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Reduced brain plasticity, including axonal regeneration and angiogenesis, is thought to contribute to poorer functional recovery in the aged brain after a stroke. CaMKK has been suggested to activate major molecular pathways that enhance brain plasticity. Here we evaluated the hypothesis that CaMKK promotes post- stroke recovery by stimulating axonal regeneration and angiogenesis in aged mice.Ischemic stroke was induced by middle cerebral artery occlusion for 60 minutes in aged WT male mice followed by reperfusion. STO-609, a pan-CaMKK inhibitor, and lentiviral vectors carrying CaMKK β (LV-CaMKK β) were started 3 days after stroke onset. Pellet reaching test (success rate) was carried out to evaluate the integrity of sensorimotor function every week for a total of 5 weeks.Pharmacological inhibition of CaMKK by STO-609 significantly worsened stroke recovery evaluated by pellet reaching test from day 14 to day 35 after stroke (Day 35:Vehicle 0.29±0.02 vs. STO 0.16±0.02, n=8 in vehicle/n=5 in STO, p<0.05). Meanwhile, it significantly reduced axonal density assessed by neurofilament light (NFL) staining (Vehicle 1.00±0.06 vs. STO 0.53± 0.14, n=4, p<0.05) and vascular density represented by CD31 (Vehicle 1.00±0.20 vs. STO 0.48±0.06, n=4, p<0.05) in the peri-infarct zone on 35 days post-stroke, without changing brain cavity size (Day 35: Vehicle 0.13±0.01 vs. STO 0.13±0.02, n=8 in Vehicle/n=5 in STO, p>0.05). Additionally, CaMKK β overexpression improved mouse performance on pellet reaching test after stroke (day 35: LV-GFP 0.26±0.02 vs. LV-CaMKK β 0.36±0.02, n=7 LV-GFP/n=9 in LV-CaMKK β, p<0.05).Conclusions: Pharmacological inhibition of CaMKK worsened post-stroke recovery while overexpression of this molecule improved outcome. We observed reduced axonal density and cerebral vascular density with CaMKK inhibition, indicating CaMKK is an endogenous activator of brain plasticity in stroke. Our data suggested that CaMKK signaling may reduce long-term disability in the population at the greatest risk of stroke, the elderly.