Abstract
Background
We have investigated the role of protein kinase C (PKC) in the mechanism of cerebral vasospasm, and showed the pivotal roles of PKC isoforms (PKCδ and α) in that mechanism. On the other hand, protein tyrosine kinase (PTK) is also activated during the maintenance of cerebral vasospasm. The aim of this study is to clarify the relationship between PKC and PTK activations in the mechanism of cerebral vasospasm, and discuss what we know and what we do not know about the roles of cross-talk mechanisms in the signal transduction systems.
Method
The experimental animal model is a “two-haemorrhage” canine model. In situ treatments using specific PKCδ and PKCα inhibitors were examined to clarify the roles of each in the mechanism of cerebral vasospasm. Using vasospastic canine basilar arteries, phosphorylation rates of tyrosine-residue of PKC isoforms were examined.
Findings
PKCδ was activated from day 4 to day 7, and PKCα on day 7. A specific PKCδ inhibitor inhibited the initiation of cerebral vasospasm, but not the maintenance. A specific PKCα inhibitor did not inhibit the initiation, but did the cerebral vasospasm in its maintenance phase. Both activations were down-regulated on day 14. PTK was activated from day 7 and continued until day 14. Although no phosphorylation of tyrosine-residue of PKCα was observed, tyrosine-residue of PKCδ was significantly phosphorylated, and the time-course and extent of PTK activation and phosphorylation of PKCδ tyrosine-residue correlated well. The vasospastic canine basilar arteries showed phenotypic changes from day 7 to day 14.
Conclusions
PKCδ plays a pivotal role in the initiation of cerebral vasospasmafter SAH, but not its maintenance. However, the translocation of PKCδ to the membrane fraction continued until day 7. These results indicate that the activated PKCδ by phosphorylation of its tyrosine-residue might contribute to the phenotypic changes of cerebral vasospastic arteries, and sustain the vasospasmover aweek. To clarify the exact crosstalk mechanisms in these signal transduction systems is extremely important to understand the mechanisms of cerebral vasospasm.
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Nishizawa, S., Koide, M., Yamaguchi-Okada, M. (2008). The roles of cross-talk mechanisms in the signal transduction systems in the pathophysiology of the cerebral vasospasm after subarachnoid haemorrhage — what we know and what we do not know. In: Kırış, T., Zhang, J.H. (eds) Cerebral Vasospasm. Acta Neurochirurgica Supplement, vol 104. Springer, Vienna. https://doi.org/10.1007/978-3-211-75718-5_11
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DOI: https://doi.org/10.1007/978-3-211-75718-5_11
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