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Mol Neurobiol ; 57(1): 150-158, 2020 Jan.
Article in English | MEDLINE | ID: mdl-31520314

ABSTRACT

Ischemic brain damage is triggered by glutamate excitotoxicity resulting in neuronal cell death. Previous research has demonstrated that N-methly-D-aspartate (NMDA) receptor activation triggers downstream calcium-dependent signaling pathways, specifically Ca2+/calmodulin-dependent protein kinase II (CaMKII). Inhibiting CaMKII is protective against hippocampal ischemic injury, but there is little known about its role in the cerebellum. To examine the neuroprotective potential of CaMKII inhibition in Purkinje cells, we subjected C57BL/6 or CaMKIIα KO male mice (8-12 weeks old) to cardiac arrest followed by cardiopulmonary resuscitation (CA/CPR). We performed a dose-response study for tat-CN19o and cerebellar injury was analyzed at 7 days after CA/CPR. Acute signaling was assessed at 6 h after CA/CPR using Western blot analysis. We observed increased phosphorylation of the T286 residue of CaMKII, suggesting increased autonomous activation. Analysis of Purkinje cell density revealed a decrease in cell density at 7 days after CA/CPR that was prevented with tat-CN19o at doses of 0.1 and 1 mg/kg. However, neuroprotection in the cerebellum required doses that were 10-fold higher than what was needed in the hippocampus. CaMKIIα KO mice subjected to sham surgery or CA/CPR had similar Purkinje cell densities, suggesting CaMKIIα is required for CA/CPR-induced injury in the cerebellum. We also observed a CA/CPR-induced activation of death-associated protein kinase (DAPK1) that tat-CN19o did not block. In summary, our findings indicate that inhibition of autonomous CaMKII activity is a promising therapeutic approach that is effective across multiple brain regions.


Subject(s)
Calcium/metabolism , Calmodulin/drug effects , Protective Agents/pharmacology , Purkinje Cells/drug effects , Animals , Calcium Signaling/drug effects , Calcium-Calmodulin-Dependent Protein Kinase Type 2/drug effects , Calcium-Calmodulin-Dependent Protein Kinase Type 2/metabolism , Male , Mice, Inbred C57BL , Neurons/drug effects , Neurons/metabolism , Purkinje Cells/metabolism
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