Glycyrrhizin Treatment Facilitates Extinction of Conditioned Fear Responses After a Single Prolonged Stress Exposure in Rats

Abstract

Background/Aims: Impaired fear memory extinction is widely considered a key mechanism of post-traumatic stress disorder (PTSD). Recent studies have suggested that neuroinflammation after a single prolonged stress (SPS) exposure may play a critical role in the impaired fear memory extinction. Studies have shown that high mobility group box chromosomal protein 1 (HMGB-1) is critically involved in neuroinflammation. However, the role of HMGB-1 underlying the development of impairment of fear memory extinction is still not known. Methods: Thus, we examined the levels of HMGB-1 in the basolateral amygdala (BLA) following SPS using Western blot and evaluated the levels of microglia and astrocytes activation in the BLA after SPS using immunohistochemical staining. We then examined the effects of pre-SPS intra-BLA administration of glycyrrhizin, an HMGB1 inhibitor, or LPS-RS, a competitive TLR4 antagonist, on subsequent post-SPS fear extinction. Results: We found that SPS treatment prolonged the extinction of contextual fear memory after the SPS. The impairment of SPS-induced extinction of contextual fear memory was associated with increased HMGB1 and Toll-like receptor 4 (TLR4) levels in the BLA. Additionally, the impairment of SPS-induced extinction of contextual fear memory was associated with increased activation of microglia and astrocyte in the BLA. Intra-BLA administrations of glycyrrhizin (HMGB-1 inhibitor) or LPS-RS (TLR4 antagonist) can prevent the development of SPS-induced fear extinction impairment. Conclusion: Taken together, these results suggested that SPS treatment may not only produce short term effects on the HMGB1/TLR4-mediated pro-inflammation, but alter the response of microglia and astrocytes to the exposure to fear associated contextual stimuli.

Understanding the influence of the perceived risk of the coronavirus disease (COVID-19) on the post-traumatic stress disorder and revisit intention of hotel guests

“…PTSD can be classified into four symptoms: intrusive thoughts, avoiding reminders, negative thoughts and feelings, and arousal and reactive symptoms; the severity of these symptoms may vary ( Alaqeel et al, 2019 ; Lai et al, 2018 ; Panagioti et al, 2015 ; Piotrowski & Range, 2019 ). Intrusive thoughts refer to the intrusion of painful memories or emotions to the consciousness, resulting in feeling or acting as if the patient is experiencing the actual trauma, and are marked by physiological responses such as severe mental pain and sudden increases in heartbeat ( Piotrowski & Range, 2019 ).…”

Glycyrrhizin treatment ameliorates post‐traumatic stress disorder‐like behaviours and restores circadian oscillation of intracranial serotonin

“…15 Our previously published results found that administration of glycyrrhizin in the basolateral amygdala prevented the development of a single long-term stress-induced fear-regression disorder, suggesting that glycyrrhizin has an antagonistic effect on PTSD. 16 However, its specific molecular mechanism requires further research, which is the starting point of the present study.…”

Putative Inflammatory Sensitive Mechanisms Underlying Risk or Resilience to Social Stress

“…Alternatively, the oxidized state of HMGB-1, designated by the formation of disulfide linkages, is capable of potentiating proinflammatory signaling as discussed above but lacks chemotactic abilities (Yang et al, 2012 ). Although the majority of studies assessing the involvement of HMGB-1 in microglial priming have come from studies using inescapable foot shock (Yang et al, 2012 ; Weber et al, 2015 ), chronic unpredictable stress (Franklin et al, 2018 ), and single prolonged stress (Lai et al, 2018 ), exposure to social stressors such as social defeat is known to enhance the intracellular concentration of reactive oxygen species (ROS; see section Oxidative Stress/Reactive Oxygen Species). Therefore, it is highly plausible that HMGB-1 may also contribute to the emergence of social stress-induced behavioral deficits.…”