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  • A provocative aspect of our study

    2020-07-31

    A provocative aspect of our study was the demonstrated efficacy of CK2 inhibition by CX-4945 when administered after an ischemic episode. Ischemic injury in young WM follows a sequential order initiated by loss of ionic KNK437 australia leading to excitotoxicity and then merging into oxidative injury (Fig. 11); ionic deregulation directly impairs axon excitability, function, and structure due to toxic accumulation of Na+ and Ca2+ (Fern et al., 1995; Stys et al., 1990; Underhill & Goldberg, 2007; Wolf et al., 2001), whereas excessive glutamate accumulation overactivates AMPA/Kainate receptors, causing oligodendrocyte death and myelin disruption. Finally, the oxidative pathway attacks WM constituents via formation of reactive oxygen species (Back et al., 2005; Juurlink, 1997; Oka et al., 1993). Because functional protection was evident when CX-4945 was applied before or after glutamate accumulation, this finding may suggest that CX-4945 simultaneously targets the excitotoxic and oxidative pathways and may have multiple distinct sites of action: one related to glutamate accumulation and the other involving a post-excitotoxic mechanism, as we have previously shown (Baltan et al., 2011a). This suggestion is supported by the observation that axon function was preserved during OGD and recovery was 50% higher with pre-injury CK2 inhibitor application compared to post-injury application. Axon function solely relies on local ATP production to maintain excitability via regulation of Na+-K+ ATPase activity. OGD causes a prominent reduction in ATP levels and loss of CFP (+) mitochondria, while CK2 inhibition resulted in sustained CFP (+) mitochondria (Baltan, 2012a; Baltan et al., 2011a; Baltan et al., 2013; Murphy et al., 2013). Because CK2 is abundantly expressed by astrocytes, it is plausible that Na+-dependent glutamate release is modified, secondary to preservation of ATP levels and Na+ levels (Baltan, 2014b), thus leading to reduced excitotoxic injury to oligodendrocytes. Alternatively, a reduction in AMPA/Kainate receptor signaling on oligodendrocytes may lead to reduced Ca2+ and Na+ entry, thus ameliorating injury (Baltan, 2009; Baltan, 2015). Furthermore, CK2 phosphorylation of AMPA receptor GluA1 subunit regulates its membrane expression (Lussier et al., 2014) and regulation of oligodendrocyte NMDA receptor subunits may alter oligodendrocyte sensitivity to glutamate (Baltan, 2015; Spitzer et al., 2016). Regulation of oligodendrocyte NMDA receptors modulates metabolic support and interactions between oligodendrocytes and axons to impact functional recovery (Saab et al., 2016). Furthermore, CK2 was shown to phosphorylate the NMDA receptor subunit GluN2B, leading to its internalization and replacement with GluN2A-containing NMDA receptors in postsynaptic densities to regulate synaptic activity in neurons (Sanz-Clemente et al., 2010; Sanz-Clemente et al., 2013). Further experiments are currently underway to assess these possibilities. CK2 inhibition promoted axon function recovery, prevented oligodendrocyte death and axonal damage, and preserved axonal mitochondrial integrity against ischemia. Although the effectiveness of CDK5 and AKT inhibition remains to be quantified based on axonal recovery, we propose WM integrity is equally protected as CK2 inhibition since these are the downstream signaling pathways activated via CK2.