title: Inhibition of calcium/calmodulin-dependent protein kinase kinase β and calcium/calmodulin-dependent protein kinase IV is detrimental in cerebral ischemia.
abstract: OBJECTIVE
  Elevation of intracellular calcium was traditionally thought to be detrimental in stroke pathology. However, clinical trials testing treatments that block calcium signaling have failed to improve outcomes in ischemic stroke. Emerging data suggest that calcium may also trigger endogenous protective pathways after stroke. Calcium/calmodulin-dependent protein kinase kinase (CaMKK) is a major kinase activated by rising intracellular calcium. Compelling evidence has suggested that CaMKK and its downstream kinase CaMK IV are critical in neuronal survival when cells are under ischemic stress. We examined the functional role of CaMKK/CaMK IV signaling in stroke.
  
  
  METHODS
  We used a middle cerebral artery occlusion model in mice.
  
  
  RESULTS
  Our data demonstrated that pharmacological and genetic inhibition of CaMKK aggravated stroke injury. Additionally, deletion of CaMKK β, one of the 2 CaMKK isoforms, reduced CaMK IV activation, and CaMK IV deletion in mice worsened stroke outcome. Finally, CaMKK β or CaMK IV knockout mice had exacerbated blood-brain barrier disruption evidenced by increased hemorrhagic transformation and activation of matrix metalloproteinase. We observed transcriptional inactivation including reduced levels of histone deacetylase 4 phosphorylation in mice with CaMKK β or CaMK IV deletion after stroke.
  
  
  CONCLUSIONS
  Our data have established that the CaMKK/CaMK IV pathway is a key endogenous protective mechanism in ischemia. Our results suggest that this pathway serves as an important regulator of blood-brain barrier integrity and transcriptional activation of neuroprotective molecules in stroke.
authors.affiliation: Department of Neurology, University of Connecticut Health Center, Farmington, CT, USA.
authors.forename: Louise D
authors.initials: LD
authors.lastname: McCullough
authors.forename: Sami
authors.initials: S
authors.lastname: Tarabishy
authors.forename: Lin
authors.initials: L
authors.lastname: Liu
authors.forename: Sharon
authors.initials: S
authors.lastname: Benashski
authors.forename: Yan
authors.initials: Y
authors.lastname: Xu
authors.forename: Thomas
authors.initials: T
authors.lastname: Ribar
authors.forename: Anthony
authors.initials: A
authors.lastname: Means
authors.forename: Jun
authors.initials: J
authors.lastname: Li
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D002545:Brain Ischemia / Q000201:enzymology / Q000209:etiology / Q000378:metabolism*; D002118:Calcium / Q000502:physiology*; D020013:Calcium Signaling / Q000502:physiology*; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D054734:Calcium-Calmodulin-Dependent Protein Kinase Type 4 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004195:Disease Models, Animal; D020244:Infarction, Middle Cerebral Artery / Q000201:enzymology / Q000209:etiology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009434:Neural Pathways / Q000201:enzymology / Q000378:metabolism / Q000473:pathology
chemical_list: D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase; D054734:Calcium-Calmodulin-Dependent Protein Kinase Type 4; C517685:Camk4 protein, mouse; C517700:Camkk2 protein, mouse; D002118:Calcium
keywords: CaMKK β and CaMK IV; cerebral ischemia