Molecular mechanisms of exaggerated acidosis on ischemic neuronal damage

为探讨免疫抑制剂FK 506对缺血再灌注后信号转导通路的影响，我们研究了缺血后蛋白激酶Cγ（PKCγ）、钙调蛋白激酶II（CaMKII）亚细胞分布的变化以及酪氨酸磷酸化水平的变化。FK 506给药可显著降低P2部分恢复24 h时PKCγ和CaMK II的易位。在恢复期24 h，FK 506处理降低了P2组分中酪氨酸磷酸化p160、p140、p100、p90和p80的水平。P2组分中持续升高的PKCγ和CaMK II水平可能与细胞死亡有关，FK 506处理可减弱这一水平。FK 506可能有助于恢复缺血后钙稳态，促进细胞存活，高血压和高碳酸血症加重缺血内酸中毒和随后的脑损伤。然而，高血糖症比高碳酸血症引起更广泛的缺血后损伤，特别是在扣带皮层。我们研究了亚细胞的变化 ...更多信息 在正常血糖和高血糖全脑缺血10 min时和之后，PKCγ和CaMK II的分布以及蛋白酪氨酸磷酸化的变化。在再灌注期间，缺血内高血糖延长了PKCγ向细胞膜的移位，而不是CaMK II，而高碳酸血症仅轻微影响。突触体膜中蛋白质的酪氨酸磷酸化，以及细胞溶质中的细胞外信号调节激酶（ERK），在高血糖缺血后的再灌注过程中显着增加，但高碳酸血症缺血后的程度较低。提示PKCγ、酪氨酸激酶和ERK系统参与了缺血性脑损伤的过程，高血糖可能通过除过度酸中毒以外的另一机制影响这些激酶，并尝试了Bcl-xL及其衍生物的线粒体神经保护机制，以及探索如何将各种基因导入缺血脑组织。少

To explore effects of Immunosuppressant FK506 on signal translduction pathway, we studied changes in subcellular distribution of protein kinase Cγ (PKCγ), CaM kinase II (CaMKII), as well as changes of tyrosine phosphorylation levels after ischemia. FK506 administration significantly decreased translocation of PKCγ and CaMKII at 24 h of recovery in P2 fraction. The levels of tyrosine phosphorylated p160, p140, p100, p90, and p80 in P2 fraction were decreased with FK506 treatment at 24h of recovery. The persistently elevated PKCγ and CaMKII level in P2 fraction which may be related to cell death, are attenuated with FK506 treatment. FK506 may contribute to recover calcium homeostasis in post ischemic phase and promote cell survival.Hyperglycemia and hypercapnia aggravate intra-ischemic acidosis and subsequent brain damage. However, hyperglycemia causes more extensive post-ischemic damage than hypercapnia, particularly in the cingulate cortex. We investigated the changes in the subcellula … More r distribution of PKCγ and CaMKII, as well as changes in protein tyrosine phosphorylation during and following 10 min normoglycemic, hyperglycemic global cerebral ischemia. During reperfusion period, the translocation to cell membranes of PKCγ, but not CaMKII, was prolonged by intra-ischemic hyperglycemia, while it was only marginally affected by hypercapnia. The tyrosine-phosphorylation of proteins in the synaptosomal membranes ; as well as the extracellular signal-regulated kinase (ERK) in the cytosol, markedly increased during reperfusion following hyperglycemic ischemia, but to a lesser degree following hypercapnic ischemia. Our data suggest that PKCγ, tyrosine kinase and ERK systems are involved in the process of ischemic damage in the cigulate cortex, where hyperglycemia may affect these kinases through an additional mechanism other than exaggerated acidosis.I also tried the mechanisms of mitochondrial neuroprotection through Bcl-xL and its derivative, and also tried to explore how to introduce various genes into ischemic brain tissue. Less