Traumatic brain injury (TBI) produces a rapid and robust inflammatory response in the brain characterized in part by activation of microglia. A novel histone deacetylase (HDAC) inhibitor, 4-dimethylamino-N-[5-(2-mercaptoacetylamino)pentyl]benzamide (DMA-PB), was administered (0, 0.25, 2.5, 25 mg/kg) systemically immediately after lateral fluid percussion TBI in rats. Hippocampal CA2/3 tissue was processed for acetyl-histone H3 immunolocalization, OX-42 immunolocalization (for microglia), and Fluoro-Jade B histofluorescence (for degenerating neurons) at 24 h after injury. Vehicle-treated TBI rats exhibited a significant reduction in acetyl-histone H3 immunostaining in the ipsilateral CA2/3 hippocampus compared to the sham TBI group (p<0.05). The reduction in acetyl-histone H3 immunostaining was attenuated by each of the DMA-PB dosage treatment groups. Vehicle-treated TBI rats exhibited a high density of phagocytic microglia in the ipsilateral CA2/3 hippocampus compared to sham TBI in which none were observed. All doses of DMA-PB significantly reduced the density of phagocytic microglia (p<0.05). There was a trend for DMA-PB to reduce the number of degenerating neurons in the ipsilateral CA2/3 hippocampus (p=0.076). We conclude that the HDAC inhibitor DMA-PB is a potential novel therapeutic for inhibiting neuroinflammation associated with TBI.

The neuroprotective effects of 17 beta -estradiol have been shown in models of central nervous system injury, including ischemia, brain injury, and more recently, spinal cord injury (SCI). Recent epidemiological trends suggest that SCIs in elderly women are increasing; however, the effects of menopause on estrogen-mediated neuroprotection are poorly understood. The objective of this study was to evaluate the effects of 17beta-estradiol and reproductive aging on motor function, neuronal death, and white matter sparing after SCI of post- and pre-menopausal rats. Two-month-old or 1- year-old female rats were ovariectomized and implanted with a silastic capsule containing 180 microg/mL of 17beta-estradiol or vehicle. Complete crush SCI at T8-9 was performed 1 week later. Additional animals of each age group were left ovary-intact but were spinal cord injured. The Basso, Beattie, Bresnahan (BBB) locomotor test was performed. Spinal cords were collected on post-SCI days 1, 7, and 21, and processed for histological markers. Administration of 17beta-estradiol to ovariectomized rats improved recovery of hind-limb locomotion, increased white matter sparing, and decreased apoptosis in both the post- and pre-menopausal rats. Also, ovary-intact 1-year-old rats did worse than ovary-intact 2-month-old rats, suggesting that endogenous estrogen confers neuroprotection in young rats, which is lost in older animals. Taken together, these data suggest that estrogen is neuroprotective in SCI and that the loss of endogenous estrogen-mediated neuroprotective seen in older rats can be attenuated with exogenous administration of 17beta-estradiol.

We study preheating in theories where the inflaton couples derivatively to scalar and gauge fields. Such couplings may dominate in natural models of inflation, in which the flatness of the inflaton potential is related to an approximate shift symmetry of the inflaton. We compare our results with previously studied models with non-derivative couplings. For sufficiently heavy scalar matter, parametric resonance is ineffective in reheating the universe, because the couplings of the inflaton to matter are very weak. If scalar matter fields are light, derivative couplings lead to a mild longwavelength instability that drives matter fields to non-zero expectation values. In this case however, long-wavelength fluctuations of the light scalar are produced during inflation, leading to a host of cosmological problems. In contrast, axion-like couplings of the inflaton to a gauge field do not lead to production of long-wavelength fluctuations during inflation. However, again because of the weakness of the couplings to the inflaton, parametric resonance is not effective in producing gauge field quanta.