Effects and mechanisms of tanshinone IIA on PTSD-like symptoms.

BACKGROUND: In recent years, Salvia miltiorrhiza and its active substances have remarkably progressed in treating central neurological disorders. Tanshinone IIA (TSA) is an active ingredient derived from the rhizome of Salvia miltiorrhiza that has been found to alleviate the symptoms of several psychiatric illnesses. Post-traumatic stress disorder (PTSD) is a mental disorder that results after experiencing a serious physical or psychological injury. The currently used drugs are not satisfactory for the treatment of PTSD. However, it has been reported that TSA can improve PTSD-like symptoms like learning and memory, cognitive disorder, and depression through multi-target regulation. PURPOSE: This paper discusses the ameliorative effects of TSA on PTSD-like symptoms and the possible mechanisms of action in terms of inhibition of neuronal apoptosis, anti-neuroinflammation, and anti-oxidative stress. Based on the pathological changes and clinical observations of PTSD, we hope to provide some reference for the clinical transformation of Chinese medicine in treating PTSD. METHODS: A large number of literatures on tanshinone in the treatment of neurological diseases and PTSD were retrieved from online electronic PubMed and Web of Science databases. CONCLUSION: TSA is a widely studied natural active ingredient against mental illness. This review will contribute to the future development of TSA as a new clinical candidate drug for improving PTSD-like symptoms.

Role of natural products in breast cancer related symptomology: Targeting chronic inflammation.

Breast cancer is the most common cancer in women worldwide. There have been many advancements in the treatment of breast cancer leading to an increased population of patients living with this disease. Accumulating evidence suggests that cancer diagnosis and aftermath experienced stress could not only affect the quality of life of cancer patients, but it could also influence their disease outcome. The magnitude of stress experienced by breast cancer patients is often compared to the post-traumatic stress disorder-like symptoms suggested to be mediated by the chronic inflammation including NF-κB, AKt, p53 and other inflammatory pathways. Here, we describe the symptomology of PTSD-like symptoms in breast cancer patients and argue that they may in fact be caused by or maintained through aspects of chronic inflammation mediated by the pro-inflammatory markers. Evidence exists that natural products that might attenuate or lessen the effects of chronic inflammation abound in the diet. We summarize some possible agents that might abate the genesis of symptoms experienced by breast cancer patients while mitigating the effect of inflammation.

Sex-dependent effects of microglial reduction on impaired fear extinction induced by single prolonged stress.

Single prolonged stress (SPS) is a preclinical rodent model for studying post-traumatic stress disorder (PTSD)-like behaviors. Previously we found that increased expression of the microglial marker Iba-1 in the ventral hippocampus after SPS exposure was associated with impaired fear extinction, suggesting that microglial activity contributed to the SPS-induced behavioral changes. To test this, we examined whether reducing microglia with the colony-stimulating factor 1 receptor blocker, PLX3397, in the diet would prevent the SPS-induced extinction impairment. Male rats exposed to SPS showed enhanced fear acquisition and impaired fear extinction memory. Adding PLX3397 to the diet prevented these behavioral changes. In contrast, PLX3397 did not prevent SPS from impairing fear extinction memory in the female rats. Despite the sex-dependent behavioral effects, we found a reduced number and area fraction of Iba-1+ microglia in both male and female rats suggesting that PLX3397 had similar effects on microglia in both sexes. Altogether, these results suggest that microglia contribute to the behavioral changes induced by SPS in male but not female rats.

Repeated ethanol exposure following avoidance conditioning impairs avoidance extinction and modifies conditioning-associated prefrontal dendritic changes in a mouse model of post-traumatic stress disorder.

Treatment of post-traumatic stress disorder is complicated by the presence of alcohol use disorder comorbidity. Little is known about the underlying brain mechanisms. We have recently shown, in mice, that the post-traumatic stress disorder-like phenotype is characterised by the increase and decrease in total dendritic number and length in the prelimbic and infralimbic areas of the medial prefrontal cortex, respectively. Here, we examined whether repeated ethanol exposure would exacerbate these changes and whether this would be associated with difficulty to extinguish passive avoidance behaviour, as an indicator of treatment resistance. We also analysed whether other known trauma-associated changes, like increased or decreased corticosterone and decreased brain-derived neurotrophic factor levels, would also be exacerbated. Male mice underwent trauma exposure (1.5-mA footshock), followed, 8 days later, by a conditioned place preference training with ethanol. Tests for fear sensitization, passive avoidance, anxiety-like behaviour, extinction acquisition and relapse susceptibility were used to assess behaviour changes. Plasma corticosterone and brain-derived neurotrophic factor levels and prefrontal dendritic changes were subsequently measured. Trauma-susceptible mice exposed to ethanol acquired a strong place preference and behaved differently from those not exposed to ethanol, with delayed avoidance extinction and higher avoidance relapse vulnerability. Ethanol potentiated trauma-associated dendritic changes in the prelimbic area and suppressed trauma-associated dendritic changes in the infralimbic area. However, ethanol had no effect on trauma-induced increased corticosterone and decreased brain-derived neurotrophic factor levels. These data suggest that the modification of prefrontal trauma-related changes, due to alcohol use, can characterise, and probably support, treatment-resistant post-traumatic stress disorder.

Chlorogenic Acid Improves PTSD-like Symptoms and Associated Mechanisms.

Chlorogenic acid (CGA) is a kind of traditional Chinese medicine, abundant in honeysuckle and eucommia, and has a wide range of biological activities, and pharmacological effects. Previous studies have shown that CGA can regulate learning, memory, cognitive ability, coupled with improvement to anxiety, depression, and other post-traumatic stress disorder (PTSD)-like symptoms. This article explores the protective effects of CGA on neurons through its anti-apoptotic effect, inhibition of neuroinflammation and oxidative stress, which may be the mechanisms of its improvement of PTSD-like symptoms. It may provide a new therapeutic strategy for the treatment of PTSD and its comorbidities.

Metabolic syndrome accentuates post-traumatic stress disorder-like symptoms and glial activation.

The relationship between individuals with post-traumatic stress disorder (PTSD) and the development of metabolic syndrome (MS) is well understood, but the relationship between individuals with preexisting MS and the development of PTSD is not yet known. Therefore, we evaluated the course of PTSD development in preexisting MS rats and we quantified the glial fibrillary acidic protein (GFAP) and ionized the calcium binding adaptor molecule 1 (Iba-1) in the cortex and hippocampus of the experimental animals. Male Wistar rats were divided into two groups: control or 10 % fructose for 5 weeks. After 5 weeks of MS induction, a group of animals was used to characterize MS. In another group, after 5 weeks of MS induction, animals were exposed to or not exposed to inescapable footshocks, followed by social isolation. After 14 days of a retention interval, the animals were re-exposed to the inescapable footshocks box, and the freezing time was evaluated. Over the following days, the animals were tested using the open field, social interaction and forced swimming tests, respectively. In another group of animals, after induction of MS and PTSD as previously described, elevated plus maze and object recognition tests were performed. Our results demonstrate that fructose solution for 5 weeks was able to induce MS, and animals with MS had more pronounced PTSD-like symptoms and a greater increase in GFAP and Iba-1 in the hippocampus and prefrontal cortex. In conclusion, MS accentuated PTSD-like symptoms that may be related to increased glial activation. This study helps reveal factors that may predispose individuals to the development of PTSD, such as metabolic disorders.

Susceptibility and Resilience to PTSD-Like Symptoms in Mice Are Associated with Opposite Dendritic Changes in the Prelimbic and Infralimbic Cortices Following Trauma.

Post-traumatic stress disorder (PTSD) is triggered by exposure to traumatic events, but not everyone who experiences trauma develops this disorder. Like humans, PTSD-like symptoms develop in some laboratory rodents (susceptible individuals), while others express less or no symptoms (resilient individuals). Here, considering (i) the putative causal role of fear conditioning in PTSD development and (ii) the involvement of the medial prefrontal cortex (mPFC) in the regulation of conditioned fear response, we tested whether trauma-associated changes in the mPFC may discriminate stress-resilient from stress-susceptible mice. From data on avoidance behavior (as a major symptom), we found that trauma-exposed mice displayed a bimodal distribution in their step-through latency, with low avoider (stress-resilient) individuals and high avoider (stress-susceptible) individuals. Dendrites of Golgi-Cox-stained neurons were analyzed in two parts of the mPFC: the prelimbic (PrL) and infralimbic (IL) areas. In the resilient phenotype, the total number of dendrites decreased in the PrL and increased in the IL; however, it decreased only in the IL in the susceptible phenotype compared to controls. These findings demonstrate that the type of post-trauma morphological changes in the mPFC is associated with susceptibility or resilience to trauma-related symptoms.

Effects of multiple brief exposures to trauma-associated cues on traumatized resilient and vulnerable rats.

Intrusive re-experiencing of a trauma is a core symptom in post-traumatic stress disorder (PTSD), and is often triggered by contextual cues associated with the event. It is not yet established if intrusive re-experiencing is the consequence of PTSD, or if it could contribute to the development of PTSD following a traumatic event. The present study (1) examined the impact of repeated brief re-exposures to trauma reminders on the strength of PTSD-like symptoms, as well as on their time-development and (2) investigated the reactivity over time to these cues in trauma resilient and vulnerable rats, defined on the basis of the PTSD-like symptoms they demonstrated. Rats were exposed to a Single Prolonged Stress, combining three different stresses (2-h restraint, 20-min forced swim and CO2 unconsciousness) delivered together with tone and odor cues and preceded by an inhibitory avoidance conditioning or a control procedure. During the following two weeks, reminded rats were briefly re-exposed to trauma-associated cues either 4 or 8 times. The results indicated that 4 re-exposures to the same cue strengthened PTSD-like symptoms (anxiety, arousal, fear to trauma-cue). However 8 re-exposures to similar or different trauma-cues did not alter PTSD-like symptoms and led to a rapid extinction of the fear reactivity to these cues. The present results further indicated that shortly after trauma, both resilient and vulnerable rats strongly reacted to trauma-associated cues, while only vulnerable rats reacted long after the trauma, suggesting a slower loss of fear responses to trauma cues in these rats. We concluded that re-experiencing may participate in, but cannot be solely responsible for, the development of long-term PTSD effects.

Sensitivity to trauma-associated cues is restricted to vulnerable traumatized rats and reinstated after extinction by yohimbine.

While post-traumatic stress disorder (PTSD) symptom is mainly characterized by re-experiencing the traumatic event, the reactivity to trauma-associated cues in resilient and vulnerable subjects has not been extensively studied. Using an animal model of PTSD induced by a single prolonged stress (SPS), the responses of traumatized Vulnerable and Resilient rats to PTSD-like symptom tests and to trauma-associated cues were investigated. In addition, the implication of the noradrenergic system in "re-experiencing" was explored. Rats received either a SPS, combining a 2h restraint stress, a 20min forced-swim followed by a 15min rest, and a loss of consciousness produced by inhaling CO2 emissions, delivered in the presence of particular cues (tone and odor), or a control procedure. PTSD-like symptoms and reactivity to various trauma-associated cues (specific, contextual, or predictive) were tested from D15 to D60 after the SPS. Rats were then divided into Resilient and Vulnerable on the basis of three main symptom tests, including the elevated plus maze, the light-dark and the acoustic startle response tests. Although Resilient rats behaved like Controls rats, Vulnerable rats developed long-term PTSD-like symptoms on the main symptoms tests (anxiety and alteration of arousal), as well as other PTSD-like outcomes (such as anhedonia and avoidance to trauma-associated cues). These Vulnerable rats were also the only ones to demonstrate strong reactivity to trauma-associated cues. In addition, the alpha-2 adrenergic receptor antagonist, Yohimbine (i.p., 1.5mg/kg/ml), was able to reinstate fear responses to an extinguished trauma-associated odor. Our results established clear relationships between Vulnerability to trauma and reactivity to trauma-associated cues and further suggest an involvement of the noradrenergic system.