Tanshinone IIA improves contextual fear- and anxiety-like behaviors in mice via the CREB/BDNF/TrkB signaling pathway.

Posttraumatic stress disorder (PTSD) is one of the most common psychiatric diseases, which is characterized by the typical symptoms such as re-experience, avoidance, and hyperarousal. However, there are few drugs for PTSD treatment. In this study, conditioned fear and single-prolonged stress were employed to establish PTSD mouse model, and we investigated the effects of Tanshinone IIA (TanIIA), a natural product isolated from traditional Chinese herbal Salvia miltiorrhiza, as well as the underlying mechanisms in mice. The results showed that the double stress exposure induced obvious PTSD-like symptoms, and TanIIA administration significantly decreased freezing time in contextual fear test and relieved anxiety-like behavior in open field and elevated plus maze tests. Moreover, TanIIA increased the spine density and upregulated synaptic plasticity-related proteins as well as activated CREB/BDNF/TrkB signaling pathway in the hippocampus. Blockage of CREB remarkably abolished the effects of TanIIA in PTSD model mice and reversed the upregulations of p-CREB, BDNF, TrkB, and synaptic plasticity-related protein induced by TanIIA. The molecular docking simulation indicated that TanIIA could interact with the CREB-binding protein. These findings indicate that TanIIA ameliorates PTSD-like behaviors in mice by activating the CREB/BDNF/TrkB pathway, which provides a basis for PTSD treatment.

Paeonol ameliorates CFA-induced inflammatory pain by inhibiting HMGB1/TLR4/NF-κB p65 pathway.

The enhanced release of inflammatory cytokines mediated by high mobility group box1 (HMGB1) leads to pain sensation, and has been implicated in the etiology of inflammatory pain. Paeonol (PAE), a major active phenolic component in Cortex Moutan, provides neuroprotective efficacy via exerting anti-inflammatory effect. However, the role and mechanism of PAE in inflammatory pain remain to be fully clarified. In this study, we showed that PAE treatment significantly ameliorated mechanical and thermal hyperalgesia of mice induced by complete Freund's adjuvant (CFA). The analgesic effect of PAE administration was associated with suppressing the enhanced expression of HMGB1 as well as the downstream signaling molecules including toll-like receptor 4 (TLR4), the nuclear NF-κB p65, TNF-α and IL-1ß after CFA insult in the anterior cingulate cortex (ACC), a key brain region responsible for pain processing. Furthermore, inhibition of HMGB1 activity by glycyrrhizin (GLY), an HMGB1 inhibitor, alleviated CFA-induced pain and also facilitated PAE-mediated analgesic effect in mice along with the decreased expression of TLR4, NF-κB p65, TNF-α and IL-1ß upon CFA injury. Collectively, we showed PAE exerted analgesic effect through inhibiting the HMGB1/TLR4/NF-κB p65 pathway and subsequent generation of cytokines TNF-α and IL-1ß in the ACC.

FMRP acts as a key messenger for visceral pain modulation.

Visceral pain is a common clinical symptom, which is caused by mechanical stretch, spasm, ischemia and inflammation. Fragile X syndrome (FXS) with lack of fragile X mental retardation protein (FMRP) protein is an inherited disorder that is characterized by moderate or severe intellectual and developmental disabilities. Previous studies reported that FXS patients have self-injurious behavior, which may be associated with deficits in nociceptive sensitization. However, the role of FMRP in visceral pain is still unclear. In this study, the FMR1 knock out (KO) mice and SH-SY5Y cell line were employed to demonstrate the role of FMRP in the regulation of visceral pain. The data showed that FMR1 KO mice were insensitive to zymosan treatment. Recording in the anterior cingulate cortex (ACC), a structure involved in pain process, showed less presynaptic glutamate release and postsynaptic responses in the FMR1 KO mice as compared to the wild type (WT) mice after zymosan injection. Zymosan treatment caused enhancements of adenylyl cyclase 1 (AC1), a pain-related enzyme, and NMDA GluN2B receptor in the ACC. However, these up-regulations were attenuated in the ACC of FMR1 KO mice. Last, we found that zymosan treatment led to increase of FMRP levels in the ACC. These results were further confirmed in SH-SY5Y cells in vitro. Our findings demonstrate that FMRP is required for NMDA GluN2B and AC1 upregulation, and GluN2B/AC1/FMRP forms a positive feedback loop to modulate visceral pain.

Estrogen-like neuroprotection of isopsoralen against spinal cord injury through estrogen receptor ERα.

Isopsoralen is a type of furocoumarin that exhibits estrogen-like activities. The aim of this study was to determine the estrogen-like neuroprotection of isopsoralen in an animal model of spinal cord injury (SCI). Results indicated that isopsoralen (intraperitoneal injection of 5 and 10 mg/kg per day for two weeks) significantly enhanced the hindlimb locomotor functions of mice with SCI, as revealed in the BMS score and angle of inclined plane tests. Morphological data showed that isopsoralen significantly attenuated the injury of the gray matter of spinal cord and induced the up-regulation of ERα levels. The neuroprotective effects of isopsolaren were blocked by the ERα antagonist MPP (0.3 mg/kg), but not by the ERß receptor antagonist PHTPP (0.3 mg/kg). Isopsolaren treatment increased phosphorylated PI3K and AKT (P-PI3K and P-AKT) in the spinal cord of SCI mice and showed a significant anti-apoptotic activity. These results suggest that isopsoralen performs estrogen-like neuroprotection against SCI-induced apoptosis by activating ERα and regulating the PI3K/AKT pathway.

Anxiolytic effects of sesamin in mice with chronic inflammatory pain.

OBJECTIVE: Sesamin is known for its role in antioxidant, antiproliferative, antihypertensive, and neuroprotective activities. However, little is known about the role of sesamin in the development of emotional disorders. Here we investigated persistent inflammatory pain hypersensitivity and anxiety-like behaviors in the mouse suffering chronic pain. METHODS: Chronic inflammatory pain was induced by hind paw injection of complete Freund's adjuvant (CFA). Levels of protein were detected by Western blot. RESULTS: Administration of sesamin could induce anxiolytic activities but had no effect on analgesia. In the basolateral amygdala, a structure involving the anxiety development, sesamin attenuated the up-regulation of NR2B-containing N-methyl-d-aspartate receptors, GluR1 subunit of the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor as well as phosphorylation of GluR1 at Ser831 (p-GluR1-Ser831), and Ca(2+)/calmodulin-dependent protein kinase II (CaMKII-alpha) in the hind paw CFA-injected mice. In the same model, we found that the sesamin blocked the down-regulation of gamma-aminobutyric acid A (GABAA-alpha-2) receptors. CONCLUSION: Our findings show that sesamin reduces anxiety-like behaviors induced by chronic pain at least partially through regulating the GABAergic and glutamatergic transmission in the amygdala of mice.

A novel translocator protein 18 kDa ligand, ZBD-2, exerts neuroprotective effects against acute spinal cord injury.

Traumatic spinal cord injury (SCI) happens accidently and often leads to motor dysfunction due to a series of biochemical and pathological events and damage, either temporarily or permanently. Translocator protein 18 (TSPO) has been found to be involved in the synthesis of endogenous neurosteroids which have multiple effects on neurons, but the internal mechanisms are not clear. N-benzyl-N-ethyl-2-(7,8-oxo-2-phenyl-9H-purin-9-yl) acetamide (ZBD-2), a newly reported ligand of TSPO, shows some neuroprotective effect against focal cerebral ischemia in vivo and NMDA-induced neurotoxicity in vitro. The present study aims to examine the role of ZBD-2 in SCI mice and elucidate the underlying molecular mechanisms. The SCI model was established by crushing spinal cord. ZBD-2 (10 mg/kg) significantly enhanced the hindlimb locomotor functions after SCI and decreased the tissue damage and conserved the white matter of the spinal cord. High-dose ZBD-2 alleviated the oxidative stress induced by SCI and regulated the imbalance between NR2B-containing NMDA and GABA receptors by increasing the levels of GAD67 in the spinal cord of SCI mice. Additionally, ZBD-2 (10 mg/kg) increased phosphorylated Akt (p-Akt) and decreased the ratio of Bax/Bcl-2. These results demonstrate that ZBD-2 performs neuroprotection against SCI through regulating the synaptic transmission and the PI3K/AKT signaling pathway.

Anxiolytic-like effects of translocator protein (TSPO) ligand ZBD-2 in an animal model of chronic pain.

The activation of Translocator protein (18 kDa) (TSPO) has been demonstrated to mediate rapid anxiolytic efficacy in stress response and stress-related disorders. This protein is involved in the synthesis of endogenous neurosteroids that promote γ-aminobutyric acid (GABA)-mediated neurotransmission in the central neural system. However, little is known about the functions and the underlying mechanisms of TSPO in chronic pain-induced anxiety-like behaviors. The novel TSPO ligand N-benzyl-N-ethyl-2-(7,8-dihydro-7-benzyl-8-oxo-2-phenyl-9H-purin-9-yl) acetamide (ZBD-2) was used in the present study. We found that ZBD-2 (0.15 or 1.5 mg/kg) significantly attenuated anxiety-like behaviors in mice with chronic inflammatory pain induced by hindpaw injection of complete Freund's adjuvant (CFA). However, the treatment did not alter the nociceptive threshold or inflammation in the hindpaw. Hindpaw injection of CFA induced the upregulation of TSPO, GluR1-containing α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, and NR2B-containing N-methyl-D-aspartate (NMDA) receptors in the basolateral amygdala (BLA). ZBD-2 administration reversed the alterations of the abovementioned proteins in the BLA of the CFA-injected mice. Electrophysiological recording revealed that ZBD-2 could prevent an imbalance between excitatory and inhibitory transmissions in the BLA synapses of CFA-injected mice. Therefore, as the novel ligand of TSPO, ZBD-2 induced anxiolytic effects, but did not affect the nociceptive threshold of mice under chronic pain. The anxiolytic effects of ZBD-2 were related to the regulation of the balance between excitatory and inhibitory transmissions in the BLA.

Neuroprotective effects of a novel translocator protein (18 kDa) ligand, ZBD-2, against focal cerebral ischemia and NMDA-induced neurotoxicity.

Ligands of the translocator protein (18 kDa) (TSPO) have demonstrated rapid anxiolytic efficacy in stress responses and stress-related disorders. This protein is involved in the synthesis of endogenous neurosteroids including pregnenolone, dehydroepiandrosterone, and progesterone. These neurosteroids promote γ-aminobutyric acid-mediated neurotransmission in the central neural system (CNS). A TSPO ligand, N-benzyl-N-ethyl-2-(7,8-dihydro-7-benzyl-8-oxo-2-phenyl-9H-purin-9-yl) acetamide (ZBD-2) was recently synthesized. The purpose of the present study was to investigate the neuroprotective effects of ZBD-2 and. In cultured cortical neurons, treatment with ZBD-2 attenuated excitotoxicity induced by N-methyl-d-aspartate (NMDA) exposure. It significantly decreased the number of apoptotic cells by downregulating GluN2B-containing NMDA receptors (NMDARs), the ratio of Bax/Bcl-2, and levels of pro-caspase-3. Systemic treatment of ZBD-2 provided significant neuroprotection in mice subjected to middle cerebral artery occlusion. These findings provide direct evidence that neuroprotection by ZBD-2 is partially mediated by inhibiting GluN2B-containing NMDA receptor-mediated excitotoxicity.

TOM40 mediates the effect of TSPO on postpartum depression partially through regulating calcium homeostasis in microglia.

AIMS: To assess the effect of the translocator protein 18 kDa (TSPO) on postpartum depression and explore its mechanism. METHODS: Postpartum depression (PPD) mouse model was established, and flow cytometry, immunofluorescence, Western blot analysis, real-time quantitative PCR, adeno-associated virus (AAV), co-immunoprecipitation-mass spectrometry and immunofluorescence co-staining were used to detect the effect of TSPO ligand ZBD-2 on PPD mice. RESULTS: ZBD-2 inhibits the overactivation of microglia in the hippocampus and amygdala of PPD model mice. ZBD-2 not only inhibited the inflammation but also repressed the burst of reactive oxygen species (ROS) and mitochondrial ROS (mtROS). Meanwhile, ZBD-2 protects mitochondria from LPS-induced damages through inhibiting the influx of calcium. ZBD-2 modulated the calcium influx by increasing the level of translocase of the outer mitochondrial membrane 40 (TOM40) and reducing the interaction of TSPO and TOM40. In addition, the effect of ZBD-2 was partially dependent on anti-oxidative process. Knockdown of TOM40 by adeno-associated virus (AAV) in the hippocampus or amygdala dramatically reduced the effect of ZBD-2 on PPD, indicating that TOM40 mediates the effect of ZBD-2 on PPD. CONCLUSIONS: TOM40 is required for the effect of ZBD-2 on treating anxiety and depression in PPD mice. This study reveals the role of microglia TSPO in PPD development and provides the new therapeutic strategy for PPD.

EGR1 Enhances Lymphangiogenesis via SOX18-Mediated Activation of JAK2/STAT3 Pathway.

BACKGROUND: Lymphangiogenesis is a process involved in the pathogenesis of many diseases. Identifying key molecules and pathway targeting this process is critical for lymphatic regeneration-associated disorders. EGR1 is a transcription factor, but its function in lymphangiogenesis is not yet known. This study is aimed at exploring the functional activity and molecular mechanism of EGR1 implicated in lymphangiogenesis. METHODS: The CCK-8 method, transwell migration assay, and tube formation assay were used to detect the cell viability, motility, and tube formation of HDLEC cells, respectively. The luciferase reporter assay was applied to detect the impact of EGR1 on SOX18 promoter activity. CHIP assay was used to analyze the direct binding of EGR1 to the SOX18 promoter. qRT-PCR and Western blot analysis were performed to investigate molecules and pathway involved in lymphangiogenesis. RESULTS: The EGR1 ectopic expression markedly increased the cell growth, mobility, tube formation, and the expression of lymphangiogenesis-associated markers (LYVE-1 and PROX1) in HDLEC cells. EGR1 interacted with the SXO18 gene promoter and transcriptionally regulated the SXO18 expression in HDLEC cells. Silencing of SOX18 abrogated the promotional activities of EGR1 on the cell viability, mobility, tube formation, and LYVE-1/PROX1 expression in HDLEC cells. SOX18 overexpression activated JAK/STAT signaling, which resulted in an increase in lymphangiogenesis in HDLEC cells. CONCLUSIONS: ERG1 can promote lymphangiogenesis, which is mediated by activating the SOX18/JAK/STAT3 cascade. ERG1 may serve as a promising target for the therapy of lymphatic vessel-related disorders.

Extracellular Vesicles Derived From Hypoxia-Conditioned Adipose-Derived Mesenchymal Stem Cells Enhance Lymphangiogenesis.

Extracellular vesicles from adipose-derived mesenchymal stem cells (ADSCs) play an important role in lymphangiogenesis; however, the underlying mechanisms are not fully understood. In this study, we aimed to investigate the function of extracellular vesicles secreted by hypoxia-conditioned ADSCs in lymphangiogenesis and explore the potential molecular mechanisms. Extracellular vesicles were extracted from ADSCs cultured under hypoxia or normoxia conditions. The uptake of extracellular vesicles by lymphatic endothelial cells (LECs) was detected by immunofluorescence staining. The effects of extracellular vesicles on the viability, migration, and tube formation of LECs were determined by CCK-8 assay, migration assay, and tube formation assay, respectively. Molecules and pathway involved in lymphangiogenesis mediated by ADSC-derived extracellular vesicles were analyzed by luciferase reporter assay, qRT-polymerase chain reaction (PCR), and Western blot. Hypoxia ADSC-derived extracellular vesicles (H-ADSC/evs) significantly enhanced the proliferation, migration, and tube formation of LECs. Hypoxia decreased the expression of miR-129 in ADSC-derived extracellular vesicles. Overexpression of miR-129 counteracted the promoting effect of H-ADSC/evs on lymphangiogenesis. In addition, decreased exosomal miR-129 expression resulted in upregulation of HMGB1 in LECs, which led to AKT activation and lymphangiogenesis enhancement. Our data reveal that extracellular vesicles derived from hypoxia-conditioned ADSCs induce lymphangiogenesis, and this effect is mediated by miR-129/HMGB1/AKT signaling. Our findings imply that hypoxia ADSC-isolated extracellular vesicles may represent as a valuable target for the treatment of diseases associated with lymphatic remodeling.

Irisin: A promising treatment for neurodegenerative diseases.

The beneficial effects of exercise on human brain function have been demonstrated in previous studies. Myokines secreted by muscle have attracted increasing attention because of their bridging role between exercise and brain health. Regulated by PPARγ coactivator 1α, fibronectin type III domain-containing protein 5 releases irisin after proteolytic cleavage. Irisin, a type of myokine, is secreted during exercise, which induces white adipose tissue browning and relates to energy metabolism. Recently, irisin has been shown to exert a protective effect on the central nervous system. Irisin secretion triggers an increase in brain-derived neurotrophic factor levels in the hippocampus, contributing to the amelioration of cognition impairments. Irisin also plays an important role in the survival, differentiation, growth, and development of neurons. This review summarizes the role of irisin in neurodegenerative diseases and other neurological disorders. As a novel positive mediator of exercise in the brain, irisin may effectively prevent or decelerate the progress of neurodegenerative diseases in models and also improve cognitive functions. We place emphasis herein on the potential of irisin for prevention rather than treatment in neurodegenerative diseases. In ischemic diseases, irisin can alleviate the pathophysiological processes associated with stroke. Meanwhile, irisin has anxiolytic and antidepressant effects. The potential therapeutic effects of irisin in epilepsy and pain have been initially revealed. Due to the pleiotropic and beneficial properties of irisin, the possibility of irisin treating other neurological diseases could be gradually explored in the future.

Mechanism of CNS regulation by irisin, a multifunctional protein.

Exercise not only builds up our body but also improves cognitive function. Skeletal muscle secretes myokine during exercise as a large reservoir of signaling molecules, which can be considered as a medium between exercise and brain health. Irisin is a circulating myokine derived from the Fibronectin type III domain-containing protein 5 (FNDC5). Irisin regulates energy metabolism because it can stimulate the "Browning" of white adipose tissue. It has been reported that irisin can cross the blood-brain barrier and increase the expression of a brain-derived neurotrophic factor (BDNF) in the hippocampus, which improves learning and memory. In addition, the neuroprotective effect of irisin has been verified in various disease models. Therefore, this review summarizes how irisin plays a neuroprotective role, including its signal pathway and mechanism. In addition, we will briefly discuss the therapeutic potential of irisin for neurological diseases.

Disrupting cannabinoid receptor interacting protein 1 rescues cognitive flexibility in long-term estrogen-deprived female mice.

Hormone therapy (HT) has failed to improve learning and memory in postmenopausal women according to recent clinical studies; however, the reason for failure of HT in improving cognitive performance is unknown. In our research, we found cognitive flexibility was improved by 17ß-Estradiol (E2) in mice 1 week after ovariectomy (OVXST), but not in mice 3 months after ovariectomy (OVXLT). Isobaric tags for relative and absolute quantitation (iTRAQ) revealed increased cannabinoid receptor interacting protein 1 (CNRIP1) in E2-treated OVXLT mice compared with E2-treated OVXST mice. Adeno-associated virus 2/9 (AAV2/9) delivery of Cnrip1 short-hairpin small interfering RNA (Cnrip1-shRNA) rescued the impaired cognitive flexibility in E2 treated OVXLT mice. This effect is dependent on CB1 function, which could be blocked by AM251-a CB1 antagonist. Our results indicated a new method to increasing cognitive flexibility in women receiving HT by disrupting CNRIP1.

Activation of GIPR Exerts Analgesic and Anxiolytic-Like Effects in the Anterior Cingulate Cortex of Mice.

Background: Chronic pain is defined as pain that persists typically for a period of over six months. Chronic pain is often accompanied by an anxiety disorder, and these two tend to exacerbate each other. This can make the treatment of these conditions more difficult. Glucose-dependent insulinotropic polypeptide (GIP) is a member of the incretin hormone family and plays a critical role in glucose metabolism. Previous research has demonstrated the multiple roles of GIP in both physiological and pathological processes. In the central nervous system (CNS), studies of GIP are mainly focused on neurodegenerative diseases; hence, little is known about the functions of GIP in chronic pain and pain-related anxiety disorders. Methods: The chronic inflammatory pain model was established by hind paw injection with complete Freund's adjuvant (CFA) in C57BL/6 mice. GIP receptor (GIPR) agonist (D-Ala2-GIP) and antagonist (Pro3-GIP) were given by intraperitoneal injection or anterior cingulate cortex (ACC) local microinjection. Von Frey filaments and radiant heat were employed to assess the mechanical and thermal hypersensitivity. Anxiety-like behaviors were detected by open field and elevated plus maze tests. The underlying mechanisms in the peripheral nervous system and CNS were explored by GIPR shRNA knockdown in the ACC, enzyme-linked immunosorbent assay, western blot analysis, whole-cell patch-clamp recording, immunofluorescence staining and quantitative real-time PCR. Results: In the present study, we found that hind paw injection with CFA induced pain sensitization and anxiety-like behaviors in mice. The expression of GIPR in the ACC was significantly higher in CFA-injected mice. D-Ala2-GIP administration by intraperitoneal or ACC local microinjection produced analgesic and anxiolytic effects; these were blocked by Pro3-GIP and GIPR shRNA knockdown in the ACC. Activation of GIPR inhibited neuroinflammation and activation of microglia, reversed the upregulation of NMDA and AMPA receptors, and suppressed the enhancement of excitatory neurotransmission in the ACC of model mice. Conclusions: GIPR activation was found to produce analgesic and anxiolytic effects, which were partially due to attenuation of neuroinflammation and inhibition of excitatory transmission in the ACC. GIPR may be a suitable target for treatment of chronic inflammatory pain and pain-related anxiety.

Neuroprotective effects of oestrogen against oxidative toxicity through activation of G-protein-coupled receptor 30 receptor.

1. 17-ß-oestradiol (E2) plays a critical role in neuroprotection through both genomic and non-genomic mechanisms. The aim of the present study was to investigate the role of G-protein-coupled receptor 30 (GPR30), a new kind of oestrogen receptor, in the neuroprotection against oxidative insult. 2. The neuroprotection evoked by GPR30 stimulation was examined in cultured cortical neurons. Hoechst 33258/propidium iodide double staining, flow cytometric analysis and western blotting were applied to assess neuronal apoptosis induced by H(2)O(2) . 3. We found that the GPR30 agonist, G1, and E2 attenuated apoptosis induced by H(2)O(2) exposure. Furthermore, G1 (1 nmol/L) or E2 (1 nmol/L) significantly increased the levels of phosphorylated extracellular signal-regulated kinase 1/2 (p-ERK1/2), Bcl-2 and pro-caspase-3. Pretreatment with ICI182780, a highly selective nuclear oestrogen receptor antagonist that is used to block the classical ERα and ERß receptors, did not totally block the neuroprotective effects of E2 (1 nmol/L) and had no effect on the neuroprotective effects of G1 (1 nmol/L). 4. Our data suggest that GPR30 is involved in the neuroprotection against oxidative insult. The neuroprotection evoked by GPR30 stimulation was associated with the signalling through the ERK1/2 kinase pathway. In addition, the anti-apoptotic activity of GPR30 was dependent on the expression of Bcl-2 and pro-caspase-3. GPR30 might be a potential therapeutic target for neuroprotection and oxidative stress.

Activation of LXRß Signaling in the Amygdala Confers Anxiolytic Effects Through Rebalancing Excitatory and Inhibitory Neurotransmission upon Acute Stress.

The balance of major excitatory (glutamate, Glu) and inhibitory (γ-aminobutyric acid, GABA), named as E/I neurotransmission, is critical for proper information processing. Anxiety-like responses upon stress are accompanied by abnormal alterations in the formation and function of synapses, resulting in the imbalance of E/I neurotransmission in the amygdala. Liver X receptors (LXRs), including LXRα and LXRß isoforms, are nuclear receptors responsible for regulating central nervous system (CNS) functions besides maintaining metabolic homeostasis. However, little is known about the contribution of LXRs in E/I balance in regulating anxiety-related behaviors induced by stress. In this study, we found stress-induced anxiety led to the expression reduction of LXRß not LXRα in mice amygdala. GW3965, a dual agonist for both LXRα and LXRß, alleviated anxiety-like behaviors of stressed mice through activation of LXRß, confirmed by the knockdown of LXRß mediated by lentiviral shRNAs in the basolateral amygdala (BLA). This was paralleled by correcting the disequilibrium of E/I neurotransmission in the stressed BLA. Importantly, GW3965 exerted anxiolytic effects by correcting the promoted amplitude and frequency of miniature excitatory postsynaptic current (mEPSC), and augmenting the decreased that of miniature inhibitory postsynaptic current (mIPSC) in the stressed BLA. This suggests that stress-induced anxiety-like behaviors can largely be ascribed to the deficit of LXRß signaling in E/I neurotransmission in BLA. These findings highlight the deficiency of LXRß signaling in the amygdala linked to anxiety disorder, and LXRß activation may represent a potential novel target for anxiety treatment with an alteration in synaptic transmission in the amygdala.

Antidepressant-like effects of translocator protein (18 kDa) ligand ZBD-2 in mouse models of postpartum depression.

The 18 kDa translocator protein (TSPO) is primarily localized in the outer mitochondrial membrane of steroid-synthesizing cells in the central and peripheral nervous systems. One of the protein's main functions is transporting substrate cholesterol into the mitochondria in a prerequisite process for steroid synthesis. Clinical trials have indicated that TSPO ligands might be valuable in treating some neuropathies and psychopathies. However, limited information is known about the role of TSPO in postpartum depression (PPD). The TSPO ligand ZBD-2, a derivative of XBD173, was synthesized in our laboratory. Behavioral tests, enzyme linked immunosorbent assay, and Western blot were employed to evaluate ZBD-2's efficacy against PPD and to elucidate the potential underlying molecular mechanism. The TSPO levels significantly decreased in the basolateral amygdala of PPD models. After treatment for 2 weeks, ZBD-2 alleviated depression-like behaviors and enhanced the TSPO level in a PPD animal model. The underlying mechanisms of ZBD-2 were related to regulate the hypothalamic-pituitary-adrenal axis, enhance 5-HT and BDNF secretion, and maintain the excitatory and inhibitory synaptic protein expression to normal levels. Our results directly confirm that ZBD-2 exerts a therapeutic effect on PPD, which provides a new target for anti-PPD drug development.

Effect of ZBD-2 on chronic pain, depressive-like behaviors, and recovery of motor function following spinal cord injury in mice.

In addition to debilitating sensory and motor deficits, patients with spinal cord injury (SCI) may experience chronic hyperpathic pain (SCI-pain). Recent studies have revealed that translocator protein (TSPO) is involved in repairing neural cells as well as reducing anxiety and depression. However, the role of TSPO in SCI-pain and pain-induced depression remains unknown. The present study aimed to determine the effects of a new TSPO ligand, ZBD-2, on SCI-pain and consequent pain-induced depressive-like behaviors in mice. Treatment with ZBD-2 at either dose significantly attenuated the symptoms of chronic SCI-pain and pain-induced depressive-like behaviors. ZBD-2 reversed SCI-induced elevation of serum corticosterone levels, an index of hyper-activation of the hypothalamic-pituitary-adrenal (HPA) axis. Additionally, administration of ZBD-2 inhibited decreases in the expression of synaptic plasticity-related signaling proteins, including brain-derived neurotrophic factor (BDNF) and cyclic AMP-responsive element binding protein (CREB). Moreover, ZBD-2 administration reversed chronic, SCI-induced gliocyte activation at the lesion site. Therefore, ZBD-2 may improve chronic SCI-pain and pain-induced depressive-like behaviors via suppression of gliocyte activation and restoration of the synaptic plasticity-related signaling systems.

The neuroprotective effect of praeruptorin C against NMDA-induced apoptosis through down-regulating of GluN2B-containing NMDA receptors.

Praeruptorin C (Pra-C), one of the principal bioactive components derived from the root of Peucedanum praeruptorum Dunn, has been widely used as an antioxidant and a calcium antagonist to treat diseases. The present study investigated the protective effect of Pra-C on cultured cortical neuron injury induced by glutamate. After challenge with 200µM N-methyl-d-aspartate (NMDA) for 30min, loss of cell viability and excessive apoptotic cell death were observed in cultured cortical neurons. Pra-C conferred protective effects against loss of cellular viability in a concentration-dependent manner. Pra-C also significantly inhibited neuronal apoptosis induced by NMDA exposure by reversing intracellular Ca(2+) overload and balancing Bcl-2 and Bax expression. Furthermore, Pra-C significantly reversed the upregulation of GluN2B-containing NMDA receptors by exposure to NMDA but did not affect the expression of GluN2A-containing NMDA receptors. These findings suggest that Pra-C partially protects cortical neurons by inhibiting the expression of GluN2B-containing NMDA receptors and regulating the Bcl-2 family.