RESUMO
Stroke is a major cause of serious disability due to the brain's limited capacity to regenerate damaged tissue and neuronal circuits. After ischemic injury, a multiphasic degenerative and inflammatory response is coupled with severely restricted vascular and neuronal repair, resulting in permanent functional deficits. Although clinical evidence indicates that revascularization of the ischemic brain regions is crucial for functional recovery, no therapeutics that promote angiogenesis after cerebral stroke are currently available. Besides vascular growth factors, guidance molecules have been identified to regulate aspects of angiogenesis in the central nervous system (CNS) and may provide targets for therapeutic angiogenesis. In this study, we demonstrate that genetic deletion of the neurite outgrowth inhibitor Nogo-A or one of its corresponding receptors, S1PR2, improves vascular sprouting and repair and reduces neurological deficits after cerebral ischemia in mice. These findings were reproduced in a therapeutic approach using intrathecal anti-Nogo-A antibodies; such a therapy is currently in clinical testing for spinal cord injury. These results provide a basis for a therapeutic blockage of inhibitory guidance molecules to improve vascular and neural repair after ischemic CNS injuries.
Assuntos
Anticorpos Anti-Idiotípicos/farmacologia , Isquemia Encefálica/tratamento farmacológico , Proteínas Nogo/genética , Receptores de Esfingosina-1-Fosfato/genética , Acidente Vascular Cerebral/tratamento farmacológico , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Isquemia Encefálica/genética , Isquemia Encefálica/imunologia , Isquemia Encefálica/patologia , Sistema Nervoso Central/efeitos dos fármacos , Sistema Nervoso Central/patologia , Modelos Animais de Doenças , Humanos , Camundongos , Neovascularização Fisiológica/genética , Neovascularização Fisiológica/imunologia , Neurônios/efeitos dos fármacos , Neurônios/patologia , Proteínas Nogo/antagonistas & inibidores , Proteínas Nogo/imunologia , Tratos Piramidais/efeitos dos fármacos , Tratos Piramidais/patologia , Recuperação de Função Fisiológica/genética , Receptores de Esfingosina-1-Fosfato/antagonistas & inibidores , Receptores de Esfingosina-1-Fosfato/imunologia , Traumatismos da Medula Espinal/tratamento farmacológico , Traumatismos da Medula Espinal/imunologia , Traumatismos da Medula Espinal/patologia , Acidente Vascular Cerebral/genética , Acidente Vascular Cerebral/imunologia , Acidente Vascular Cerebral/patologiaRESUMO
A biotechnological process is reported, which enables an enzymatic reduction without the need for addition of an organic co-substrate for in situ-cofactor recycling. The process is based on merging the fields of enzymatic reductive amination with formate dehydrogenase-based in situ-cofactor recycling and algae biotechnology by means of the photoautotrophic microorganism Chlamydomonas reinhardtii, providing the needed formate in situ by formation from carbon dioxide, water and light. This biotransformation has been exemplified for the synthesis of various aliphatic amines known as bulk chemicals.