Blockage of the Upregulation of Voltage-Gated Sodium Channel Nav1.3 Improves Outcomes after Experimental Traumatic Brain Injury

Excessive active voltage-gated sodium channels are responsible for the cellular abnormalities associated with secondary brain injury following traumatic brain injury (TBI). We previously presented evidence that significant upregulation of Na(v)1.3 expression occurs in the rat cortex at 2h and 12h post-TBI and is correlated with TBI severity. In our current study, we tested the hypothesis that blocking upregulation of Na(v)1.3 expression in vivo in the acute stage post-TBI attenuates the secondary brain injury associated with TBI. We administered either antisense oligodeoxynucleotides (ODN) targeting Na(v)1.3 or artificial cerebrospinal fluid (aCSF) at 2h, 4h, 6h, and 8h following TBI. Control sham animals received aCSF administration at the same time points. At 12h post-TBI, Na(v)1.3 messenger ribonucleic acid (mRNA) levels in bilateral hippocampi of the aCSF group were significantly elevated, compared with the sham and ODN groups (p<0.01). However, the Na(v)1.3 mRNA levels in the uninjured contralateral hippocampus of the ODN group were significantly lowered, compared with the sham group (p<0.01). Treatment with antisense ODN significantly decreased the number of degenerating neurons in the ipsilateral hippocampal CA3 and hilar region (p<0.01). A set of left-to-right ratio value analyzed by magnetic resonance imaging T2 image on one day, three days, and seven days post-TBI showed marked edema in the ipsilateral hemisphere of the aCSF group, compared with that of the ODN group (p<0.05). The Morris water maze memory retention test showed that both the aCSF and ODN groups took longer to find a hidden platform, compared with the sham group (p<0.01). However, latency in the aCSF group was significantly higher than in the ODN group (p<0.05). Our in vivo Na(v)1.3 inhibition studies suggest that therapeutic strategies to block upregulation of Na(v)1.3 expression in the brain may improve outcomes following TBI.