Hippocampal Endoplasmic Reticulum Stress Novel Target in PTSD Pharmacotherapy

Posttraumatic stress disorder (PTSD) is an anxiety disorder that occurred in individual who had experienced severe traumatic stresses. This disorder is accompanied by functional impairments in daily activities, comorbidities (such as depression) and increased risk of suicide. Some studies also demonstrate that PTSD is linked to structural and functional impairment of hippocampus. Hippocampal defect has been found in PTSD model, especially in single-prolonged stress (SPS)-induced animal model, with excessive or prolonged endoplasmic reticulum (ER) stress-induced neuronal apoptosis as a proposed mechanism. Unfortunately, this cellular event has not been studied and validated in humans suffering from PTSD. Two chaperones known as glucose-regulated protein 78 (GRP78) and sigma-1 receptor (Sig1R) have been demonstrated to exhibit central roles in mitigating the effects of severe ER stress on cell survival. Several selective serotonin-reuptake inhibitors (SSRIs), such as fluvoxamine and sertraline, are also found to be an agonist and antagonist of sigma-1 receptor (Sig1R) in animal brain cells, respectively. There is also link between antidepressant use and risk of suicidal ideation. Therefore, the authors propose that hippocampal ER stress may be involved in PTSD pathobiology. Pharmacodynamics of currently available therapeutic agents for PTSD and its comorbidities on hippocampal ER stress should be clearly elucidated to promote therapy optimization and drug development. Keywords: ER Stress; GRP78; Hippocampus; PTSD; Sigma-1 Receptor; Therapy