PAI-1 protein is a key molecular effector in the transition from normal to PTSD-like fear memory

Abstract

Moderate stress increases memory and facilitates adaptation. In contrast, intense stress can induce pathological memories as observed in post-traumatic stress disorders (PTSD). A shift in the balance between the expression of tPA and PAI-1 proteins is responsible for this transition. In conditions of moderate stress, glucocorticoid hormones increase the expression of the tPA protein in the hippocampal brain region which by triggering the Erk1/2MAPK signaling cascade strengthens memory. When stress is particularly intense, very high levels of glucocorticoid hormones then increase the production of PAI-1 protein, which by blocking the activity of tPA induces PTSD-like memories. PAI-1 levels after trauma could be a predictive biomarker of the subsequent appearance of PTSD and pharmacological inhibition of PAI-1 activity a new therapeutic approach to this debilitating condition.

The Protective Effect of Panax notoginseng Mixture on Hepatic Ischemia/Reperfusion Injury in Mice via Regulating NR3C2, SRC, and GAPDH

“…Once MR binds to its ligand aldosterone, the MR configuration changes can occur. It can activate the nuclear localization signal, make the activated receptor–ligand complex quickly transfer to the nucleus, participate in the reaction of gene promoter or interact with other transcription factors, and induce the activation or inhibition of transcription and to regulate MR-related signaling pathways and a variety of physiological and pathological responses ( Bouarab et al, 2021 ). Our experimental results showed that compared with the sham group, the expression of MR was increased in the HIRI group ( p ˂ 0.01).…”

PTSD as an Endothelial Disease: Insights From COVID-19

“…Moreover, as furin and plasmin regulate synaptic plasticity and the fibrinolytic system, an impaired tissue-type plasminogen activator (tPA)/PAI-1 ratio, may lower the resilience for both PTSD and COVID-19. Indeed, severe COVID-19 and impaired fear extinction were associated with tPA/PAI-1 dyshomeostasis (Bouarab et al, 2021;Zuo et al, 2021).…”

“…et al, 2016). Both severe COVID-19 and PTSD were associated with upregulated PAI-1, a negative tPA regulator, indicating that targeting this protein may be therapeutic for both diseases (Cesari et al, 2010;Idell et al, 2017;Bouarab et al, 2021). Indeed, PAI-1 has been identified as a potential target in COVID-19 and its antagonists, such as statins, are currently in clinical trials (NCT04634799) (NCT04472611) (Bouarab et al, 2021;Kellici et al, 2021; Figure 2).…”

“…COVID-19-induced endothelial senescence and altered BBB may facilitate PAI-1 extravasation and interference with the stress-processing centers in amygdala, hippocampus, and mPFC. Several studies connected tPA/PAI-1 imbalance to PTSD, fear, anxiety, and depression, suggesting that restoring the fibrinolytic homeostasis may ameliorate the symptoms of SRDs (Pawlak et al, 2003;Bouarab et al, 2021). In addition, senescent ECs upregulate PAI-1, disrupting both plasmin activation and BDNF maturation, predisposing to PTSD (Pawlak et al, 2003;Tsai, 2017;Vaughan et al, 2017; Figure 2).…”

“…This may enable ANG II to aberrantly activate its receptors in the amygdala, hippocampus, and the medial prefrontal cortex (mPFC), lowering the PTSD resilience (Marinzalda Mde et al, 2014;Terock et al, 2019;Yu et al, 2019;Shkreli et al, 2020). Increased BBB permeability facilitates endothelin-1 (ET-1) and plasminogen activator inhibitor 1 (PAI-1) extravasation and interaction with their respective receptors in the stress-processing pathways, predisposing to PTSD (Kurihara et al, 2000;Jiang et al, 2016;Chen et al, 2017a;Bouarab et al, 2021). Moreover, as mitochondria express ANG II type 1 receptors (AT-1Rs), the virus may disrupt these organelles, shifting metabolism, from oxidative phosphorylation (OXPHOS) to glycolysis and lactate accumulation (Barron et al, 2004;Doughan et al, 2008;Mellon et al, 2019;Sabbatinelli et al, 2019;Gordon et al, 2020;Sher et al, 2020;Icard et al, 2021).…”