RESUMO
Despite different aetiologies, age-related macular degeneration and most inherited retinal disorders culminate in the same final common pathway, the loss of photoreceptors. There are few treatments and none reverse the loss of vision. Photoreceptor replacement by transplantation is proposed as a broad treatment strategy applicable to all degenerations. Recently, we demonstrated restoration of vision following rod-photoreceptor transplantation into a mouse model of stationary night-blindness, raising the critical question of whether photoreceptor replacement is equally effective in different types and stages of degeneration. We present a comprehensive assessment of rod-photoreceptor transplantation across six murine models of inherited photoreceptor degeneration. Transplantation is feasible in all models examined but disease type has a major impact on outcome, as assessed both by the morphology and number of integrated rod-photoreceptors. Integration can increase (Prph2(+/Δ307)), decrease (Crb1(rd8/rd8), Gnat1(-/-), Rho(-/-)), or remain constant (PDE6ß(rd1/rd1), Prph2(rd2/rd2)) with disease progression, depending upon the gene defect, with no correlation with severity. Robust integration is possible even in late-stage disease. Glial scarring and outer limiting membrane integrity, features that change with degeneration, significantly affect transplanted photoreceptor integration. Combined breakdown of these barriers markedly increases integration in a model with an intact outer limiting membrane, strong gliotic response, and otherwise poor transplantation outcome (Rho(-/-)), leading to an eightfold increase in integration and restoration of visual function. Thus, it is possible to achieve robust integration across a broad range of inherited retinopathies. Moreover, transplantation outcome can be improved by administering appropriate, tailored manipulations of the recipient environment.
Assuntos
Cegueira Noturna/cirurgia , Atrofia Óptica Hereditária de Leber/cirurgia , Células Fotorreceptoras Retinianas Bastonetes/transplante , Retinite Pigmentosa/cirurgia , Animais , Western Blotting , Contagem de Células , Nucleotídeo Cíclico Fosfodiesterase do Tipo 6/metabolismo , Citometria de Fluxo , Subunidades alfa de Proteínas de Ligação ao GTP/genética , Subunidades alfa de Proteínas de Ligação ao GTP/metabolismo , Proteínas de Filamentos Intermediários/metabolismo , Glicoproteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microscopia Confocal , Microscopia Eletrônica de Transmissão , Proteínas do Tecido Nervoso/metabolismo , Cegueira Noturna/genética , Atrofia Óptica Hereditária de Leber/genética , Periferinas , Células Fotorreceptoras Retinianas Bastonetes/ultraestrutura , Retinite Pigmentosa/genética , Transducina/genética , Transducina/metabolismo , Resultado do Tratamento , Proteínas rho de Ligação ao GTP/genética , Proteínas rho de Ligação ao GTP/metabolismoRESUMO
Las enfermedades mitocondriales son un raro grupo de enfermedades que se manifiestan a través de un defecto en la cadena de transporte de electrones o de la fosforilación oxidativa. Se trata de una alteración del ADN nuclear o del mitocondrial que provoca miopatía hipotónica, encefalopatía y aumento del ácido láctico. Para su correcto diagnóstico deben realizarse, entre otras pruebas, una biopsia muscular y una resonancia magnética. El anestesista debe realizar su trabajo en un paciente con miopatía sin diagnosticar y con riesgo de complicaciones cardiorrespiratorias y neurológicas, por ello es importante el conocimiento de las acciones sobre la cadena respiratoria de los agentes anestésicos. Presentamos el desarrollo esquemático de las enfermedades de la cadena respiratoria mitocondrial y su manejo anestésico
Diseases of the mitochondrial respiratory chain are a rare pathologic group that can be manifested through a defect in the transport chain of electrons or by oxidative phosphorylation alteration. It is a disturbance of the nuclear or mitochondrial DNA, causing hypotonic myopathy, encephalopathy and hyperlactacidemya. For its correct diagnosis must be performed muscle biopsy and magnetic resonance. The anaesthetist must do their work in a patient without a correct diagnostic of myopathy, and a high risk of cardiorrespiratory and neurologic complications. Thats why its important the knowledge of the actions of de anaesthetic agents by de respiratory chain. We present the schematic development of the mitochondrial respiratory chain diseases and its anaesthetic management
