| Research Abstract |
This study was aimed to clarify the functional roles of glial cells in neuron-glia interactions in pathological situations, such as ischemic brain injury. The following results were obtained.
1. A stab wound injury on rat cerebral cortex increased immunoreactive endothelin-1 and reactive astrocytes at the injured site, and this was reversed by a endothelin B receptor antagonist.
2. Endothelin induced cytoskeletal actin re-organization in cultured astrocytes, and this action was dependent on activation of the small GTP-binding protein Rho, and tyrosine phosphorylation of focal adhesion proteins.
3. CaィイD12+ィエD1depletion followed by reperfusion with CaィイD12+ィエD1-containing medium causes cell death in cultured astrocytes (CaィイD12+ィエD1paradox-like injury), but not in neurons. This was triggered by an increased CaィイD12+ィエD1 influx through NCX in the reverse mode followed by generation of reactive oxygen species and activation of calcineurin and NF-κB.
4. The CaィイD12+ィエD1 paradox-like injury was attenuated by inhibitors of NCX, calcineurin, caspase, or cathepsine, and also by cognitive enhancers, and nerve growth factor (NGF).
In the present study, we revealed that endothelin signalling are involved in morphological astrocytic changes and cellular actions (activation). We also investigated the mechanisms underlying delayed glial cell death with respect to NCX activation and intracellular signaling molecules, and revealed that the CaィイD12+ィエD1paradox injury of cultured astrocytes is considered to be an in vitro model of ischemia/reperfusion injury. It is anticipated that these studies on activation and cell injury of astrocytes will contribute to development of new drugs that modulate the function of astrocytes.
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