Ischemic stroke leads to neuronal damage induced by excitotoxicity, inflammation, and oxidative stress. Astrocytes play diverse roles in stroke and ischemia‐induced inflammation, and autophagy is ...critical for maintaining astrocytic functions. Our previous studies showed that the activation of G protein‐coupled receptor 30 (GPR30), an estrogen membrane receptor, protected neurons from excitotoxicity. However, the role of astrocytic GPR30 in maintaining autophagy and neuroprotection remained unclear. In this study, we found that the neuroprotection induced by G1 (GPR30 agonist) in wild‐type mice after a middle cerebral artery occlusion was completely blocked in GPR30 conventional knockout (KO) mice but partially attenuated in astrocytic or neuronal GPR30 KO mice. In cultured primary astrocytes, glutamate exposure induced astrocyte proliferation and decreased astrocyte autophagy by activating mammalian target of rapamycin (mTOR) and c‐Jun N‐terminal kinase (JNK) and inhibiting p38 mitogen‐activated protein kinase (MAPK) pathway. G1 treatment restored autophagy to its basal level by regulating the p38 pathway but not the mTOR and JNK signaling pathways. Our findings revealed a key role of GPR30 in neuroprotection via the regulation of astrocyte autophagy and support astrocytic GPR30 as a potential drug target against ischemic brain damage.
Main Points
Astrocytic GPR30 was involved in the neuroprotection.
Autophagic deficiency of astrocytes induced by glutamate promoted inflammatory cytokine release.
GPR30 activation restored autophagy balance in astrocytes by regulating the p38 MAPK pathway.
Cortical areas including the anterior cingulate cortex (ACC) play critical roles in different types of chronic pain. Most of previous studies focus on the sensory inputs from somatic areas, and less ...information about plastic changes in the cortex for visceral pain. In this study, chronic visceral pain animal model was established by injection with zymosan into the colon of adult male C57/BL6 mice. Whole cell patch‐clamp recording, behavioral tests, western blot, and Cannulation and ACC microinjection were employed to explore the role of adenylyl cyclase 1 (AC1) in the ACC of C57/BL6 and AC1 knock out mice. Integrative approaches were used to investigate possible changes of neuronal AC1 in the ACC after the injury. We found that AC1, a key enzyme for pain‐related cortical plasticity, was significantly increased in the ACC in an animal model of irritable bowel syndrome. Inhibiting AC1 activity by a selective AC1 inhibitor NB001 significantly reduced the up‐regulation of AC1 protein in the ACC. Furthermore, we found that AC1 is required for NMDA GluN2B receptor up‐regulation and increases of NMDA receptor‐mediated currents. These results suggest that AC1 may form a positive regulation in the cortex during chronic visceral pain. Our findings demonstrate that the up‐regulation of AC1 protein in the cortex may underlie the pathology of chronic visceral pain; and inhibiting AC1 activity may be beneficial for the treatment of visceral pain.
Anterior cingulate cortex (ACC) plays critical roles in different types of chronic pain. Calcium‐stimulated, neuronal selective adenylyl cyclase subtype 1 (AC1) is critical for injury‐triggered cortical plasticity and chronic pain. We demonstrate that AC1 protein was up‐regulated in the ACC for a long‐period of time in a mouse model of chronic visceral pain. AC1 activity is required for the up‐regulation of AC1 protein, suggesting that AC1 may form a positive feedback in the cortex during chronic visceral pain. This is the first time to demonstrate that AC1 protein can undergo long‐term increases in central neurons after peripheral injuries.
•Chronic minocycline treatment reduces the anxiety-like behaviors induced by repeated restraint stress in mice.•Minocycline inhibites the microglia activation, and decreases the levels of IL-6 and ...TNF-α in the amygdala.•PPAR-γ/NF-κB pathway in the amygdala is involved in the modulation of the anxiolytic effects of minocycline.•Minocycline may exert the anxiolytic effects through modulating neuroinflammation.
Anxiety disorders are chronic, disabling conditions across the world, and bring a great burden to individuals and society. Although advances have been made in understanding of the pathophysiology of these diseases, no mechanistically new drugs for anxiety disorders have reached the market in the past two decades. Some evidence indicates that stress increases neuroinflammatory signaling, which is related to the development of anxiety and depression. Minocycline, a broad-spectrum tetracycline-antibiotic, has been reported to suppress microglia activation-mediated brain endogenous inflammation. However, it is still unknown whether minocycline can be developed to treat stress-induced anxiety disorders and what is the underlying mechanisms. We chose the anxiety model induced by repeated stress consisting of 2 h of restraint on each of 7 consecutive days. The behavioral test results showed that chronic minocycline treatment, not acute minocycline treatment, increased the time spent in the center area in the open field test and the number of open arm entries and time spent in open arms in the elevated plus maze test, which were comparable with the effect of buspirone. Further mechanism studies demonstrated that chronic minocycline treatment inhibited the microglia activation and decreased the levels of interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-α). In addition, peroxisome proliferator-activated receptor gamma/ nuclear factor kappa B (PPAR-γ/NF-κB) signaling pathway was also modulated by chronic minocycline treatment. In conclusion, our findings support the hypothesis that immune dysregulation plays an important role in stress-induced anxiety disorders, and minocycline can be developed to be used in these diseases.
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.
Neutrophil infiltration has been linked to worse clinical outcomes after ischemic stroke. Microglia, a key type of immune-competent cell, engage in cross-talk with the infiltrating immune cells in ...the inflamed brain area, yet the molecular mechanisms involved remain largely unexplored. In this study, we investigated the mechanisms of how canonical transient receptor potential 1 (TRPC1) modulated neutrophil infiltration in male mouse cerebral ischemia and reperfusion injury (CIRI) models. Our findings revealed a notable upregulation of TRPC1 in microglia within both middle cerebral artery occlusion reperfusion (MCAO/R) and in vitro oxygen-glucose deprivation/regeneration (OGD/R) model. Conditional Trpc1 knockdown in microglia markedly reduced infarct volumes and alleviated neurological deficits. Microglia conditional Trpc1 knockdown mice displayed less neutrophil infiltration in peri-infarct area. Trpc1 knockdown microglia exhibited a reduced primed proinflammatory phenotype with less secretion of CC-Chemokines ligand (CCL) 5 and CCL2 after MCAO/R. Blocking CCL5/2 significantly mitigated neutrophil infiltration in microglia/neutrophil transwell co-culture system upon OGD/R condition. Trpc1 knockdown markedly reduced store-operated calcium entry and nuclear factor of activated T-cells c1 (NFATc1) level in OGD/R treated microglia. Overexpression of Nfatc1 reversed the CCL5/2 reducing effect of Trpc1 knockdown, which is mediated by small interfering RNA in BV2 cells upon OGD/R. Our data indicate that upregulation of TRPC1 in microglia stimulates the production of CCL5/2 through the Ca2+/NFATc1 pathway. Upregulated CCL5/2 leads to an increase in neutrophil infiltration into the brain, thereby aggravating reperfusion injury. Our results demonstrate the importance of TRPC1 in microglia-mediated neuroinflammation and suggest a potential means for reducing CIRI induced neurological injury.
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•TRPC1 is upregulated in microglia after MCAO/R.•Knockdown of microglia Trpc1 ameliorates brain injury caused by MCAO/R.•Knockdown of microglia Trpc1 reduces neutrophil infiltration after MCAO/R.•Microglia TRPC1 promotes neutrophil infiltration through upregulating CCL2 and CCL5.•TRPC1 regulates CCL2 and CCL5 expression in microglia through Ca2+/CaN/NFATc1 pathway.
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.
•As a mediator between exercise and physical health, irisin plays a neuroprotective role.•Irisin can increase the expression of BDNF and improve cognitive function.•Irisin participates in neurogenesis and promotes neuronal differentiation.•Irisin regulates energy metabolism, oxidative stress, neuroinflammation, and telomere length.•Irisin-induced autophagy is a potential therapeutic target for neurodegenerative diseases.
Chronic pain is commonly accompanied with anxiety disorder, which complicates treatment. In this study, we investigated the analgesic and anxiolytic effects of Formononetin (FMNT), an active ...component of traditional Chinese medicine red clover (Trifolium pratense L.) that is capable of protecting neurons from N-methyl-D-aspartate (NMDA)-evoked excitotoxic injury, on mice suffering from complete Freund's adjuvant (CFA)-induced chronic inflammatory pain. The results show that FMNT administration significantly reduces anxiety-like behavior but does not affect the nociceptive threshold in CFA-injected mice. The treatment reverses the upregulation of NMDA, GluA1, and GABA
receptors, as well as PSD95 and CREB in the basolateral amygdala (BLA). The effects of FMNT on NMDA receptors and CREB binding protein (CBP) were further confirmed by the potential structure combination between these compounds, which was analyzed by in silico docking technology. FMNT also inhibits the activation of the NF-κB signaling pathway and microglia in the BLA of mice suffering from chronic inflammatory pain. Therefore, the anxiolytic effects of FMNT are partially due to the attenuation of inflammation and neuronal hyperexcitability through the inhibition of NMDA receptor and CBP in the BLA.
Background
Chronic pain is frequently comorbid with anxiety disorder, thereby complicating its treatment. Polydatin, a component from the root of Polygonum cuspidatum, has shown neuroprotection in ...the central nervous system. However, its effects on pain and anxiety processing have been rarely investigated. In this study, mice were injected with complete Freund’s adjuvant (CFA) at the hindpaw to induce pain- and anxiety-like behaviors.
Results
Treatment with polydatin (25 mg/kg) alleviated the anxiety-like behaviors but not pain perception in these mice. Polydatin treatment reversed the upregulation of N-methyl-D-aspartic acid receptors and GluA1-containing α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptors in the amygdala of CFA-injected mice. Additionally, this treatment reduced the levels of proinflammatory cytokines, namely, tumor necrosis factor-alpha and interleukin-1β, in the amygdala. Furthermore, activated nuclear factor kappa-B signaling was blocked in the amygdala from CFA-injected mice. By using docking technology, we found potential structural binding between polydatin and IκB kinase beta.
Conclusion
This study indicates the anxiolytic effects of polydatin by suppressing inflammatory cytokines in the amygdala.
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 17β-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.
•Estrogen fails to rescue cognitive flexibility in long-term estrogen-deprived female mice.•CNRIP1 protein is increased in long-term estrogen-deprived female mice compared with short-term group.•Disrupting CNRIP1 rescues cognitive flexibility long-term estrogen-deprived female mice after estrogen treatment.
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