Neuronal injury in NCX3 knockout mice following permanent focal cerebral ischemia and in NCX3 knockout cortical neuronal cultures following oxygen-glucose deprivation and glutamate exposure.

Abstract

In this study we subjected NCX3 knockout and wildtype mice to permanent focal cerebral ischemia by intraluminal middle cerebral artery occlusion. Analysis of brain sections by 2,3,5-Triphenyl-2H-tetrazolium chloride staining, 12 hours after middle cerebral artery occlusion revealed no difference in infarct volume between NCX3 knockout and wildtype mice. In addition, we evaluated the effect of NCX3 protein knockdown on neuronal viability in primary cortical neuronal cultures following in vitro ischemia (oxygen-glucose deprivation) and L-glutamate (glutamate) exposure. In vitro experiments revealed that neuronal viability was higher in NCX3 knockout neuronal cultures than in the wildtype cultures following ischemic and glutamate insults. The reduced sensitivity of neurons from NCX3 knockout mice to in vitro ischemia and excitotoxicity indicates that NCX3 calcium entry mode activity contributes to calcium overload and neuronal death. However our in vivo finding of a lack of differential sensitivity on infarct volume in NCX3 knockout and wildtype mice suggests that any benefit of reduced NCX3 activity is overridden following permanent focal cerebral ischemia. Taken together, these findings suggest that reduced NXC3 activity limits calcium neurotoxicity during severe transient, but not during severe sustained ischemic insults. These results have important implications for the development of the NCX3 protein as a therapeutic target to reduce ischemic brain injury.

Drug development in targeting ion channels for brain edema

“…Both NCX3 −/− and NCX2 − /− mice showed increased infarction volume in tMCAO models, suggesting their potentially beneficial role in ischemia/reperfusion states, during which they are likely to operate in the forward mode to reduce intracellular Ca 2+ [ 215 , 216 ]. The beneficial effect of NCX, however, has not been observed in NCX3 − /− mice subjected to pMCAO [ 217 ].…”

High levels of synaptosomal Na+–Ca2+ exchangers (NCX1, NCX2, NCX3) co-localized with amyloid-beta in human cerebral cortex affected by Alzheimer's disease

“…Targeted disruption of NCX3 leads to defective neuromuscular transmission [12]. Under ischemic conditions, NCX3-deficient mice exhibit increased neuronal damage [13, 23]. Studies also showed that NCX plays a major role in restoring baseline Ca 2+ levels following glutamate-induced depolarization in cortical and hippocampal neurons [11, 24].…”