To preserve the central nervous system (CNS) function after a traumatic injury, therapeutic agents must be administered to protect neurons as well as glial cells. Cell death in CNS injuries and diseases are attributed to many factors including glutamate toxicity and oxidative stress. We examined whether melatonin, a potent anti-oxidant and free radical scavenger, would attenuate apoptotic death of rat C6 astroglial cells under glutamate excitotoxicity and oxidative stress. Exposure of C6 cells to 500 µM L-glutamic acid (LGA) and 100 µM hydrogen peroxide (H 2 O 2 ) for 24 hr caused significant increases in apoptosis. Apoptosis was evaluated by Wright staining and ApopTag assay. Melatonin receptor 1 appeared to be involved in the protection of these cells from excitotoxic and oxidative damage. Cells undergoing excitotoxic and oxidative stress for 15 min were then treated with 150 nM melatonin, which prevented Ca 2+ influx and cell death. Western blot analyses showed alterations in Bax and Bcl-2 expression resulting in increased Bax:Bcl-2 ratio during apoptosis. Western blot analyses also showed increases in calpain and caspase-3 activities, which cleaved 270 kD α-spectrin at specific sites to generate 145 kD spectrin breakdown product (SBDP) and 120 kD SBDP, respectively. However, 15-min post-treatment of C6 cells with melatonin dramatically reduced Bax:Bcl-2 ratio and proteolytic activities, decreasing LGA or H 2 O 2 -induced apoptosis. Our data showed that melatonin prevented proteolysis and apoptosis in C6 astroglial cells. The results suggest that melatonin may be an effective cytoprotective agent against glutamate excitotoxicity and oxidative stress in CNS injuries and diseases.

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Fragile X syndrome (FXS) is the most common form of inherited mental retardation. In exploring abnormalities associated with the syndrome, we have recently demonstrated abnormal vascular density in a FXS mouse model (Galvan and Galvez, ). One of the most prominent regulators of vascular growth is VEGF-A (Vascular Endothelial Growth Factor A), suggesting that FXS is associated with abnormal VEGF-A expression. In addition to its role in vascular regulation, VEGF-A also induces cellular changes such as increasing cell proliferation, and axonal and neurite outgrowth independent of its effects on vasculature. These VEGF-A induced cellular changes are consistent with FXS abnormalities such as increased axonal material, dendritic spine density, and cell proliferation. In support of these findings, the following study demonstrated that FXS mice exhibit increased expression of VEGF-A in brain. These studies suggest that increased VEGF-A expression in FXS is contributing to non-vascular FXS abnormalities. To explore the role of VEGF-A in mediating non-vascular FXS abnormalities, the monoclonal antibody Bevacizumab was used to block free VEGF-A. Bevacizumab treatment was found to decrease FXS Synapsin-1 expression, a presynaptic marker for synapse density, and reduce FXS testicle weight to control levels. Blocking VEGF-A also alleviated FXS abnormalities on novel object recognition, a test of cognitive performance. These findings demonstrate that VEGF-A is elevated in FXS brain and suggest that its expression promotes non-vascular FXS abnormalities. © 2016 Wiley Periodicals, Inc. Develop Neurobiol 77: 14-25, 2017.

Suppressing perioperative inflammation and post-operative atrial fibrillation requires effective drug delivery platforms (DDP). Localized anti-inflammatory and anti-arrhythmic agent release may be more effective than intravenous treatment to improve patient outcomes. This study utilized a dexamethasone (DEX) and amiodarone (AMIO)-loaded Parylene-C (PPX) nano-structured film to inhibit inflammation and atrial fibrillation. The PPX film was tested in an established pericardial adhesion rabbit model. Following sternotomy, the anterior pericardium was resected and the epicardium was abraded. Rabbits were randomly assigned to five treatment groups: control, oxidized PPX (PPX-Oxd), PPX-Oxd infused with DEX (PPX-Oxd[DEX]), native PPX (PPX), and PPX infused with DEX and AMIO (PPX[AMIO, DEX]). 4 weeks post-sternotomy, pericardial adhesions were evaluated for gross adhesions using a 4-point grading system and histological evaluation for epicardial neotissue fibrosis (NTF). Atrial fibrillation duration and time per induction were measured. The PPX[AMIO, DEX] group had a significant reduction in mean adhesion score compared with the control group (control 2.75 ± 0.42 vs. PPX[AMIO, DEX] 0.25 ± 0.42, P < 0.001). The PPX[AMIO, DEX] group was similar to native PPX (PPX 0.38 ± 0.48 vs. PPX[AMIO, DEX] 0.25 ± 0.42, P=NS). PPX-Oxd group adhesions were indistinguishable from controls (PPX-Oxd 2.83 ± 0.41 vs. control 2.75 ± 0.42, P=NS). NTF was reduced in the PPX[AMIO, DEX] group (0.80 ± 0.10 mm) compared to control (1.78 ± 0.13 mm, P < 0.001). Total duration of atrial fibrillation was decreased in rabbits with PPX[AMIO, DEX] films compared to control (9.5 ± 6.8 s vs. 187.6 ± 174.7 s, p = 0.003). Time of atrial fibrillation per successful induction decreased among PPX[AMIO, DEX] films compared to control (2.8 ± 1.2 s vs. 103.2 ± 178 s, p = 0.004). DEX/AMIO-loaded PPX films are associated with reduced perioperative inflammation and a diminished atrial fibrillation duration. Epicardial application of AMIO, DEX films is a promising strategy to prevent post-operative cardiac complications.

Impulsivity is a personality trait associated with a heightened risk for drug use and other psychiatric conditions. Because impulsivity-related disorders typically emerge during adolescence, there has been interest in exploring methods for identifying adolescents that will be at risk to develop substance use disorders in adulthood. Here, we used a rodent model to assess inhibitory control (impulsive action) and impulsive decision making (impulsive choice) during adolescence (43-50 days old) or adulthood (93-100 days old) and then examined the impact of development on these impulsivity traits by re-testing rats 50 days later. Impulsive action was not stable from adolescence to adulthood in male rats and was lowest in adult male rats, relative to adolescents and female rats. Impulsive choice was stable across development and unaffected by age or sex. Next, we examined the connection between our model of impulsivity and two measures relevant to substance abuse research: the initiation of voluntary alcohol drinking and dopamine D receptor (D R) expression in the prelimbic prefrontal cortex. Consumption of saccharin-sweetened ethanol during 30-minute sessions in adulthood was associated with adolescent, but not adult, impulsive action, particularly in male rats. Prelimbic D R expression was reduced in individuals with high levels of impulsive choice, and this relationship appeared to be strongest among female rats. The results of this study demonstrate that impulsive choice, along with its connection to D R expression, is relatively unchanged by the process of development. For impulsive action, however, individual levels of impulsivity during adolescence predict drinking in adulthood despite changes in the measure during development.