RESUMO
Treatments that stimulate neuronal excitability enhance motor performance after stroke. cAMP-response-element binding protein (CREB) is a transcription factor that plays a key role in neuronal excitability. Increasing the levels of CREB with a viral vector in a small pool of motor neurons enhances motor recovery after stroke, while blocking CREB signaling prevents stroke recovery. Silencing CREB-transfected neurons in the peri-infarct region with the hM4Di-DREADD blocks motor recovery. Reversing this inhibition allows recovery to continue, demonstrating that by manipulating the activity of CREB-transfected neurons it is possible to turn off and on stroke recovery. CREB transfection enhances remapping of injured somatosensory and motor circuits, and induces the formation of new connections within these circuits. CREB is a central molecular node in the circuit responses after stroke that lead to recovery from motor deficits.
Assuntos
Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Córtex Motor/fisiopatologia , Neurônios Motores/fisiologia , Plasticidade Neuronal/fisiologia , Recuperação de Função Fisiológica/fisiologia , Acidente Vascular Cerebral/fisiopatologia , Animais , Mapeamento Encefálico , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Perfilação da Expressão Gênica , Masculino , Camundongos Endogâmicos C57BL , Córtex Motor/metabolismo , Neurônios Motores/metabolismo , Plasticidade Neuronal/genética , Técnicas de Patch-Clamp , Acidente Vascular Cerebral/genéticaRESUMO
Addition of L-carnitine and some of its analogs to low-serum incubation medium of murine hepatocytic C2.8 cells prolonged maintenance of life and enhanced cell growth, as compared to controls. The drug acted synergistically with hepatocyte growth factor (HGF). Addition of L-carnitine to cells that had grown confluently in medium supplemented with HGF, significantly delayed the onset of cell death (apoptosis) initiated after HGF deprivation. Protection by L-carnitine was dose-dependent and stereospecific. Similar findings were obtained with three analogs of L-carnitine (i.e. isovaleryl-L-carnitine-HCl, isovaleryl-L-carnitine acid fumarate and butyryl L-carnitine taurine amide). In contrast, four different analogs (i.e. isovaleryl-L-carnitine-eptyl-ester-HCl, isovaleryl-L-carnitine-idroxy-butyric-HCl, L-threonyl-L-carnitine-HCl and L-paramethyl-cinnamoil-carnitine-HCl) were inactive. Although the mechanism of cytoprotection stimulated by L-carnitine remains unresolved, the data suggest that this compound serves as a co-factor that influences C2.8 cells to become less susceptible to damaging actions of noxious agents or conditions initiated after HGF withdrawal.
