RESUMO
Norrin is an angiogenic signaling molecule that activates canonical Wnt/ß-catenin signaling, and is involved in capillary formation in retina and brain. Moreover, Norrin induces vascular repair following an oxygen-induced retinopathy (OIR), the model of retinopathy of prematurity in mice. Since insulin-like growth factor (IGF)-1 is a very potent angiogenic molecule, we investigated if IGF-1 is a downstream mediator of Norrin's angiogenic properties. In retinae of transgenic mice with an ocular overexpression of Norrin (ßB1-Norrin), we found at postnatal day (P)11 a significant increase of IGF-1 mRNA compared to wild-type littermates. In addition, after treatment of cultured Müller cells or dermal microvascular endothelial cells with Norrin we observed an increase of IGF-1 and its mRNA, an effect that could be blocked with DKK-1, an inhibitor of Wnt/ß-catenin signaling. When OIR was induced, the expression of IGF-1 was significantly suppressed in both transgenic ßB1-Norrin mice and wild-type littermates when compared to wild-type animals that were housed in room air. Furthermore, at P13, one day after the mice had returned to normoxic conditions, IGF-1 levels were significantly higher in transgenic mice compared to wild-type littermates. Finally, after intravitreal injections of inhibitory α-IGF-1 antibodies at P12 or at P12 and P14, the Norrin-mediated vascular repair was significantly attenuated. We conclude that Norrin induces the expression of IGF-1 via an activation of the Wnt/ß-catenin signaling pathway, an effect that significantly contributes to the protective effects of Norrin against an OIR.
Assuntos
Proteínas do Olho/fisiologia , Fator de Crescimento Insulin-Like I/metabolismo , Proteínas do Tecido Nervoso/fisiologia , Neovascularização Retiniana/metabolismo , Animais , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Modelos Animais de Doenças , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Células Ependimogliais/efeitos dos fármacos , Células Ependimogliais/metabolismo , Proteínas do Olho/farmacologia , Humanos , Fator de Crescimento Insulin-Like I/antagonistas & inibidores , Camundongos , Camundongos Transgênicos , Proteínas do Tecido Nervoso/farmacologia , Oxigênio/efeitos adversos , RNA Mensageiro/metabolismo , Ratos , Ratos Wistar , Neovascularização Retiniana/etiologia , Via de Sinalização Wnt/fisiologiaRESUMO
AIM: A substantial gap between young people's need for mental health care services and their actual access to such services led worldwide organizations (e.g., the WHO) to recommend the implementation of early intervention programs and youth mental health services. Some countries around the world have established structures to meet this recommendation. In this paper, we describe soulspace as the first integrated youth mental health service for young people aged between 15 and 35 years in Berlin, Germany. METHODS: We introduce soulspace as easily accessible mental health care for young people, and we characterize soulspace along the lines of the internationally established eight key principles of integrated youth mental health services (Killackey, et al., 2020, World Economic Forum). Soulspace is a cooperation between clinical outpatient units of psychiatric clinics for adolescents and young adults as well as a community-based counselling service. It provides initial contact, counselling, diagnostics, and treatment. RESULTS: Our analyses of the pathways to soulspace and the characteristics of the soulspace users suggest that the low threshold is a facilitator to help finding for young people in comparison to more conventional early intervention models. That is, having transferred the early intervention center in a youth-facing counselling service as was done in soulspace seems to have reduced the threshold to seek help for families and for young people in need for support. CONCLUSIONS: In summary, with soulspace, an easily accessible mental health care service was established that integrates counselling and specialized psychiatric treatment if needed.
Assuntos
Prestação Integrada de Cuidados de Saúde , Serviços de Saúde Mental , Humanos , Adolescente , Adulto Jovem , Masculino , Feminino , Serviços de Saúde Mental/organização & administração , Adulto , Berlim , Prestação Integrada de Cuidados de Saúde/organização & administração , Transtornos Mentais/terapia , Acessibilidade aos Serviços de Saúde , Serviços de Saúde do Adolescente/organização & administração , Alemanha , Serviços Comunitários de Saúde Mental/organização & administração , Intervenção Médica PrecoceRESUMO
PURPOSE: To investigate whether and how leukemia inhibitory factor (Lif) is involved in mediating the neuroprotective effects of Norrin on retinal ganglion cells (RGC) following excitotoxic damage. Norrin is a secreted protein that protects RGC from N-methyl-d-aspartate (NMDA)-mediated excitotoxic damage, which is accompanied by increased expression of protective factors such as Lif, Edn2 and Fgf2. METHODS: Lif-deficient mice were injected with NMDA in one eye and NMDA plus Norrin into the other eye. RGC damage was investigated and quantified by TUNEL labeling 24 h after injection. Retinal mRNA expression was analyzed by quantitative real-time polymerase chain reaction following retinal treatment. RESULTS: After intravitreal injection of NMDA and Norrin in wild-type mice approximately 50% less TUNEL positive cells were observed in the RGC layer when compared to NMDA-treated littermates, an effect which was lost in Lif-deficient mice. The mRNA expression for Gfap, a marker for Müller cell gliosis, as well as Edn2 and Fgf2 was induced in wild-type mice following NMDA/Norrin treatment but substantially blocked in Lif-deficient mice. CONCLUSIONS: Norrin mediates its protective properties on RGC via Lif, which is required to enhance Müller cell gliosis and to induce protective factors such as Edn2 or Fgf2.
Assuntos
Proteínas do Olho/farmacologia , Fator Inibidor de Leucemia/metabolismo , Proteínas do Tecido Nervoso/farmacologia , Neuroproteção/efeitos dos fármacos , Neurotoxinas/toxicidade , Células Ganglionares da Retina/patologia , Animais , Endotelina-2/metabolismo , Células Ependimogliais/efeitos dos fármacos , Células Ependimogliais/patologia , Proteínas do Olho/metabolismo , Fator 2 de Crescimento de Fibroblastos/metabolismo , Gliose/patologia , Humanos , Fator Inibidor de Leucemia/deficiência , Camundongos Endogâmicos C57BL , N-Metilaspartato/farmacologia , Proteínas do Tecido Nervoso/metabolismo , Nervo Óptico/efeitos dos fármacos , Nervo Óptico/patologia , Fenótipo , Células Ganglionares da Retina/efeitos dos fármacos , Células Ganglionares da Retina/metabolismo , Neurônios Retinianos/efeitos dos fármacos , Neurônios Retinianos/patologia , Transdução de SinaisRESUMO
Norrin is a secreted signaling molecule activating the Wnt/ß-catenin pathway. Since Norrin protects retinal neurons from experimental acute injury, we were interested to learn if Norrin attenuates chronic damage of retinal ganglion cells (RGC) and their axons in a mouse model of glaucoma. Transgenic mice overexpressing Norrin in the retina (Pax6-Norrin) were generated and crossed with DBA/2J mice with hereditary glaucoma and optic nerve axonal degeneration. One-year old DBA/2J/Pax6-Norrin animals had significantly more surviving optic nerve axons than their DBA/2J littermates. The protective effect correlated with an increase in insulin-like growth factor (IGF)-1 mRNA and an enhanced Akt phosphorylation in DBA/2J/Pax6-Norrin mice. Both mouse strains developed an increase in intraocular pressure during the second half of the first year and marked degenerative changes in chamber angle, ciliary body and iris structure. The degenerations were slightly attenuated in the chamber angle of DBA/2J/Pax6-Norrin mice, which showed a ß-catenin increase in the trabecular meshwork. We conclude that high levels of Norrin and the subsequent constitutive activation of Wnt/ß-catenin signaling in RGC protect from glaucomatous axonal damage via IGF-1 causing increased activity of PI3K-Akt signaling. Our results identify components of a protective signaling network preventing degeneration of optic nerve axons in glaucoma.