Ten eleven translocases (TETs) mediate the conversion of 5-hydroxymethyl cytosine (5-mC) to 5-hydroxymethyl cytosine (5-hmC). The TET3 isoform and 5hmC are known to be enriched in the neurons in brain. TET3 is known to promote cell survival by inducing the expression of anti-inflammatory genes. Vitamin C (ascorbate) is a potent activator of TET3. Hence, we tested the efficacy of ascorbate in curtailing secondary brain damage and promoting motor and cognitive functional recovery after traumatic brain injury (TBI) induced in adult C57BL/6 mice by controlled cortical impact (CCI). Mice were given 3 doses of 500 mg/Kg ascorbate i.p. at 5 min, 1 day and 2 days after CCI injury (n =7/cohort). Seven saline treated mice were used as control. Both cohorts of mice were subjected to motor function analysis by rotarod test (between days 5 and 28) and cognitive function analysis (between das 21 and 23) after the injury. Mice were pretrained for 3 days before each test. Mice were euthanized on day 21 and the cortical injury (lesion) volume was estimated using cresyl violet stained serial brain sections. Post-TBI motor dysfunction was significantly reduced in the ascorbate-treated cohort compared to vehicle control (p < 0.05 by 2-way repeated measures ANOVA with Sidak’s post hoc test). Ascorbate treated cohort stayed in the platform quadrant significantly longer than the vehicle control mice in the Morris water maze test (probe trial on day 24; p < 0.05 by Mann-Whitney U test). In addition, the cortical lesion volume was also significantly smaller in the ascorbate treated mice compared with the vehicle treated mice (p < 0.05 by Mann-Whitney U test). These results indicate that epigenetic modulation by ascorbate is promoter of better functional outcomes after TBI. Funded by US Veterans Administration and US NIH.

Traumatic Brain Injury (TBI) constitutes a public health problem around the world that annually claims thousands of lives and is associated with extensive disability and great economic impact; it is defined as the sudden alteration of the brain tissue or its physiological functions as a result of the influence of external forces that exceed the resistance of the tissue. The objectives of this work were to temporally characterize the tissue, behavioral and molecular changes of the hippocampus after moderate TBI in Wistar rats as well as to determine if early management with minocycline can reverse and/or improve the consequences of the injury. It was found that diffuse TBI is associated with neuronal loss in the hippocampus, alterations in the axons and myelin sheaths, as well as reactive gliosis in all subregions, with increased activity of the matrix protease MMP9. Early intervention with minocycline achieved a positive effect on the reduction of neuronal dead, axonal degeneration, and neurofilament compaction with a very slight effect on MMP9 activity. This work is expected to contribute to the knowledge of the phenomena associated with the temporal pathophysiology of diffuse TBI in the hippocampus and further open up the possibilities of pharmacological intervention.

Traumatic brain injury (TBI) is a major cause of mortality and morbidity in the world. TBI induces a chronic disease process causing visual loss which in turn affects day to day life of patients as well as their families. Understanding the underlying molecular mechanisms of TBI-induced vision impairment is a great challenge for neurobiologists, ophthalmologists, and other clinical practitioners. Our animal research study shows that TBI causes damage to the optic nerve and thinning of the retina culminating in compromised vision processing and perception. Axonal degeneration and demyelination in optic nerve and retinal ganglion cells (RGCs) loss in the retina is a crucial feature of vision impairment triggered by TBI. We have found that histone 3 dimethylation at lysine 9 residues (H3K9Me2) on antioxidants gene promoters like SOD can trigger oxidative stress in RGCs and oligodendrocyte precursor cells (OPCs) that was strongly correlated with retinal thinning, impairment of the retrograde transport of axons from visual cortex to neural retina, and demyelination of optic nerve following TBI. Our study suggests that epigenetic regulation of genes associated with oxidative stress could be a potential therapeutic target to restore visual deficits after TBI.

Objectives: Brain-Derived Neurotrophic Factor (BDNF) mediates the neuronal response to injury. It has been hypothesized that BDNF is a potential biomarker of sport-related concussion (SRC). BDNF expression is exercise-dependent, and aerobic exercise is a standard treatment for SRC. This study assessed salivary BDNF expression in athletes with acute SRC and throughout a 2-week aerobic exercise intervention.

Methods: Athletes with acute SRC (n= 32, 66% male, 15.6 ± 1.4 yrs) and healthy controls (n= 28, 66% male, 16.0 ± 1.6 yrs) provided saliva samples weekly (Day 0, 7 and 14). Concussed and control participants were randomly prescribed individualized aerobic exercise at high (5 days/week for 30 minutes) or low volumes (3 days/week for 20 minutes). Prescribed exercise intensity was based on the results from each participant’s graded exercise test. Participants completed standard clinical examinations and symptom reports during each visit. An optimized Enzyme-Linked Immunosorbent Assay (ELISA) for BDNF (R&D systems) was used to assess samples in triplicate.

Results: ELISA standard curves were high quality (healthy r2= 1.00, concussed r2= 0.98). At the initial visit, concussed females had higher salivary BDNF than healthy participants (p=0.002). There was no difference between concussed and healthy males’ BDNF at the initial visit (p=0.627). Over time, concussed females consistently showed higher salivary BDNF expression than healthy females, whereas males were not different. BDNF level was not affected by the volume of exercise participants completed (p=0.767) or by history of prior concussions (p=0.85).

Conclusion: The data suggest that salivary BDNF may be assessed for post-concussion monitoring in adolescent athletes but may be more informative for females. Unexpectedly, exercise volume did not affect BDNF, suggesting that a longer exercise intervention would be required to impact BDNF expression. BDNF levels were not affected by time, regardless of recovery, consistent with reports that physiological dysfunction persists beyond clinical recovery from SRC. In conclusion, salivary BDNF offers a non-invasive and convenient analyte that may aid in concussion diagnosis and for monitoring post-concussion treatment response. However, further research is needed to understand the effects of sex, exercise, and recovery on salivary BDNF after SRC.

Acknowledgment: Support for this project by the Clinical Translational Science Institute at the University at Buffalo (UL1TR001412).