Calcium/calmodulin‐dependent protein kinase kinase β is neuroprotective in stroke in aged mice

Stroke is a devastating neurological disease and the leading cause of long‐term disability, particularly in the elderly. Calcium/calmodulin‐dependent protein kinase kinase β (CaMKK β) is a major kinase activated by elevated levels of intracellular calcium. Our previous findings in young mice have suggested that Ca MKK β is neuroprotective as KO mice had worse stroke outcomes. Because age is an important determinant of stroke outcome, we evaluated the functional role of Ca MKK β in stroke in aged mice. We used middle cerebral artery occlusion to induce stroke in aged wild‐type ( WT ) and Ca MKK β KO male mice. Lentiviral vectors carrying Ca MKK β ( LV ‐Ca MKK β) were used to overexpress Ca MKK β in the mouse brain. Baseline levels of Ca MKK β in the aged brain were significantly lower than those in young mice. LV ‐Ca MKK β treatment reduced infarcts and neurological deficits assessed 3 days after stroke. In chronic survival experiments, Ca MKK β KO mice showed increased tissue loss in the ipsilateral hemisphere 3 weeks after stroke. In addition, KO mice showed poorer functional recovery during the 3‐week survival period, as measured by the rotarod test, corner test, locomotor activity assay, and novel object recognition test, compared with WT controls. The loss of blood–brain barrier proteins, inactivation of survival gene expression such as B‐cell lymphoma 2 (Bcl‐2) and an increase in inflammatory cytokines in the serum were observed after stroke with Ca MKK β inhibition. We demonstrate that Ca MKK β is neuroprotective in stroke in aged mice. Therefore, our data suggest that Ca MKK β may be a potential target for reducing long‐term disability after stroke.