais , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Caspases/efeitos dos fármacos , Caspases/metabolismo , Contagem de Células , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Modelos Animais de Doenças , Eletrorretinografia , Eritropoetina/administração & dosagem , Feminino , Marcação In Situ das Extremidades Cortadas/métodos , Esclerose Múltipla/fisiopatologia , Proteínas da Mielina , Glicoproteína Associada a Mielina/administração & dosagem , Glicoproteína Mielina-Oligodendrócito , Fármacos Neuroprotetores/administração & dosagem , Nervo Óptico/fisiopatologia , Fosforilação , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt , Ratos , Ratos Endogâmicos BN , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/farmacologia , Células Ganglionares da Retina/fisiologia , Transdução de Sinais/efeitos dos fármacosRESUMO
We have investigated the role of caspase-8 and its mode of activation during apoptosis of adult rat retinal ganglion cells (RGCs) in vivo. Retinal pro-caspase-8 expression was almost completely restricted to RGCs. Although caspase-8 is known to be involved in death-receptor-dependent apoptosis, measurable caspase-8 activity or even RGC death could be induced by neither tumor necrosis factor-alpha nor Fas ligand injections into unlesioned eyes. However, substantial caspase-8 activation could be detected after optic nerve transection as shown by a fluorogenic activity assay and Western blot analysis. Intravitreal injection of caspase-8 inhibitors significantly attenuated degeneration of RGCs and reduced the number of RGCs showing caspase-3 activation. A late peak of caspase-8 activity and additive protective effects of caspase-8 and -9 inhibition on axotomized RGCs place caspase-8 in our model rather late in the apoptosis cascade, possibly after the onset of mitochondrial dysfunction.
Assuntos
Apoptose , Axotomia , Caspases/metabolismo , Células Ganglionares da Retina/enzimologia , Animais , Western Blotting , Caspase 3 , Caspase 8 , Caspase 9 , Contagem de Células , Feminino , Imuno-Histoquímica , Ratos , Ratos Sprague-Dawley , Fatores de TempoRESUMO
Tumor-necrosis-factor-alpha (TNF-alpha) prevented secondary death of retinal ganglion cells (RGCs) after axotomy of the optic nerve in vivo. This RGC rescue was confirmed in vitro in a mixed retinal culture model. In accordance with our previous findings, TNF-alpha decreased outward potassium currents in RGCs. Antagonism of the TNF-alpha-induced decrease in outward potassium currents with the potassium channel opener minoxidilsulfate (as verified by electrophysiology) abolished neuroprotection. Western blot analysis revealed an upregulation of phospho-Akt as a consequence of TNF-alpha-induced potassium current reduction. Inhibition of the phosphatidylinositol 3-kinase-Akt pathway with wortmannin decreased TNF-alpha-promoted RGC survival. These data point to a functionally relevant cytokine-dependent neuroprotective signaling cascade in adult CNS neurons.