OBJECTIVES: To observe the effect of 4-(arylethynyl)-pyrrolo[2,3-d] pyrimidine (10b) on post-traumatic stress disorder (PTSD)-like behaviors and ERK1/2-SGK1 signaling pathway in mice. METHODS: C57BL/6 mouse models exposed to single prolonged stress (SPS) were treated with daily gavage of saline, 10b at low, moderate and high doses, or paroxetine for 14 days. The changes in PTSD-like behaviors of SPS mice with different treatments were observed using behavioral tests. Western blotting and immunofluorescence assay were used to detect the protein expression levels of mGluR5, p-ERK, and SGK1 in the hippocampus of the mice. Pathological changes in the liver and kidney tissues of the mice were examined using HE staining. Molecular docking and molecular dynamics analyses were employed to evaluate the binding stability between the compound 10b and mGluR5. RESULTS: Compared to the normal control mice, the SPS mice exhibited obvious PTSD-like behaviors with increased hippocampal expressions of mGluR5 and p-ERK proteins and decreased SGK1 protein expression. Compound 10b significantly ameliorated behavioral abnormalities in SPS mice, inhibited mGluR5 expression, and reversed the dysregulation of p-ERK and SGK1. No obvious liver or kidney toxicity was observed after 10b treatment. Molecular docking and dynamics studies demonstrated a stable interaction between 10b and mGluR5. CONCLUSIONS The compound 10b ameliorates PTSD-like behaviors induced by SPS in mice possibly by inhibiting mGluR5 expression to modulate the ERK1/2-SGK1 signaling pathway.
Animals ; Stress Disorders, Post-Traumatic/drug therapy* ; Receptor, Metabotropic Glutamate 5/metabolism* ; Mice, Inbred C57BL ; Mice ; Protein Serine-Threonine Kinases/metabolism* ; Pyrimidines/pharmacology* ; Immediate-Early Proteins/metabolism* ; Signal Transduction/drug effects* ; MAP Kinase Signaling System/drug effects* ; Male ; Molecular Docking Simulation ; Hippocampus/metabolism*

OBJECTIVE: To elucidate the specific mechanisms by which electroacupuncture (EA) alleviates anxiety and fear behaviors associated with posttraumatic stress disorder (PTSD), focusing on the role of lipocalin-2 (Lcn2). METHODS: The PTSD mouse model was subjected to single prolonged stress and shock (SPS&S), and the animals received 15 min sessions of EA at Shenmen acupoint (HT7). Behavioral tests were used to investigate the effects of EA at HT7 on anxiety and fear. Western blotting and enzyme-linked immunosorbent assay were used to quantify Lcn2 and inflammatory cytokine levels in the prefrontal cortex (PFC). Additionally, the activity of PFC neurons was evaluated by immunofluorescence and in vivo electrophysiology. RESULTS: Mice subjected to SPS&S presented increased anxiety- and fear-like behaviors. Lcn2 expression in the PFC was significantly upregulated following SPS&S, leading to increased expression of the proinflammatory cytokines tumor necrosis factor-α and interleukin-6 and suppression of PFC neuronal activity. However, EA at HT7 inhibited Lcn2 release, reducing neuroinflammation and hypoexcitability in the PFC. Lcn2 overexpression mitigated the effects of EA at HT7, resulting in anxiety- and fear-like behaviors. CONCLUSION EA at HT7 can ameliorate PTSD-associated anxiety and fear, and its mechanism of action appears to involve the inhibition of Lcn2-mediated neural activity and inflammation in the PFC. Please cite this article as: Yang YD, Zhong W, Chen M, Tang QC, Li Y, Yao LL, et al. Electroacupuncture alleviates behaviors associated with posttraumatic stress disorder by modulating lipocalin-2-mediated neuroinflammation and neuronal activity in the prefrontal cortex. J Integr Med. 2025; 23(5):537-547.
Electroacupuncture ; Stress Disorders, Post-Traumatic/metabolism* ; Animals ; Lipocalin-2/metabolism* ; Prefrontal Cortex/physiopathology* ; Male ; Mice ; Neurons/physiology* ; Disease Models, Animal ; Fear ; Behavior, Animal ; Mice, Inbred C57BL ; Neuroinflammatory Diseases/metabolism* ; Anxiety/therapy* ; Acupuncture Points

OBJECTIVE: To observe the effect of Shugan Tiaoshen acupuncture (acupuncture for soothing the liver and regulating the spirit) on the protein kinase C/extracellular signal-regulated kinase/cAMP response element-binding protein (PKC/ERK/CREB) signaling pathway in the bed nucleus of the stria terminalis (BNST) of rats with post-traumatic stress disorder (PTSD), and to explore the mechanism of acupuncture on alleviating anxiety and fear in PTSD. METHODS: Fifty SPF-grade male SD rats were randomly divided into a blank group (10 rats) and a PTSD model group (40 rats). The PTSD model was induced by using a combination of closed electric shock and forced exhaustive swimming. Thirty successfully modeled rats were randomly assigned to a model group, a medication group, and an acupuncture group, with 10 rats in each group. The rats in the medication group were treated with paroxetine hydrochloride solution by gavage, once daily for 12 consecutive days. The rats in the acupuncture group were treated with acupuncture at "Baihui" (GV 20) and bilateral "Neiguan" (PC 6), "Shenmen" (HT 7), "Taichong" (LR 3). "Baihui" (GV 20) was needled daily, while the other acupoints were alternately needled on the left side on odd days and the right side on even days, once daily for 12 consecutive days. Anxiety and fear behaviors changes were assessed by using the open field test and elevated plus maze test. Histological changes in the BNST were observed by using HE staining and Nissl staining. The expression of PKC, phosphorylated PKC (p-PKC), ERK1/2, phosphorylated ERK1/2 (p-ERK1/2), and p-CREB proteins in the BNST were detected by using Western blot. RESULTS: Compared with the blank group, the model group showed decreased time and total distance spent in the center of the open field and on the open arms of the elevated plus maze (P<0.05); the BNST tissues in the model group exhibited a reduced number of neurons, disorganized cell arrangement, cell shrinkage, nuclear condensation, abnormal neuronal structure, uneven Nissl staining, and reduced Nissl bodies. The model group showed increased protein expression of p-PKC and p-PKC/PKC ratio (P<0.05) and decreased protein expression of p-ERK1/2, p-CREB, and p-ERK1/2/ERK1/2 ratio (P<0.05). Compared with the model group, the medication group and the acupuncture group showed increased time and total distance spent in the center of the open field and on the open arms of the elevated plus maze (P<0.05); the BNST tissues showed increased number of neurons, more organized cell arrangement, improved neuronal structure, and increased Nissl bodies; the medication group and the acupuncture group also showed decreased p-PKC protein expression and p-PKC/PKC ratio (P<0.05) and increased p-ERK1/2, p-CREB protein expression, and p-ERK1/2/ERK1/2 ratio (P<0.05). CONCLUSION Shugan Tiaoshen acupuncture could alleviate anxiety and fear behaviors in PTSD rats, and improve neuronal damage in the BNST. The mechanism may be related to the regulation of the PKC/ERK/CREB signaling pathway in the BNST.
Animals ; Male ; Rats ; Rats, Sprague-Dawley ; Acupuncture Therapy ; Protein Kinase C/metabolism* ; Stress Disorders, Post-Traumatic/metabolism* ; Anxiety/metabolism* ; Cyclic AMP Response Element-Binding Protein/metabolism* ; Humans ; Septal Nuclei/metabolism* ; Signal Transduction ; Extracellular Signal-Regulated MAP Kinases/metabolism* ; Acupuncture Points ; Behavior, Animal

OBJECTIVE: This study investigated trends in the study of phytochemical treatment of post-traumatic stress disorder (PTSD). METHODS: The Web of Science database (2007-2022) was searched using the search terms "phytochemicals" and "PTSD," and relevant literature was compiled. Network clustering co-occurrence analysis and qualitative narrative review were conducted. RESULTS: Three hundred and one articles were included in the analysis of published research, which has surged since 2015 with nearly half of all relevant articles coming from North America. The category is dominated by neuroscience and neurology, with two journals, Addictive Behaviors and Drug and Alcohol Dependence, publishing the greatest number of papers on these topics. Most studies focused on psychedelic intervention for PTSD. Three timelines show an "ebb and flow" phenomenon between "substance use/marijuana abuse" and "psychedelic medicine/medicinal cannabis." Other phytochemicals account for a small proportion of the research and focus on topics like neurosteroid turnover, serotonin levels, and brain-derived neurotrophic factor expression. CONCLUSION Research on phytochemicals and PTSD is unevenly distributed across countries/regions, disciplines, and journals. Since 2015, the research paradigm shifted to constitute the mainstream of psychedelic research thus far, leading to the exploration of botanical active ingredients and molecular mechanisms. Other studies focus on anti-oxidative stress and anti-inflammation. Please cite this article as: Gao B, Qu YC, Cai MY, Zhang YY, Lu HT, Li HX, Tang YX, Shen H. Phytochemical interventions for post-traumatic stress disorder: A cluster co-occurrence network analysis using CiteSpace. J Integr Med. 2023; 21(4):385-396.
Humans ; Stress Disorders, Post-Traumatic/drug therapy* ; Hallucinogens/therapeutic use* ; Substance-Related Disorders/drug therapy*

Although posttraumatic stress disorder (PTSD) is on the rise, traumatic events and their consequences are often hidden or minimized by patients for reasons linked to PTSD itself. Traumatic experiences can be broadly classified into mental stress (MS) and traumatic brain injury (TBI), but the cellular mechanisms of MS- or TBI-induced PTSD remain unknown. Recent evidence has shown that the morphological remodeling of astrocytes accompanies and arguably contributes to fearful memories and stress-related disorders. In this review, we summarize the roles of astrocytes in the pathogenesis of MS-PTSD and TBI-PTSD. Astrocytes synthesize and secrete neurotrophic, pro- and anti-inflammatory factors and regulate the microenvironment of the nervous tissue through metabolic pathways, ionostatic control, and homeostatic clearance of neurotransmitters. Stress or trauma-associated impairment of these vital astrocytic functions contribute to the pathophysiological evolution of PTSD and may present therapeutic targets.
Astrocytes ; Brain Injuries, Traumatic ; Fear ; Humans ; Stress Disorders, Post-Traumatic/therapy*

This paper aims to investigate the active components and mechanism of Valerianae Jatamansi Rhizoma et Radix against post-traumatic stress disorder(PTSD) based on network pharmacology and molecular docking. The main components and targets of Valerianae Jatamansi Rhizoma et Radix were obtained by literature mining methods, SwissTargetPrediction, BATMAN and ETCM database. PTSD-related genes were collected from DrugBank, TTD and CTD databases. The protein-protein interaction(PPI) network was constructed based on STRING, and the core targets of Valerianae Jatamansi Rhizoma et Radix in the treatment of PTSD were selected according to the topological parameters. Cytoscape 3.7.2 was used to construct the compound-target network. DAVID database was used for GO enrichment analysis and KEGG enrichment analysis. The relationship network of "compound-target-pathway" was constructed through Cytoscape 3.7.2 to analyze and obtain the key targets and their corresponding components in the network, and their results were verified by molecular docking. The results showed that a total of 47 components(such as valeraldehyde, dihydrovalerin, valerate, chlorovaltrate K, 8-hydroxypinoresinol, 6-hydroxyluteolin, apigenin, farnesin, vanillin, luteolin, kaempferol, glycosmisic acid and pogostemon) of Valerianae Jatamansi Rhizoma et Radix may act on 94 key targets such as CNR1, MAOA, NR3 C1, MAPK14, MAPK8, HTR2 C and DRD2. Totally 29 GO terms were obtained by GO functional enrichment analysis(P<0.05), and 20 signaling pathways were obtained from KEGG pathway enrichment, mainly involving neuroactive ligand-receptor interaction, serotonergic synapse, calcium signaling pathway, cAMP signaling pathway, dopaminergic synapse, retrograde endocannabinoid signaling, neurotrophin signaling pathway, gap junction, cholinergic synapse, estrogen signaling pathway, glutamatergic synapse and long-term potentiation. Molecular docking analysis showed that hydrogen bonding, π-π interaction and hydrophobic effecting may be the main forms of interaction. This study used the network of compound-target-pathway and molecular docking technology to screen the effective components of Valerianae Jatamansi Rhizoma et Radix against PTSD, and explore its anti-PTSD mechanism, so as to provide scientific basis for exploring the anti-PTSD drugs from traditional Chinese medicine and clarifying its mechanism of action.
Drugs, Chinese Herbal ; Medicine, Chinese Traditional ; Molecular Docking Simulation ; Rhizome ; Stress Disorders, Post-Traumatic/drug therapy*

"Timely, near, and expectation" is the main principle of battlefield rescue for military combat stress reaction (CSR). Post-traumatic stress disorder (PTSD) is the most common form of CSR and a long-term persistent mental disorder that is caused by unusual threatening or catastrophic psychological trauma. Chinese medicine (CM) has abundant resources, is simple, easy to master, with few side effects. This article summarizes the cellular and animal experimental mechanisms of CM treatment on PTSD, suggesting that traditional Chinese herbs and acupuncture can protect brain functional areas, and adjust hypothalamus-pituitary-adrenal axis. Traditional Chinese herbs and acupuncture have shown good anti-stress efficacy and fewer side effects in clinical application, which may improve the CSR in the battlefield.
Animals ; Humans ; Hypothalamo-Hypophyseal System ; Medicine, Chinese Traditional ; Military Personnel ; Pituitary-Adrenal System ; Stress Disorders, Post-Traumatic/therapy*

Intermittent hypoxia (IH) has preventive and therapeutic effects on hypertension, myocardial infarction, cerebral ischemia and depression, but its effect on post-traumatic stress disorder (PTSD) has not been known. In this study, we used inescapable electric foot shock combined with context recapture to build PTSD mouse model. The levels of fear and anxiety were valued by the open field, the elevated plus maze (EPM) and the fear conditioning tests; the level of spatial memory was valued by Y maze test; the number of Fos positive neurons in hippocampus, amygdala and medial prefrontal cortex was valued by immunohistochemical staining; and the protein expressions of hypoxia inducible factor-1α (HIF-1α), vascular endothelial growth factor (VEGF) and brain derived neurotrophic factor (BDNF) in these brain area were valued by Western blot. The results showed that IH and model (foot shock) had an interaction on percentage of entering open arms (OE%) in EPM and freezing time and the number of fecal pellets in fear conditioning test. IH increased OE% in EPM and reduced the freezing time and the number of fecal pellets in fear conditioning test in PTSD model mice. At the same time, IH reduced the number of Fos positive neurons in the hippocampus, amygdala and medial prefrontal cortex of PTSD model mice, and increased the protein expression levels of HIF-1α, VEGF and BDNF in these brain tissues. In conclusion, IH pretreatment can relieve fear and anxiety behavior in post-traumatic stress model mice, suggesting that IH may be an effective means of preventing PTSD.
Animals ; Anxiety ; therapy ; Brain-Derived Neurotrophic Factor ; metabolism ; Fear ; Hypoxia ; Hypoxia-Inducible Factor 1, alpha Subunit ; metabolism ; Mice ; Stress Disorders, Post-Traumatic ; therapy ; Vascular Endothelial Growth Factor A ; metabolism

This study examined the add-on efficacy of eye movement desensitization and reprocessing (EMDR) therapy among adult civilians with post-traumatic stress disorder (PTSD) who continued to be symptomatic after more than 12 weeks of initial antidepressant treatment. Scores for the Clinician Administered PTSD Scale (CAPS) were rated pre- and post-EMDR and at a 6-month follow-up. After an average of six sessions of EMDR treatment, seven of 14 patients (50%) showed more than a 30% decrease in CAPS score and eight (57%) no longer met the criteria for PTSD. Our results indicate that EMDR could be successfully added after failure of initial pharmacotherapy for PTSD.
Adult* ; Antidepressive Agents ; Drug Therapy* ; Eye Movement Desensitization Reprocessing ; Eye Movements* ; Follow-Up Studies ; Humans ; Stress Disorders, Post-Traumatic*

Each year many people are exposed to life-threatening disaster and traumatic events that put them at risk for trauma- and stressor-related disorders such as posttraumatic stress disorder. This report reviews research on the psychosocial interventions currently employed for the prevention and treatment of trauma- and stressor-related disorders. Cognitive behavioral therapy, including cognitive therapy and prolonged exposure, has been shown to improve several outcomes. Considerable progress has also been made in the use of eye movement desensitization and reprocessing. Trauma- and stressor-related disorders are associated with complex outcomes and multiple comorbid emotional, social, and physical health difficulties. Further advances are required in the intervention for populations with complex and chronic forms and in the development of integrated and well-related systems of care.
Adult* ; Cognitive Therapy ; Disasters ; Eye Movements ; Humans ; Stress Disorders, Post-Traumatic