Inflammation and Oxidative Stress Are Elevated in the Brain, Blood, and Adrenal Glands during the Progression of Post-Traumatic Stress Disorder in a Predator Exposure Animal Model

Abstract

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.

Oxidative Stress and Inflammation Induced by Environmental and Psychological Stressors: A Biomarker Perspective

“…This has been hypothesized to be the case in PTSD, where a study measuring levels of inflammatory cytokines and markers of OS suggests that inflammatory cytokines induce ROS production, which then amplifies the inflammatory response (169).…”

Proinflammatory milieu in combat-related PTSD is independent of depression and early life stress

“…The mechanisms by which peripheral inflammation may influence the central nervous system are still unclear, as reviewed by Andrews and Neises (2012). Cytokines are produced in the periphery, mainly by immune cells, and can cross the blood brain barrier (BBB) via passive and active transport mechanisms (Schiepers et al, 2005) and once in the brain, can activate microglia (Wilson et al, 2013). In one animal study, it was shown that lymphocytes may infiltrate the BBB following psychological stress (Lewitus et al, 2008), thus linking stress-related peripheral inflammation to signs of neuroinflammation and possibly behavioral changes.…”

“…Few clinical studies have been able to investigate this but in support of a primarily central process, Baker et al (2001) found that combat veterans with PTSD display higher levels of IL-6 in CSF, but not in plasma, compared to controls. Moreover, a recent animal model of PTSD found that inflammation in the brain was associated with PTSD, and that disease progression was also associated with increased oxidative stress in the brain as well as in the periphery (Wilson et al, 2013). However, another animal model of traumatic brain injury (TBI) and PTSD found that the presence of behaviors suggestive of PTSD did not exacerbate neuroinflammation associated with TBI (Acosta et al, 2013), speaking against a robust linkage between neuroinflammation and PTSD.…”

220. Molecular Indicators of Stress-Induced Neuroinflammation in a Mouse Model Simulating Features of Post-Traumatic Stress Disorder

“…[57][58][59] In short, activated neuroinflammation is implicated in inhibited neurogenesis and synaptic plasticity (cognitive deficits) leading to the development and persistence of the behavioral manifestations of PTSD. Whereas, somatic inflammation seems to be directly involved in tissue damage, triggering and maintaining somatic comorbid pathologies.…”