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Excessive activation of voltage-gated sodium channel Nav1.3 has been recently reported in secondary traumatic brain injury (TBI). However, the molecular mechanisms underlying regulating voltage-gated sodium channel (Nav1.3) has not been well understood. The present study used a TBI rat model induced by a fluid percussion device and performed a circRNA microarray (n=3) to profile the altered circRNAs in the hippocampus after TBI. After PCR validation, certain circRNA was selected to investigate the function and mechanism in regulating Nav1.3 in the TBI rat model by intracerebroventricular (ICV) injection with lentivirus. The neurological outcome was evaluated by Morris water maze (MWM) test, modified Neurological Severity Score (mNSS), brain water content measurement, hematoxylin, and eosin (H&E) staining. The related molecular mechanisms were explored with PCR, western blotting, luciferase reporter, chromatin immunoprecipitation (ChIP), and electrophoretic mobility shift assay (EMSA). A total of 347 circRNAs were observed to be differentially expressed (FC ≥1.2 and p < 0.05) after TBI, including 234 up-regulated and 113 down-regulated circRNAs. Among 10 validated circRNAs, we selected circRNA_009194 with the maximized up-regulated fold change (n=5, FC=4.45, p

Microglia are the primary immune cells in the central nervous system and undergo significant morphological and transcriptional changes after traumatic brain injury (TBI). However, their exact contribution to the pathogenesis of TBI is still debated and remains to be elucidated. In the present study, thy-1 GFP mice received a colony-stimulating factor 1 receptor inhibitor (PLX3397) for 21 consecutive days, then were subjected to moderate fluid percussion injury (FPI). Brain samples were collected at 1 day and 3 days after FPI for flow cytometry analysis, immunofluorescence, dendrite spine quantification, terminal deoxynucleotidyl transferase dUTP nick end labeling assay, and Western blot. We found that PLX3397 treatment significantly attenuated the percentages of resident microglia and infiltrated immune cells. Depletion of microglia promoted neurite outgrowth, preserved dendritic spines and reduced total brain cell and neuronal apoptosis after FPI, which was accompanied by decreased the protein levels of endoplasmic reticulum stress marker proteins, C/EBP-homologous protein and inositol-requiring kinase 1α. Taken together, these findings suggest that microglial depletion may exert beneficial effects in the acute stage of FPI.

This study evaluated the effects of clinically relevant concentrations of amantadine (AMT) on cognitive outcome and hippocampal cell survival in adult rats after lateral fluid percussion traumatic brain injury (TBI). AMT is an antagonist of the N-methyl-D-aspartate-type glutamate receptor, increases dopamine release, blocks dopamine reuptake, and has an inhibitory effect on microglial activation and neuroinflammation. Currently, AMT is clinically used as an antiparkinsonian drug. Amantadine or saline control was administered intraperitoneally, starting at 1 h after TBI followed by dosing three times daily for 16 consecutive days at 15, 45, and 135 mg/kg/day. Terminal blood draws were obtained from TBI rats at the time of euthanasia at varying time points after the last amantadine dose. Pharmacokinetics analysis confirmed that the doses of AMT achieved serum concentrations similar to those observed in humans receiving therapeutic doses (100-400 mg/day). Acquisition of spatial learning and memory retention was assessed using the Morris water maze (MWM) on days 12-16 after TBI. Brain tissues were collected and stained with Cresyl-violet for long-term cell survival analysis. Treatment with 135mg/kg/day of AMT improved acquisition of learning and terminal cognitive performance on MWM. The 135-mg/kg/day dosing of AMT increased the numbers of surviving CA2-CA3 pyramidal neurons at day 16 post-TBI. Overall, the data showed that clinically relevant dosing schedules of AMT affords neuroprotection and significantly improves cognitive outcome after experimental TBI, suggesting that it has the potential to be developed as a novel treatment of human TBI.