Yunchun Chen

Ginsenoside Rd attenuates mitochondrial dysfunction and sequential apoptosis after transient focal ischemia

We previously found that ginsenoside Rd (Rd), one of the major active ingredients in Panax ginseng, protects neuronal cells from hydrogen peroxide and oxygen-glucose deprivation, an in vitro model of cerebral ischemia. In this study, we examined the protective effects of Rd in an animal model of focal cerebral ischemia. Rats administered with Rd or vehicle were subjected to transient middle cerebral artery occlusion (MCAO). Rd (50 mg/kg) significantly reduced the infarct volume by 52.8%. This reduction of injury volume was associated with an improvement in neurological function and was sustained for at least 2 weeks after the induction of ischemia. To evaluate the underlying mechanisms of Rd against stroke, brain tissues were assayed for mitochondrial enzyme activities, mitochondrial membrane potential (MMP), production of reactive oxygen species (ROS), energy metabolites, and apoptosis. Rd markedly protected mitochondria as indicated by preserved respiratory chain complex activities and aconitase activity, lowered mitochondrial hydrogen peroxide production, and hyperpolarized MMP. Microdialysis results illustrated that Rd significantly decreased the accumulation of lactate, the end product of anaerobic glycolysis, and increased pyruvate, the end product of aerobic glycolysis, hence inducing a lower lactate/pyruvate ratio. Additionally, in vitro studies further exhibited that Rd protected isolated mitochondria from calcium-induced damage by attenuating mitochondrial swelling, preserving MMP and decreasing ROS production. Moreover, Rd treatment reduced mitochondrial release of cytochrome c (CytoC) and apoptosis-inducing factor (AIF), thereby minimizing mitochondria-mediated apoptosis following ischemia. In conclusion, these findings demonstrated that Rd exerts neuroprotective effects in transient focal ischemia, which may involve an integrated process of the mitochondrial protection, energy restoration and inhibition of apoptosis.

Different regional gray matter loss in recent onset PTSD and non PTSD after a single prolonged trauma exposure

Objective Gray matter loss in the limbic structures was found in recent onset post traumatic stress disorder (PTSD) patients. In the present study, we measured regional gray matter volume in trauma survivors to verify the hypothesis that stress may cause different regional gray matter loss in trauma survivors with and without recent onset PTSD. Method High resolution T1-weighted magnetic resonance imaging (MRI) were obtained from coal mine flood disaster survivors with (n = 10) and without (n = 10) recent onset PTSD and 20 no trauma exposed normal controls. The voxel-based morphometry (VBM) method was used to measure the regional gray matter volume in three groups, the correlations of PTSD symptom severities with the gray matter volume in trauma survivors were also analyzed by multiple regression. Results Compared with normal controls, recent onset PTSD patients had smaller gray matter volume in left dorsal anterior cingulate cortex (ACC), and non PTSD subjects had smaller gray matter volume in the right pulvinar and left pallidum. The gray matter volume of the trauma survivors correlated negatively with CAPS scores in the right frontal lobe, left anterior and middle cingulate cortex, bilateral cuneus cortex, right middle occipital lobe, while in the recent onset PTSD, the gray matter volume correlated negatively with CAPS scores in bilateral superior medial frontal lobe and right ACC. Conclusion The present study identified gray matter loss in different regions in recent onset PTSD and non PTSD after a single prolonged trauma exposure. The gray matter volume of left dorsal ACC associated with the development of PTSD, while the gray matter volume of right pulvinar and left pallidum associated with the response to the severe stress. The atrophy of the frontal and limbic cortices predicts the symptom severities of the PTSD.

Free and Easy Wanderer Plus (FEWP), a polyherbal preparation, ameliorates PTSD-like behavior and cognitive impairments in stressed rats

Free and Easy Wanderer Plus (FEWP) is a well-known traditional Chinese medicine that has been shown to be effective in treating various mood disorders. The purpose of the present study was to determine whether FEWP could ameliorate stress-associated behavior in rats. Following the exposure to enhanced single prolonged stress (ESPS) paradigm, consisting of 2-hr constraint, 20-min forced swimming, ether-induced loss of consciousness, and an electric foot shock, animals were administered orally with FEWP (2.5, 5, or 10mg/kg daily) or vehicle for 2 weeks. Animals were then tested in the open field, elevated plus-maze, and Morris water maze. ESPS exposure resulted in pronounced anxiety-like behavior, without impairing locomotor activity, as indicated by significant decreases of time spent and number of entries into open arms in the elevated plus-maze test, and unaltered distance traveled in the open field test compared to unexposed animals. ESPS-exposed animals also displayed marked cognitive impairments, with significant increases of distance traveled and the escape latency to the underwater platform, and a striking decrease of time spent in the target quadrant with and without the removal of the platform in the water maze test. However, repeated treatment with FEWP, particularly at higher doses, reversed the aforementioned behavioral values in the elevated plus-maze and water maze tests to the levels similar to unexposed animals. These results indicate that FEWP possesses anxiolytic and cognition-improving effects and may be an effective herbal preparation for the treatment of stress-associated conditions, such as posttraumatic stress disorder (PTSD).

Evidence of a dissociation pattern in default mode subnetwork functional connectivity in schizophrenia

The default mode network (DMN) is suggested to play a pivotal role in schizophrenia; however, the dissociation pattern of functional connectivity of DMN subsystems remains uncharacterized in this disease. In this study, resting-state fMRI data were acquired from 55 schizophrenic patients and 53 matched healthy controls. DMN connectivity was estimated from time courses of independent components. The lateral DMN exhibited decreased connectivity with the unimodal sensorimotor cortex but increased connectivity with the heteromodal association areas in schizophrenics. The increased connectivity between the lateral DMN and right control network was significantly correlated with negative and anergia factor scores in the schizophrenic patients. The anterior and posterior DMNs exhibited increased and decreased connectivity with the right control and lateral visual networks, respectively, in schizophrenics. The altered DMN connectivity may underlie the hallucinations, delusions, thought disturbances, and negative symptoms involved in schizophrenia. Furthermore, DMN connectivity patterns could be used to differentiate patients from controls with 76.9% accuracy. These findings may shed new light on the distinct role of DMN subsystems in schizophrenia, thereby furthering our understanding of the pathophysiology of schizophrenia. Elucidating key disease-related DMN subsystems is critical for identifying treatment targets and aiding in the clinical diagnosis and development of treatment strategies.

Differential effects of classical and atypical antipsychotic drugs on rotenone-induced neurotoxicity in PC12 cells

Although classical and atypical antipsychotics may have different effects against neurotoxicity, the underlying mechanisms remain to be elucidated. In the present study, we compared the atypical agents, risperidone (RIP), olanzapine (OLZ), and quetiapine (QTP), with the classical agent haloperidol (HAL) in reducing cytotoxicity induced by rotenone, a mitochondrial complex I inhibitor, in PC12 cells. We also determined whether there were differential effects of RIP and HAL on the expression of brain-derived neurotrophic factor (BDNF), signal transducers and activators of transcription-3 (STAT-3), and the immediate early gene c-fos, as well as intracellular levels of calcium. Exposure to 6 muM rotenone for 24 h resulted in a significant decrease in cell viability and apoptotic alteration. The rotenone-induced cytotoxicity was dose-dependently worsened by pretreatment with HAL, but significantly improved by the aforementioned atypical agents at low doses. Real-time PCR analysis revealed that HAL pretreatment significantly increased BDNF mRNA expression but did not alter c-fos and STAT-3 expression compared to rotenone-exposed cells. Unlike HAL, RIP pretreatment produced a significant elevation of all the three substance mRNA expression and the expression intensity was 2.6- to 4.6-fold greater than HAL. Pretreatment with RIP, but not HAL, also effectively prevented an elevation of intracellular levels of calcium provoked by rotenone. These results suggest that the protective effects of atypical antipsychotics are associated with a greater capacity to enhance pro-cell survival factors, therapeutic biomarker expression, and blockade of calcium influx. This may provide an alternative for explaining therapeutic advantages of atypical agents observed in clinical use.

Citalopram alleviates chronic stress induced depression-like behaviors in rats by activating GSK3β signaling in dorsal hippocampus

Aside from monoamine disturbances, recent evidence has implicated particular intracellular pathways, including Wnt signaling, in the pathogenesis of major depressive disorder. In the present study, we investigated the role of Wingless (Wnt)-Dishevelled (DVL)-glycogen synthase kinase 3β (GSK3β) signaling in the depression-like behaviors exhibited by rats exposed to chronic forced swim stress. We found that the rats subjected to forced swim stress for 14 consecutive days exhibited obvious depression-like behaviors and showed decreased levels of phosphorylated GSK3β and β-catenin in the hippocampus. Chronic citalopram treatment alleviated the depression-like behaviors and reversed the disruptions of the phosphorylated GSK3β and β-catenin in stressed rats. Furthermore, when the stressed rats with citalopram treatment received bilateral, dorsal hippocampus infusions of a DVL inhibitor, sulindac, the depression-like effects induced by chronic stress reappeared. These findings suggest that the Wnt-DVL-GSK3β signaling in the hippocampus is markedly involved in the pathophysiology of depression induced by chronic stress. The Wnt-DVL-GSK3β pathway may mediate the therapeutic action of citalopram, and the manipulation of DVL could be a target for novel antidepressants.

Anti-depressive mechanism of repetitive transcranial magnetic stimulation in rat: the role of the endocannabinoid system.

Repetitive transcranial magnetic stimulation (rTMS) to treat depression has been thoroughly investigated in recent years. However, the underlying mechanisms are not fully understood. In this study, a chronic unpredictable mild stress (CUMS) paradigm was applied to male Sprague Dawley rats. Then rTMS was performed for 7 consecutive days, and the anti-depressive effects were evaluated by the sucrose preference test (SPT), the forced swimming test (FST), and the open-field test (OFT). Hippocampal cannabinoid type I receptor (CB1) expression was measured, and the expression levels of brain-derived neurotrophic factor (BDNF), Bcl-2, and Bax and the number of bromodeoxyuridine (BrdU)-positive cells were also investigated. These parameters were also observed after the selective CB1 receptor antagonist AM251 was used as a blocking agent. The results showed that CUMS induced a significant decrease in sucrose preference, a significant increase in immobility time in the FST, and a significantly decreased horizontal distance in the OFT. In addition, reduced hippocampal CB1 receptor, BDNF, and Bcl-2/Bax protein expression levels in CUMS rats, as well as decreased cell proliferation were also observed in the dentate gyrus. Meanwhile, rTMS treatment up-regulated cell proliferation; elevated CB1 receptor, BDNF, and Bcl-2/Bax expression levels in the hippocampus; and ameliorated depressive-like behaviors. All of these beneficial effects were abolished by AM251. These results indicate that rTMS increases BDNF production and hippocampal cell proliferation to protect against CUMS-induced changes through its effect on CB1 receptors.

Sertraline promotes hippocampus-derived neural stem cells differentiating into neurons but not glia and attenuates LPS-induced cellular damage.

Sertraline is one of the most commonly used antidepressants in clinic. Although it is well accepted that sertraline exerts its action through inhibition of the reuptake of serotonin at presynaptic site in the brain, its effect on the neural stem cells (NSCs) has not been well elucidated. In this study, we utilized NSCs separated from the hippocampus of fetal rat to investigate the effect of sertraline on the proliferation and differentiation of NSCs. The study demonstrated that sertraline had no effect on NSCs proliferation but it significantly promoted NSCs to differentiate into serotoninergic neurons other than glia cells. Furthermore, we found that sertraline protected NSCs against the lipopolysaccharide-induced cellular damage. These data indicate that sertraline can promote neurogenesis and protect the viability of neural stem cells.

Sevoflurane preconditioning-induced neuroprotection is associated with Akt activation via carboxy-terminal modulator protein inhibition

BACKGROUND Sevoflurane preconditioning has a neuroprotective effect, but the underlying mechanism is not fully understood. The aim of the present investigation was to evaluate whether sevoflurane-induced cerebral preconditioning involves inhibition of carboxy-terminal modulator protein (CTMP), an endogenous inhibitor of Akt, in a rat model of focal cerebral ischaemia. METHODS Male Sprague-Dawley rats were exposed to 2.7% sevoflurane for 45 min. One hour later, rats were subjected to 60 min of focal cerebral ischaemia. The phosphoinositide 3-kinase inhibitors wortmannin and LY294002 were administered 10 min before preconditioning. Rats in the lentiviral transduction group received an intracerebroventricular injection of lentiviral vector Ubi-MCS-CTMP 3 days before ischaemia. Neurological deficits and infarct volumes were evaluated 24 h and 7 days after reperfusion. Phosphorylation of Akt, glycogen synthase kinase-3β (GSK3β), and expression of CTMP were determined at 1, 3, 12, and 24 h after reperfusion. Akt activity was measured at 3 h after reperfusion. RESULTS Sevoflurane preconditioning improved neurological score and reduced infarct size at 24 h of reperfusion. Pretreatment with wortmannin or LY294002 attenuated these neuroprotective effects. Expression of CTMP correlated with reduced Akt activity after ischaemia, while sevoflurane preconditioning preserved Akt activity and increased phosphorylation of GSK3β. CTMP over-expression diminished the beneficial effects of sevoflurane preconditioning. CONCLUSIONS Activation of Akt signalling via inhibition of CTMP is involved in the mechanism of neuroprotection provided by sevoflurane preconditioning.

Ziprasidone ameliorates anxiety-like behaviors in a rat model of PTSD and up-regulates neurogenesis in the hippocampus and hippocampus-derived neural stem cells.

Ziprasidone, a widely used atypical antipsychotic drug, has been demonstrated to have therapeutic effects in patients with post-traumatic stress disorder (PTSD), but its underlying mechanisms remain poorly understood. One possible explanation is that the neuroprotective and neurogenetic actions of ziprasidone can attenuate the neuronal apoptosis which occurs in the hippocampus. To test this hypothesis, the present study was designed to assess the effects of ziprasidone treatment on anxiety-like behaviors, hippocampal neurogenesis, and in vivo/in vitro expression of pERK1/2 and Bcl-2 in male Sprague-Dawley rats. The methodology involved 3 different experiments, and the investigations also included the assessment of U0126 interference in ziprasidone treatment. It was found that the in vivo, administration of ziprasidone not only reversed the anxiety-like behaviors in rats that exposed to an enhanced single prolonged stress paradigm, but also restored the proliferation and the protein expression of pERK1/2 and Bcl-2 in the hippocampus of these rats. Also, mild concentrations of ziprasidone promoted the in vitro proliferation of hippocampal-derived neural stem cells (NSCs) and increased the levels of pERK1/2 and Bcl-2 in NSCs. Interestingly, the observed effects of ziprasidone were inhibited by U0126. These data support the use of ziprasidone for the treatment of PTSD and indicate that the changes in the ERK1/2 signaling cascade may play a critical role in the pathophysiology of PTSD and its treatment modalities. Further investigations are needed to elucidate the detailed signal cascades involved in the pathophysiology of stress-related disorders, and confirm the efficacy of ziprasidone in anti-PTSD treatment.