Increased Expression of Calcium/Calmodulin-Dependent Protein Kinase Type II Subunit Delta after Rat Traumatic Brain Injury

Abstract

Many cellular responses to Ca(2+) signals are mediated by Ca(2+)/calmodulin-dependent enzymes, among which is the Ca(2+)/calmodulin-dependent protein kinase II (CaMKII). CaMKII was originally described in rat brain tissue. In rat brain, four different subunits of the kinase have been identified: α, β, γ, and δ. This study aims to investigate changes of CaMKIIδ after traumatic brain injury and its possible role. Rat traumatic brain injury (TBI) model was established by controlled cortical injury system. In the present study, we mainly investigated the expression and cellular localization of CaMKIIδ after traumatic brain injury. Western blot analysis revealed that CaMKIIδ was present in normal rat brain cortex. It gradually increased, reached a peak at the third day after TBI, and then decreased. Importantly, more CaMKIIδ was colocalized with neuron. In addition, Western blot detection showed that the third day postinjury was also the apoptosis peak indicated by the elevated expression of caspase-3.Importantly, immunohistochemistry analysis revealed that injury-induced expression of CaMKIIδ was colabeled by caspase-3 (apoptosis cells marker). Moreover, pretreatment with the CaMKII inhibitor (KN62) reduced the injury-induced activation of caspase-3. Noticeably, the CaMKII inhibitor KN-62 could reduce TBI-induced cell injury assessed with lesion volume and attenuate behavioral outcome evaluated by motor test. These data suggested that CaMKIIδ may be implicated in the apoptosis of neuron and the recovery of neurological outcomes. However, the inherent mechanisms remained unknown. Further studies are needed to confirm the exact role of CaMKIIδ after brain injury.

Hydrogen Sulfide Offers Neuroprotection on Traumatic Brain Injury in Parallel with Reduced Apoptosis and Autophagy in Mice

“…There were no specific methods to detect necrosis, thus we focused on apoptosis and autophagy. Apoptosis plays a significant role in the pathophysiology of brain injury in TBI model [2], [39]. Among these genes, Bcl-2 and Caspase-3 are widely regarded as the most important apoptotic regulators, and their relative levels determine the fate of cells.…”

“…Each year, TBI contributes to a substantial number of deaths and cases of permanent disability. TBI initiates a series of biophysiological and pathological reactions, including activation of excitatory amino acids receptor, Ca 2+ overload, mitochondrial injury and energy metabolic blockage, production of oxyradical, caspases activation, and activation of inflammatory reaction [1], [2], that contribute to subsequent tissue damage and associated neuronal cell death, such as apoptosis, necrosis, necroptosis, and autophagy. Current standards of care in acute, subacute and chronic phases of injury are primarily supportive, however, effective pharmacological therapy remains limited [3].…”

Altered Calcium Signaling Following Traumatic Brain Injury

“…Similar to these findings, Goforth et al (1999) showed a decreased desensitization of the AMPA receptor subtype of glutamate receptors in a subpopulation of cortical neurons following stretch injury. A subsequent study showed that this reduced desensitization was mediated through NMDA receptors and activation of Ca 2+ calmodulin-dependent protein kinase II (CaMKII; Goforth et al, 2004), which is generally elevated after TBI (Folkerts et al, 2007; Zhang et al, 2012). Interestingly, using another in vitro injury model, cortical neurons display an injury-induced increase in Ca 2+ -permeable AMPA receptors, which is mediated by CaMKIIα phosphorylation (Spaethling et al, 2008).…”

Phenoxybenzamine Is Neuroprotective in a Rat Model of Severe Traumatic Brain Injury

“…There is evidence that CaM/CaMKII increases the trafficking of AMPA receptors to the cell surface leading to greater excitotoxic death during acute injury [32]. Supporting a neurodestructive role for CaMKII, Zhang et al [33] found that TBI increased the expression of CaMKIIδ. Pre-treating rats with a CaMKIIδ inhibitor before TBI resulted in a significant decrease in lesion volume and a significant increase in neuromotor function [33].…”

“…Supporting a neurodestructive role for CaMKII, Zhang et al [33] found that TBI increased the expression of CaMKIIδ. Pre-treating rats with a CaMKIIδ inhibitor before TBI resulted in a significant decrease in lesion volume and a significant increase in neuromotor function [33]. Zhang et al .…”