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  • During ischemia the impact of CK


    During ischemia, the impact of CK2 on mitochondria varies in different organs/tissues. For example, CK2α upregulation during ischemia leads to disrupted mitochondrial homeostasis and mediates cardiomyocyte ischemic injury [31]. Specifically, ischemia/reperfusion (I/R) progressively increases CK2α to curtail FUN14 domain protein 1 (FUNDC1)-dependent mitophagy via post-transcriptional inactivation of FUNDC1, thus impairing mitochondrial protective systems to amplify cardiomyocyte death signals. On the other hand, the impact of CK2 inhibition in a model of transient ischemia (middle cerebral artery occlusion (MCAO) model) suggested that NADPH oxidase isoform 2 (NOX2) activation releases ROS after CK2 inhibition, triggering the release of apoptogenic factors (AIF) from the mitochondria and inducing DNA damage after ischemic CCT251545 injury [32]. It is not clear why these different results have been observed; however, it may be that in WM and heart, the source of ROS is determined by mitochondria and that in GM it is dictated by NADPH oxidase regulating CK2 signaling differently.
    CK2 signaling pathways to protect WM from ischemic injury CK2 activates CDK5 during ischemia and AKT/GSK3β throughout the ischemic and reperfusion periods. We have shown that inhibition of CDK5 with roscovitine protects WM from ischemic injury only when applied before OGD in young and aging WM [1,33]. This result suggests that CDK5 is activated during OGD only and that it is substantial such that inhibition during OGD leads to improved axon function. Interestingly, CDK5 inhibition with indolinone A and knocking out CDK5 in mice are protective in MCAO models [34]. In addition, in a MCAO model, post-ischemic application of a CDK5 inhibitory peptide, P5-TAT, decreased infarct volume [35]. These results suggest that CDK5 inhibition could be a potential therapeutic target to protect both WM and GM when applied during an ischemic episode, independent of age. Systematically investigating the AKT signaling pathway [[39], [40], [41]] showed that only the pan-AKT inhibitor MK-2206 was beneficial to axon function when applied before OGD in young and aging MONs [1]. These results raised a question as to why individual inhibition of the AKT or CDK5 pathways failed to exert post-ischemic protection, while CK2 inhibition was beneficial before or after injury. MK-2206 targets the inactive conformation of AKT, where the PH domain engages the kinase domain, thus preventing phosphorylation and activation [36,37]. Therefore, we further tested the possibility that AKT inhibition after OGD required an inhibitor that targets the active conformation of AKT. For these experiments, we examined the effectiveness of a new selective allosteric pan-AKT inhibitor, ARQ-092, which targets the inactive and active conformations of AKT [38] with equal potency. When ARQ-092 was applied before OGD, we observed a level of protection similar to MK-2206. However, in contrast to MK-2206, ARQ-092 promoted axon function recovery when applied after the end of OGD. This protection was observed in both young and aging MONs. On the other hand, in GM, AKT CCT251545 signaling is associated with neuronal cell survival [45] and oligodendrocyte progenitor cell (OPC) and oligodendrocyte survival [42,43]; therefore, for a therapeutic intervention to be successful, the reason for this difference needs to be determined. Note that these later conclusions were reached from experiments that inhibited AKT for a long duration (chronic inhibition). Overall, this difference may be related to the AKT isoform expressed in WM and other organs/tissues together with the duration of AKT inhibition. This possibility is currently being investigated. Overall, this evidence suggests that acute CDK5 and AKT inhibition are sufficient to protect axon function against ischemia when applied before injury, while inhibition of the active conformation of AKT is necessary to exert post-ischemic protection independent of age.