This study sought to analyze specific pathophysiological mechanisms involved in the progression of post-traumatic stress disorder (PTSD) by utilizing an animal model. To examine PTSD pathophysiology, we measured damaging reactive oxygen species and inflammatory cytokines to determine if oxidative stress and inflammation in the brain, adrenal glands, and systemic circulation were upregulated in response to constant stress. Pre-clinical PTSD was induced in naïve, male Sprague-Dawley rats via a predator exposure/psychosocial stress regimen. PTSD group rats were secured in Plexiglas cylinders and placed in a cage with a cat for one hour on days 1 and 11 of a 31-day stress regimen. In addition, PTSD group rats were subjected to psychosocial stress whereby their cage cohort was changed daily. This model has been shown to cause heightened anxiety, exaggerated startle response, impaired cognition, and increased cardiovascular reactivity, all of which are common symptoms seen in humans with PTSD. At the conclusion of the predator exposure/psychosocial stress regimen, the rats were euthanized and their brains were dissected to remove the hippocampus, amygdala, and pre-frontal cortex (PFC), the three areas commonly associated with PTSD development. The adrenal glands and whole blood were also collected to assess systemic oxidative stress. Analysis of the whole blood, adrenal glands, and brain regions revealed oxidative stress increased during PTSD progression. In addition, examination of pro-inflammatory cytokine (PIC) mRNA and protein demonstrated neurological inflammatory molecules were significantly upregulated in the PTSD group vs. controls. These results indicate oxidative stress and inflammation in the brain, adrenal glands, and systemic circulation may play a critical role in the development and further exacerbation of PTSD. Thus, PTSD may not be solely a neurological pathology but may progress as a systemic condition involving multiple organ systems.

Post-Traumatic Stress Disorder (PTSD) can develop in response to a traumatic event involving a threat to life. To date, no diagnostic biomarkers have been identified for PTSD. Recent research points toward physiological abnormalities in the hypothalamic-pituitary-adrenal (HPA) axis, sympathoadrenal medullary and immune system that may be implicated in the disorder. The modulation of neurotransmitters is another possible mechanism, but their role in the progression of PTSD is poorly understood. Low serotonin (5-HT) may be a factor, but it may not be the only neurotransmitter affected as modulation affects levels of other neurotransmitters. In this study, we hypothesized the predator exposure/psychosocial stress rodent model of PTSD may alter levels of 5-HT and other neurotransmitters in the rat hippocampus and prefrontal cortex (PFC). Male Sprague-Dawley rats were used in this experiment. We induced PTSD via a predator exposure/psychosocial stress model, whereby rats were placed in a cage with a cat for 1 hour on days 1 and 11 of the 31-day experiment. Rats also received psychosocial stress via daily cage cohort changes. On day 32, the rats were sacrificed and the brains dissected to remove the hippocampus and PFC. Norepinephrine (NE), 5-Hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA), dopamine (DA), and 3,4-Dihydroxyphenylacetic acid (DOPAC), and 5-HT levels in the hippocampus and PFC were measured with high-performance liquid chromatography (HPLC). In the hippocampus, 5-HT and HVA were lower, while NE and DOPAC were higher, in the PTSD group vs. controls. In the PFC, only 5-HT was lower, while NE, DA, and DOPAC were higher, in the PTSD group vs. controls. The rate limiting enzymes tyrosine hydroxylase and tryptophan hydroxylase were also examined and confirmed our findings. These results demonstrate that the predator exposure/psychosocial stress model of PTSD produces neurotransmitter changes similar to those seen in human patients and may cause a heightened noradrenergic response.

Serotonin (5-HT), norepinephrine (NE), and other neurotransmitters are modulated in post-traumatic stress disorder (PTSD). In addition, pro-inflammatory cytokines (PIC) are elevated during the progression of the disorder. Currently, the only approved pharmacologic treatments for PTSD are the selective-serotonin reuptake inhibitors (SSRI) sertraline and paroxetine, but their efficacy in treating PTSD is marginal at best. In combat-related PTSD, SSRIs are of limited effectiveness. Thus, this study sought to analyze the effects of the SSRI sertraline on inflammation and neurotransmitter modulation via a predator exposure/psychosocial stress animal model of PTSD. We hypothesized that sertraline would diminish inflammatory components and increase 5-HT but might also affect levels of other neurotransmitters, particularly NE. PTSD-like effects were induced in male Sprague-Dawley rats (n = 6/group × 4 groups). The rats were secured in Plexiglas cylinders and placed in a cage with a cat for 1 h on days 1 and 11 of a 31-day stress regimen. PTSD rats were also subjected to psychosocial stress via daily cage cohort changes. At the conclusion of the stress regimen, treatment group animals were injected intraperitoneally (i.p.) with sertraline HCl at 10 mg/kg for 7 consecutive days, while controls received i.p. vehicle. The animals were subsequently sacrificed on day 8. Sertraline attenuated inflammatory markers and normalized 5-HT levels in the central nervous system (CNS). In contrast, sertraline produced elevations in NE in the CNS and systemic circulation of SSRI treated PTSD and control groups. This increase in NE suggests SSRIs produce a heightened noradrenergic response, which might elevate anxiety in a clinical setting.

A 1-year-old cat was presented with general discomfort but no neurologic deficits on physical examination. An extradural spinal cord compression at the level of T10-11 and T11-12 was evident on myelography and computed tomography examination. Hemilaminectomy was performed to decompress the spinal cord. Histopathology of the abnormal pedicle and lamina revealed vertebral angiomatosis. This rare vascular malformation was the cause of the spinal cord compression in this cat. It is seen in cats less than 2 years of age and affected the thoracic spine in all four previously reported cases.

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Human ribosomal protein S3 (RPS3) has previously been shown to have alternative roles beyond its participation in protein synthesis. For example, our in vitro studies have shown that RPS3 has an extraordinarily high binding affinity for 7, 8-dihydro-8-oxoguanine (8-oxoG). Notably, in cells exposed to oxidative stress RPS3 translocates to the nucleus where it co-localizes with foci of 8-oxoG. We have engineered transgenic mice over expressing RPS3 in an attempt to determine the outcome of RPS3 translocation in a whole animal. Mouse embryonic fibroblasts (MEF's) isolated from these transgenic mice showed an increased accumulation of DNA damage in cells exposed to oxidative damage when compared to MEF's from wild-type mice. In MEF's exposed to oxidative stress we observed the translocation of RPS3 from the cytoplasm to the nucleus and co-localizing to 8-oxoG foci, an observation that could involve the blocking of the repair of this mutagenic base and thereby explain why transgenic MEF's exposed to oxidative stress have higher levels of DNA damage.

CD2 and CD58 are two important co-stimulatory molecules involved in generating the signal II required for normal immune signaling. However, this interaction can be targeted to be of benefit in cases of abnormal immune signaling seen in autoimmune diseases. Our objective in this study was to design a peptidomimetic (compound 7) based on a β-strand structure of the adhesion domain of CD2 protein to inhibit CD2-CD58 protein-protein interaction and its effect on immunomodulation in the collagen-induced arthritis (CIA) model. The ability of compound 7 to bind to CD58 protein was assessed using flow cytometry. The effect of compound 7 on modulating the immune response was evaluated in an autoimmune disease using CIA in mice. The stability of compound 7 was evaluated in mouse serum using mass spectrometry. Antibody (Ab) binding inhibition studies suggested that compound 7 binds to CD58 protein. Compound 7 was successful in modulating immune responses when administered in the CIA mouse model along with reducing anti-collagen Ab levels and decreasing the level of interferon gamma (IFN-γ) relative to control treatments. Compound 7 was found to be non-immunogenic and stable in mouse serum up to 48 h. Results suggest that compound 7 can serve as a lead compound for immunomodulation, and could be a therapeutic agent for the autoimmune disease rheumatoid arthritis (RA).

SUMMARY Sympathetic activity and obesity have a reciprocal relationship. Firstly, hypothalamic obesity is associated with decreased sympathetic activity. Caffeine and ephedrine increase sympathetic activity and induce weight loss, of which 25% is due to increased metabolic rate and 75% is due to a reciprocally decreased food intake. Secondly, hormones and drugs that affect body weight have an inverse relationship between food intake and metabolic rate. Neuropeptide Y decreases sympathetic activity and increases food intake and body weight. Thirdly, a gastric pacemaker Transcend® and vagotomy increase the ratio of sympathetic to parasympathetic activation, decrease food intake, and block gut satiety hormones. Weight loss with the pacemaker or vagotomy is variable. Significant weight reduction is seen only in a small group of those treated. This suggests that activation of the sympathetic arm of the autonomic nervous system may be most important for weight loss. Systemic sympathetic activation causes weight loss in obese patients, but side effects limited its use. We hypothesize that selective local electrical sympathetic stimulation of the upper gastrointestinal tract may induce weight loss and offer a safer, yet effective, obesity treatment. Celiac ganglia delivers sympathetic innervation to the upper gastrointestinal tract. Voltage regulated electrical simulation of the rat celiac ganglia increased metabolic rate in a dose-dependent manner. Stimulation of 6, 3, or 1.5 V increased metabolic rate 15.6%, 6.2%, and 5%, respectively in a single rat. These responses support our hypothesis that selective sympathetic stimulation of the upper GI tract may treat obesity while avoiding side effects of systemic sympathetic activation.