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.

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.

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.

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.

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.

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.

Scutellarin alleviates depression-like behaviors induced by LPS in mice partially through inhibition of astrocyte-mediated neuroinflammation.

Depression is a kind of common mental disorder associated with neuroinflammation, and astrocytes play a vital role in regulating and mediating neuroinflammation in central nervous system. Scutellarin has significant anti-inflammatory and neuroprotective effects. However, whether scutellarin exerts antidepressant effect remains unknown. In present study, it was found that scutellarin suppressed LPS-induced neuroinflammation in the hippocampus and alleviated depression-like behaviors in mice. In addition, scutellarin inhibited LPS-induced elevation of TNFα, IL-1ß, IL-6 and iNOS, and reversed the downregulation of IL-4 and BDNF in astrocytes in vitro. Furthermore, the activated TLR4/NF-κB pathway in LPS-treated astrocytes was suppressed by scutellarin. Collectively, these results suggest that scutellarin ameliorates depression-like behaviors induced by neuroinflammation partially through inhibiting the TLR4/NF-κB pathway in astrocytes.

Activation of microglial G­protein-coupled receptor 30 protects neurons against excitotoxicity through NF-κB/MAPK pathways.

Neuroexcitotoxicity is a common feature in neuronal damage and neurodegenerative diseases. Our previous studies have confirmed that neuronal and astrocytic G­protein-coupled receptor 30 (GPR30) play a key role in neuroprotection in vivo and in vitro. Microglia are considered as immune cells in the central nervous system. However, the role of microglial GPR30 in neuroprotection against neuroexcitotoxicity remained unclear. In this study, MTT, Western blot, immunocytochemical staining, phagocytosis assay and wound healing assay were employed to detect the effect of GPR30 in N9 microglial cells after exposure to glutamate. We found that the treatment of GPR30 specific agonist G1 inhibited glutamate-induced proliferation and activation in N9 microglial cells. G1 inhibited M1 polarization, facilitated M2 polarization, and decreased over-phagocytosis but had no effect on migration ability in microglia. The result of neurons and microglia co-culture showed that the activation of microglial GPR30 protected neurons from excitotoxicity through the NF-κB/MAPK signaling pathways. Our findings suggested a key role of microglial GPR30 in excitatory neuronal damage and neurodegenerative diseases.