RESUMO
Spreading depolarizations (SDs) occur frequently in patients with malignant hemispheric stroke. In animal-based experiments, SDs have been shown to cause secondary neuronal damage and infarct expansion during the initial period of infarct progression. In contrast, the influence of SDs during the delayed period is not well characterized yet. Here, we analyzed the impact of SDs in the delayed phase after cerebral ischemia and the potential protective effect of ketamine. Focal ischemia was induced by distal occlusion of the left middle cerebral artery in C57BL6/J mice. 24 h after occlusion, SDs were measured using electrocorticography and laser-speckle imaging in three different study groups: control group without SD induction, SD induction with potassium chloride, and SD induction with potassium chloride and ketamine administration. Infarct progression was evaluated by sequential MRI scans. 24 h after occlusion, we observed spontaneous SDs with a rate of 0.33 SDs/hour which increased during potassium chloride application (3.37 SDs/hour). The analysis of the neurovascular coupling revealed prolonged hypoemic and hyperemic responses in this group. Stroke volume increased even 24 h after stroke onset in the SD-group. Ketamine treatment caused a lesser pronounced hypoemic response and prevented infarct growth in the delayed phase after experimental ischemia. Induction of SDs with potassium chloride was significantly associated with stroke progression even 24 h after stroke onset. Therefore, SD might be a significant contributor to delayed stroke progression. Ketamine might be a possible drug to prevent SD-induced delayed stroke progression.
Assuntos
Isquemia Encefálica , Progressão da Doença , Ketamina , Camundongos Endogâmicos C57BL , Ketamina/farmacologia , Animais , Camundongos , Masculino , Isquemia Encefálica/prevenção & controle , Isquemia Encefálica/diagnóstico por imagem , Isquemia Encefálica/tratamento farmacológico , Modelos Animais de Doenças , Imageamento por Ressonância Magnética , Depressão Alastrante da Atividade Elétrica Cortical/efeitos dos fármacos , Infarto da Artéria Cerebral MédiaAssuntos
Envelhecimento/fisiologia , Transplante de Rim/fisiologia , Animais , Regulação da Expressão Gênica , Transplante de Rim/patologia , Modelos Animais , Nefrectomia , Proteinúria , Ratos , Ratos Endogâmicos F344 , Ratos Endogâmicos Lew , Reação em Cadeia da Polimerase Via Transcriptase ReversaAssuntos
Imunossupressores/farmacologia , Transplante de Rim/fisiologia , Rim/efeitos dos fármacos , Animais , Everolimo , Rim/fisiologia , Masculino , Ácido Micofenólico/análogos & derivados , Ácido Micofenólico/farmacologia , Prednisolona/farmacologia , Ratos , Ratos Endogâmicos F344 , Ratos Endogâmicos Lew , Fatores de Risco , Sirolimo/análogos & derivados , Sirolimo/farmacologia , Tacrolimo/farmacologia , Resultado do TratamentoAssuntos
Sobrevivência de Enxerto/fisiologia , Heme Oxigenase (Desciclizante)/metabolismo , Transplante de Rim/fisiologia , Rim/irrigação sanguínea , Traumatismo por Reperfusão/enzimologia , Animais , Indução Enzimática , Heme Oxigenase-1 , Protoporfirinas/farmacologia , Ratos , Ratos Endogâmicos F344 , Traumatismo por Reperfusão/prevenção & controle , Fatores de Tempo , Transplante HomólogoRESUMO
In a previous experiment we demonstrated the induction of tolerance by the allograft itself. In this model of weak histoincompatibility, second grafts of donor origin replacing chronically rejected first renal allografts were accepted long term. Additionally grafted donor-specific hearts functioned indefinitely while adoptive transfer experiments demonstrated the development of donor-specific transferable tolerance. In the current experiment we compared intragraft gene expression of chronically rejected first and tolerant second grafts by RT-PCR. Second renal allografts of donor origin (F-344) replaced first grafts 2, 4, 8, 12, and 16 weeks after the initial engraftment. No immunosuppression was used during second engraftment. Grafts were followed by serial proteinuria; morphological and immunohistological studies (APAAP/infiltrating cells, ICAM-1, MHC II expression) and competitive RT-PCR analyses (expressed as arbitary units AU/cDNA) for relevant cells and cytokines (CD-3, IFNgamma, IL-10, and IL-4) were assessed by the end of the observation period (16 weeks). Macrophages/monocytes (ED-1+) and T-cells (CD-5 and CD-4+) infiltrated first allografts in high numbers by 12 weeks associated with strong structural signs of chronic graft rejection (ca. 30% arterio- and glomerulosclerosis, tubular atrophy and interstitial fibrosis). Cellular infiltrates in second grafts were prominent, however significantly reduced, while histological changes were minor. At cDNA levels, CD-3 transcripts were elevated in second renal allografts performed 2, 4, and 8 weeks after the initial engraftment while comparable levels were observed when second engraftment was performed after 12 and 16 weeks. Analyses of relevant cytokines demonstrated a TH1/TH2 shift independent from the time interval between first and second engraftment. These results emphasize the role of alloresponsiveness for the development of chronic graft dysfunction. Mechanisms of tolerance induction in our model are associated with a distinct alloresponsive pattern. A crucial role for regulatory T-cells is suggested.