Print page Print page
Switch language
The Capital Region of Denmark - a part of Copenhagen University Hospital

CaMKII inhibition with KN93 attenuates endothelin and serotonin receptor-mediated vasoconstriction and prevents subarachnoid hemorrhage-induced deficits in sensorimotor function

Research output: Contribution to journalJournal article

  1. Necrotizing enterocolitis is associated with acute brain responses in preterm pigs

    Research output: Contribution to journalJournal article

  2. Early ficolin-1 is a sensitive prognostic marker for functional outcome in ischemic stroke

    Research output: Contribution to journalJournal article

  3. Cellular sources of dysregulated cytokines in relapsing-remitting multiple sclerosis

    Research output: Contribution to journalJournal article

  1. Headache advances in 2017: a new horizon in migraine therapy

    Research output: Contribution to journalJournal article

  2. PACAP and its role in primary headaches

    Research output: Contribution to journalReview

  3. The CGRP Pathway in Migraine as a Viable Target for Therapies

    Research output: Contribution to journalJournal article

View graph of relations

BACKGROUND: It has been suggested that transcriptional upregulation of cerebral artery contractile endothelin (ETB) and 5-hydroxytryptamine (5-HT1B) receptors play an important role in the development of late cerebral ischemia and increased vasoconstriction after subarachnoid hemorrhage (SAH). We tested the hypothesis that inhibition of calcium calmodulin-dependent protein kinase II (CaMKII) may reduce cerebral vasoconstriction mediated by endothelin and serotonin receptors and improve neurological outcome after experimental SAH.

METHODS: SAH was induced in adult rats by injection of 250 μL autologous blood into the basal cisterns. The CaMKII activity in cerebral vessels was studied by Western blot and immunohistochemistry. The vasomotor responses of middle cerebral and basilar arteries were measured in a sensitive myograph system. The functional outcome was examined by the rotating pole test 2 and 3 days after SAH.

RESULTS: SAH induced a rapid early increase in phosphorylated CaMKII protein at 1 h that was attenuated by cisternal administration of the CaMKII inhibitor KN93 (0.501 μg/kg) 45 min prior and immediately after SAH as evaluated by Western blot. Application of KN93 at 1 h and every 12 h post-SAH significantly reduced vascular CaMKII immunoreactivity at 72 h. In addition, contractile responses of cerebral arteries to endothelin-1 (ET-1) and 5-hydroxycarboxamide (5-CT) were increased at this time-point. KN93 treatment significantly attenuated the contraction induced by ET-1 and 5-CT. Importantly, treatment with the CaMKII inhibitor prevented SAH-induced deficits in neurological function, as evaluated by the rotating pole test, and similar sensorimotor scores were seen in sham-operated animals.

CONCLUSIONS: The present study has shown that SAH is associated with increased contractile responses to ET-1 and 5-CT in cerebral arteries and enhanced early activation of CaMKII. Treatment with the CaMKII inhibitor KN93 attenuated the contractile responses and prevented impaired sensorimotor function after SAH.

Original languageEnglish
JournalJournal of Neuroinflammation
Pages (from-to)207
StatePublished - 2014

ID: 44854240