Oxidative Stress, Inflammation, and Neuroprogression in Chronic PTSD

Abstract

Posttraumatic stress disorder is a serious and often disabling syndrome that develops in response to a traumatic event. Many individuals who initially develop the disorder go on to experience a chronic form of the condition that in some cases can last for many years. Among these patients, psychiatric and medical comorbidities are common, including early onset of age-related conditions such as chronic pain, cardiometabolic disease, neurocognitive disorders, and dementia. The hallmark symptoms of posttraumatic stress-recurrent sensory-memory reexperiencing of the trauma(s)-are associated with concomitant activations of threat- and stress-related neurobiological pathways that occur against a tonic backdrop of sleep disturbance and heightened physiological arousal. Emerging evidence suggests that the molecular consequences of this stress-perpetuating syndrome include elevated systemic levels of oxidative stress and inflammation. In this article we review evidence for the involvement of oxidative stress and inflammation in chronic PTSD and the neurobiological consequences of these processes, including accelerated cellular aging and neuroprogression. Our aim is to update and expand upon previous reviews of this rapidly developing literature and to discuss magnetic resonance spectroscopy as an imaging technology uniquely suited to measuring oxidative stress and inflammatory markers in vivo. Finally, we highlight future directions for research and avenues for the development of novel therapeutics targeting oxidative stress and inflammation in patients with PTSD.

Inflammation in Post-Traumatic Stress Disorder (PTSD): A Review of Potential Correlates of PTSD with a Neurological Perspective

“…Studies that investigated the alterations in these selected inflammatory markers were considered eligible, including levels of proinflammatory and anti-inflammatory cytokines. Specifically, cytokines that are most prevalently observed as being altered in relation to PTSD were selected as follows: serum proinflammatory cytokines interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α, and interferon (IFN)-γ as well as C-reactive protein (CRP) which is influenced by proinflammatory cytokines [28], serum anti-inflammatory cytokines IL-4 and IL-10 [29], and PTSD-and oxidative stress-related genes including the brain-derived neurotrophic factor (BDNF), arachidonate 12-lipoxygenase (ALOX12), arachidonate 15-lipoxygenase (ALOX15), and retinoic acid orphan receptor alpha (RORA) [30]. Neuroimaging-based studies were also included such as MRI and PET, along with markers of inflammation to examine the moderating role of specific inflammatory markers in the alteration of the brain.…”

Traumatic Stress and Accelerated Cellular Aging: From Epigenetics to Cardiometabolic Disease

“…While there is scant literature concerning PTSD and immune system functioning, there is relatively more research examining associations between PTSD and inflammation. We recently reviewed the role of PTSD-associated inflammation in accelerated aging and neurocognitive decline [73] and refer readers to that publication for more in depth discussion of this topic. The general pattern of results across that line of research provides support for associations between PTSD and C-reactive protein [74, 75, 76•], TNFα [76•, 77], IL-6 [77], and IL-1β [77].…”

“…This suggests that epigenetic aging could be influenced by activation of the biological stress response system, which also contributes to cardiometabolic pathology [29]. Second, oxidative stress could contribute to accelerated aging [30••, 73]. Free radicals form as part of the cellular response to pathogens and give rise to inflammation, which, if not countered by anti-oxidants, promotes oxidative stress.…”

Genome wide association study of hippocampal subfield volume in PTSD cases and trauma-exposed controls

“…SUGP2 is a splicing factor involved in pre-mRNA processing mechanisms(30); TMEM161A, when overexpressed, plays a role in protection against oxidative stress (31); and SLC25A42 belongs to a large family of nuclear-encoded transporters that are involved in metabolic pathways and cell functions and is widely expressed in the central nervous system (32,33). In summary, we have identified a SNP associated with R-HATA volume that also appears to impact RNA editing of GluRs and regulate expression of a gene involved in oxidative stress; both are processes which have been previously implicated in the pathophysiology of PTSD (34)(35)(36).…”