All of these experiments in GM matter injury models have
All of these experiments in GM matter injury models have identified an array of signaling mechanisms that are potentially important. First, Kim et al. proposed that CK2 acts as a negative modulator of NADPH oxidase . Then Blanquet et al.  found that increased CK2 correlated with inhibition of the activity of MKK(3/6), p38, and deacetylases. Subsequent studies investigated the mechanisms by which CK2 inhibition of NOX2 led to neuronal survival using superoxide dismutase 1 (SOD1) transgenic mutant and gp91(Nox2) knock-out mice . These results suggest that NOX2 activation releases ROS after CK2 inhibition, triggering the release of apoptogenic factors (AIF) from mitochondria and inducing DNA damage after ischemic Dyngo-4a of injury. Overall, they concluded that there is a reciprocal relationship between ROS and CK2 protein levels. And finally, studies were performed to test the mechanism of compounds that showed neuroprotection in a MCAO model such as apelin-13, 5d, a novel analogue of the racemic 3-n-butylphthalide, and cilostazol [, , ]. The authors concluded that the neuroprotective effects observed with apelin-13 and 5d may be partly mediated by an increase in CK2 activity, such that apelin-13 regulated CK2 by activating the apelin receptor/Gαi/Gαq-CK2 and restoring p-eIF2α-ATF4-CHOP/GRP78 to attenuate neuronal apoptosis, and 5d decreased NADPH oxidase activity by positively regulating CK2 [52,53]. Experiments with cilostazol suggested that its protective mechanism was produced by the maxi-K channel opening coupled to upregulation of CK2 phosphorylation and downregulation of PTEN phosphorylation . The exact mechanisms of how channel opening increases and how PTEN phosphorylation decreases CK2 have not been elucidated, nor has the impact of CK2 inhibitor been tested to abrogate the effect of cilostazol. The authors suggest that CK2 activation may serve as a therapeutic target for inhibiting neuronal cell apoptosis in ischemic cells and thus may offer a cell survival strategy. These proposed mechanisms of CK2 protection identified in GM and neuronal injury remain to be tested in WM.
A lesson from Cancer research Interestingly, cancer research has been instrumental in identifying novel therapeutic targets and mechanism(s) for cerebral ischemic injury. In cancer, CK2 activity has been shown to be upregulated such that cells become dependent upon high CK2 levels for their survival . CK2 has been shown to increase glucose metabolism in bladder cancer cells, thus contributing to the Warburg effect . Could the protective effect of CK2 inhibition in WM be mediated by a metabolic switch during the ischemic period? For instance, Zhang et al.  have shown that CK2 inhibition was associated with decreased levels of AKTS4 phosphorylation and decreased levels of glycolysis-related genes. Also, CK2 could regulate glycolysis by phosphorylating glycolytic enzymes [59,60]. Taken together, these results suggest that CK2 inhibition may suppress high glycolysis levels by reducing CK2 and AKT phosphorylation of enzymes/transporter in the glycolytic pathway. It is plausible that I/R leads to increased glycolysis, resulting in an increase in metabolic intermediates for the tricarboxylic acid cycle; however, with decreasing O2 levels, this would lead to increased lactate levels, decreased pH, and activation of the pentose phosphate pathway (PPP). Note that an increase in glycolysis in the face of compromised oxidative phosphorylation leads to increased lactate and an increase in PPP pathway activation, which is essential to generate the building blocks (lipids, nucleic acids) that are necessary to sustain the high mitotic rates of tumors . Therefore, we hypothesize that during ischemia and early reperfusion when ATP is compromised , it is more important to relieve the metabolic constraints than to generate the building blocks for repair. However, after this transient repression of CK2 activity during I/R, it is important to release this inhibition so that CK2 can aid in the repair process (Fig. 3).