Blockage of the Upregulation of Voltage-Gated Sodium Channel Na_v1.3 Improves Outcomes after Experimental Traumatic Brain Injury

Abstract

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 2 h and 12 h 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 2 h, 4 h, 6 h, and 8 h following TBI. Control sham animals received aCSF administration at the same time points. At 12 h 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.

Alterations in Ion Channel Expression Surrounding Implanted Microelectrode Arrays in the Brain

“…In addition, electrophysiological abnormalities following axonal injury can persist in both axotomized and neighboring intact neurons 29 . The authors attributed these electrophysiological abnormalities to changes in the expression of sodium channels 10,29,35 , where blocking sodium channel upregulation following TBI has been shown to improve outcomes by reducing excitability 13 . The authors additionally attributed abnormal activity to A-type potassium channels (with fast-activating/inactivating kinetics 60 ), where reductions in channel expression has been shown to contribute to seizure susceptibility within initial days following TBI 12 by increasing the excitability and firing rates of local neurons 12 .…”

“…Neuronal loss and glial encapsulation are well-known consequences of implanting commonly used electrode designs [7][8][9] , but impacts on the residual function of remaining neurons are unknown. Ion channel expression and function is highly dynamic and modulated by many factors 1 , including changes to the surrounding environment caused by injury [10][11][12][13] and inflammation [14][15][16] . Channel modulation can impact not only the signal generation capabilities of single neurons, but also their frequencies, patterns, and waveform characteristics that underlie information encoding 1,2 .…”

Age and Diet Affect Genetically Separable Secondary Injuries that Cause Acute Mortality Following Traumatic Brain Injury in Drosophila

“…The transcription mechanism is likely to involve the Toll pathway because Drs is predominantly regulated by the Toll pathway, as are secreted peptide-encoding genes in the Bom family that, like Drs, had age- and diet-regulated expression that negatively correlated with the MI 24 (Lemaitre and Hoffmann 2007; Clemmons et al 2015) (Table 2). The Drs-specific function may be related its ability to inactivate a voltage-gated sodium channel, since blocking upregulation of a sodium channel improves outcomes in a rat TBI model (Cohen et al 2009; Huang et al 2014). …”

Effects of Ranolazine on Astrocytes and Neurons in Primary Culture

“…At therapeutic concentrations, Rn blocks voltage-gated sodium channels (VGSCs), preferentially the late sodium current ( I NaL ) [ 32 ]. Sodium channel inhibitors exert neuro-protective effects in experimental models of brain ischemia [ 33 ] and traumatic brain injury [ 34 ]. Moreover, phenytoin and carbamazepine were effective in animal models of autoimmune encephalomyelitis (EAE) [ 35 ].…”