Regulating synaptic formation and transmission is critical for the physiology and pathology of psychiatric disorders. The adenosine A2A receptor subtype has attracted widespread attention as a key ...regulator of neuropsychiatric activity, neuroprotection and injury. In this study, we systematically investigated the regulatory effects of a novel A2A receptor agonist, PSB-0777, on the expression of synaptic proteins and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid glutamate receptors (AMPA receptors) at the cellular level in a time- and dose-dependent manner. After 30 min of high-dose PSB-0777 stimulation, the expression of Synapsin-1 (Syn-1), postsynaptic density protein 95 (PSD95), and AMPA receptors and the number of synapses were rapidly and significantly increased in rat primary cortical neurons compared with the control. Sustained elevation was found in the low and medium-dose groups after 24 h and 3 d of treatment. In contrast, after stimulation with PSB-0777 for 3 consecutive days, the expression of Syn-1 was decreased, and PSD95, AMPA receptors and the number of synapses were no longer increased in the high-dose group. Our study focuses on the detailed and systematic regulation of synaptic proteins and AMPA receptors by an A2A receptor agonist, PSB-0777, which may result in both beneficial and detrimental effects on neurotransmission and neuroprotection and may contribute to the pathophysiology of psychiatric disorders related to A2A receptors. These experimental data may contribute to understanding of the mechanisms for neuroprotective and therapeutic effect of A2A receptor agonists.
Fruit juice is a complex mixture, in which polyphenols are active compounds for human health. In this paper, the effects of membrane properties, such as materials and molecular weight cutoff (MWCO), ...on fouling behavior of four typical polyphenols in model fruit juice ultrafiltration process were investigated. Zeta potential, contact angle, SEM image, and fouling resistances were determined. Static adsorption and rejection content of polyphenols on membranes were measured. Quantitative structure-activity relationship (QSAR) model has been developed to demonstrate the relationships between rejection and molecular parameters. Results showed that materials, MWCOs, hydrophobic properties, electrical parameters, and molecular parameters are critical factors. Membranes which were hydrophobic and positively charged have higher permeate flux and lower fouling resistance. Polyphenols were adsorbed by membranes as irreversible fouling and also had an important contribution in cake layer fouling. Retention of polyphenols on polyethersulfon 5-kDa membrane was the largest, while that on PVDF 50-kDa membrane was the least. According to QSAR analysis, rejections of polyphenols were higher when the molecules have smaller dipole moment, larger connectivity index
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•GLP treatment led to a rapid and robust antidepressant effect in the CSDS mice.•GLP attenuated IL-1β and TNF-α, enhanced IL-10 and BDNF expression.•GLP inhibited the activation of microglia and the ...proliferation of astrocytes.•GLP significantly enhanced GluA1 S845 phosphorylation, GluA1, and GluA2 expression.•GLP exerted antidepressant effects on CSDS mice via modulation of Dectin-1.
Major depressive disorder (MDD) is a prevalent, chronic, and recurrent disease. At least one-third of patients have treatment-resistant depression; therefore, there is an urgent need for novel drug development. Cumulative studies have suggested an inflammatory mechanism for the pathophysiology of MDD. Ganoderma lucidum polysaccharides (GLP) is an anti-inflammatory and immunomodulatory agent. Here, we found that an injection of GLP led to a rapid and robust antidepressant effect after 60 min in the tail suspension test. This antidepressant effect remained after 5 days of treatment with GLP in the forced swim test. Unlike psychostimulants, GLP did not show a hyperactive effect in the open field test. After 60 min or 5 days of treatment, GLP exhibited an antidepressant effect in a chronic social defeat stress (CSDS) depression animal model. Moreover, after 5 days of treatment, GLP attenuated the expression of the proinflammatory cytokines IL-1β and TNF-α, enhanced the expression of the anti-inflammatory cytokine IL-10 and the neurotrophic factor BDNF, and inhibited the activation of microglia and proliferation of astrocytes in the hippocampus of CSDS mice. In addition, after 5 days of treatment, GLP significantly enhanced GluA1 S845 phosphorylation as well as GluA1 and GluA2 expression levels in the hippocampus of CSDS mice. To determine whether the antidepressant effect was mediated by Dectin-1, we found that GLP treatment enhanced Dectin-1 expression in the hippocampus in CSDS mice, and the Dectin-1-specific inhibitor laminarin almost completely blocked the antidepressant effect of GLP. This study identified GLP, an agonist of Dectin-1, as a novel and rapid antidepressant with clinical potential and multiple beneficial mechanisms, particularly in regulating the neuroimmune system and, subsequently, AMPA receptor function.
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Major depressive disorder (MDD) is a common, chronic, recurrent disease. The existing drugs are ineffective for approximately half of patients, so the development of antidepressant ...drugs with novel mechanisms is urgent. Cumulative evidence has shown neuro-inflammation plays a key role in the etiology of major depressive disorder. Clinical studies implicated that bile acids, an important component of gut-brain axis, inhibit neuro-inflammation and mediate the pathophysiology of the MDD. Here, we found that ganoderic acid A (GAA) modulated bile acid receptor FXR (farnesoid X receptor), inhibited brain inflammatory activity, and showed antidepressant effects in the chronic social defeat stress depression model, tail suspension, forced swimming, and sucrose preference tests. GAA directly inhibited the activity of the NLRP3 inflammasome, and activated the phosphorylation and expression of the AMPA receptor by modulating FXR in the prefrontal cortex of mice. If we knocked out FXR or injected the FXR-specific inhibitor z-gugglesterone (GS), the antidepressant effects induced by GAA were completely abolished. These results suggest that GAA modulates the bile acid receptor FXR and subsequently regulates neuroimmune and antidepressant behaviors. GAA and its receptor FXR have potential as targets for the treatment of MDD.
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Multiple sclerosis (MS), as an inflammatory demyelinating disorder of central nervous system, is the leading cause of non-traumatic neurologic disability in young adults. The ...pathogenesis of MS remains unknown, however, a dysregulation of glia-neuroimmune signaling plays a key role during progressive disease stage. Most of the existing drugs are aimed at the immune system, but there is no approved drug by promoting remyelination after demyelination so far. There is a great interest in identifying novel agents for treating MS bytargeting to switch the immune imbalance from pro-inflammation and apoptosis to anti-inflammation and regeneration during remyelination phase. Here, we reported that ganoderic acid A (GAA) significantly enhanced the remyelination and rescued motor deficiency in two animal models of MS, including cuprizone-induced demyelination and myelin oligodendrocyte glycoprotein (MOG) 35–55-induced experimental autoimmune encephalomyelitis model. In these two independent MS animal models, GAA modulated neuroimmune to enhance the anti-inflammatory and regeneration markers IL-4 and BDNF, inhibited inflammatory markers IL-1β and IL-6, followed by down-regulation of microglia activation and astrocyte proliferation. Pharmacological and genetic ablation of farnesoid-X-receptor (FXR) abolished GAA-induced remyelination and restoration of motor deficiency in MS mice. Thus, GAA is a novel and potential therapeutic agent that can rescue MS neuroimmune imbalance and remyelination through an FXR receptor-dependent mechanism. Clinical investigation on the therapeutic effect of GAA in improving remyelination of the MS patients to rescue the motor function is warranted.
Regulating synaptic formation and transmission is critical for the physiology and pathology of psychiatric disorders. The adenosine A2A receptor subtype has attracted widespread attention as a key ...regulator of neuropsychiatric activity, neuroprotection and injury. In this study, we systematically investigated the regulatory effects of a novel A2A receptor agonist, PSB-0777, on the expression of synaptic proteins and AMPA receptors at the cellular level in a time- and dose-dependent manner. After 30 minutes of high-dose PSB-0777 stimulation, the expression of Syn-1, PSD95, and AMPA receptors and the number of synapses were rapidly and significantly increased in rat primary cortical neurons compared with the control. Sustained elevation was found in the low and medium-dose groups after 24 hours and 3 days of treatment. In contrast, after stimulation with PSB-0777 for 3 consecutive days, the expression of Syn-1 was decreased, and PSD95, AMPA receptors and the number of synapses were no longer increased in the high-dose group. Our study focuses on the detailed and systematic regulation of synaptic proteins and AMPA receptors by an A2A receptor agonist, PSB-0777, which may result in both beneficial and detrimental effects on neurotransmission and neuroprotection and may contribute to the pathophysiology of psychiatric disorders related to A2A receptors. These experimental data may contribute to understanding of the mechanisms for neuroprotective and therapeutic effect of A2A receptor agonists.
Molecular abnormalities within the Glucocorticoid Receptor (GR) stress signaling pathway involved in dysfunction of mitochondria and confer vulnerability to stress‐related psychiatric disorders. ...Bcl‐2 associated athanogene (Bag‐1) is a target for the actions of mood stabilizers. Bag‐1 interacts with GR, thereby regulating glucocorticoid function. In this study, we investigate the potential role of Bag‐1 in regulating GR translocation into mitochondria. Corticosterone (CORT) treatment significantly enhanced Bag‐1/GR complex formation and GR mitochondrial translocation in cultured rat cortical neurons after treatment for 30 min and 24 hr. By contrast, after stimulation with CORT for 3 days, localization of the Bag‐1/GR complex and mitochondrial GR were reduced. Similar results were obtained in mice, in which administrated CORT in drinking water for 21 days significantly impaired the GR levels in the mitochondria, while Bag‐1 over‐expression rescued this reduction. Furthermore, chronic CORT exposure led to anhedonia‐like and depression‐like behaviors in the sucrose‐consumption test and forced swimming test, and these behaviors were rescued by Bag‐1 over‐expression. These results suggest that Bag‐1 mediates GR trafficking to mitochondria and regulates affective resilience in response to a CORT increase and provide potential insight into the mechanisms by which Bag‐1 and GR could contribute to the physiology and pathogenesis of psychiatric disorders in response to the change of stress hormone.
Bag‐1 is a target of mood stabilizers, which can regulating the function of GR. The abnormalities of GR stress signaling pathway involved in dysfunction of mitochondria and stress‐mediated psychiatric disorders. However, the process of GR translocation into mitochondria is unknown. We found that acute corticosterone treatment enhanced Bag‐1/GR complex formation and GR mitochondrial translocation. By contrast, chronic corticosterone reduced Bag‐1/GR complex and mitochondrial GR levels, while Bag‐1 over‐expression rescued these reductions and the depression‐like behaviors induced by chronic corticosterone. Our findings suggested that Bag‐1 is critical for GR trafficking to mitochondria and regulates affective resilience in response to corticosterone stimulation.
Multiple sclerosis (MS) is an inflammatory demyelination disease characterized by autoimmune damage to the central nervous system. In this disease, failure of remyelination could cause persistent ...disability. Cordycepin, also known as 3′-deoxyadenosine, exerts anti-inflammatory, anti-oxidic, anti-apoptotic and neuroprotective effects. The cuprizone (CPZ) model has been widely used to study MS as it mimics some characteristics of demyelination disease. To determine whether cordycepin promotes remyelination and functional recovery after CPZ-induced demyelination, we administered cordycepin to the CPZ-induced demyelination mice. Cordycepin reversed CPZ-induced loss of body weight and rescued motor dysfunction in the model mice. Cordycepin effectively promoted remyelination and enhanced MBP expression in the corpus callosum. Cordycepin also inhibited the CPZ-induced increase in the number of Iba1-positive microglia, GFAP-positive astrocytes and Olig2-positive oligodendroglial precursor cells in the corpus callosum and cerebral cortex. Pro-inflammatory cytokine expression (IL-1β and IL-6) was inhibited while anti-inflammatory cytokine IL-4 and neurotrophic factor BDNF release was elevated in the corpus callosum and hippocampus after cordycepin treatment. In addition, we also found that cordycepin ameliorated CPZ-induced body weight loss, motor dysfunction, demyelination, glial cells activation and pro-inflammatory cytokine expression in the corpus callosum and hippocampus. Our results suggest that cordycepin may represent a useful therapeutic agent in demyelination-related diseases via suppression of neuroinflammation.
•Cordycepin promoted remyelination and rescued motor dysfunction after cuprizone-induced demyelination.•Cordycepin inhibited the cuprizone-induced increase in the positive number of microglia, astrocytes and OPCs.•Cordycepin inhibited cuprizone-induced pro-inflammatory cytokine expression (IL-1β and IL-6).•Cordycepin promoted anti-inflammatory cytokine IL-4 and neurotrophic factor BDNF release.
Rationale
Converging evidence suggests that neuroimmunity plays an important role in the pathophysiology of anxiety. Interleukin (IL)-4 is a key cytokine regulating neuroimmune functions in the ...central nervous system. More efficient anxiolytics with neuro-immune mechanisms are urgently needed.
Objective
To determine whether 3′-deoxyadenosine (3′-dA) exerts an anxiolytic effect and to examine the role of IL-4 in the anxiolytic effect of 3′-dA in mice.
Methods
We investigated the effects of 3′-dA on anxiety-like behaviors using elevated plus maze (EPM) or light-dark box (LDB) tests after 45 min or 5 days of treatment. Expression of IL-4, IL-10, IL-1β, TNF-α, and IL-6 in the prefrontal cortex (PFC) was detected by Western blot and/or double immunostaining. Intracerebroventricular injection of RIL-4Rα (an IL-4-specific inhibitor) and intraperitoneal injection of 3′-dA or imipramine were co-administered, followed by EPM test.
Results
3′-dA exhibited a stronger and faster anxiolytic effect than imipramine in behavioral tests. Furthermore, 3′-dA enhanced IL-4 expression after 45 min or 5 days, TNF-α and IL-1β expression decreased significantly after a 5-day treatment with 3′-dA, and IL-10 expression increased after a 5-day treatment with 3′-dA or imipramine in the PFC. IL-4 was expressed in neurons and in some astrocytes and microglia. IL-4 expression showed a strong positive correlation with reduced anxiety behaviors. RIL-4Rα completely blocked the anxiolytic effects induced by 3′-dA and imipramine.
Conclusions
This study identifies a novel and common anxiolytic IL-4 signaling pathway and provides an innovative drug with a novel neuro-immune mechanism for treating anxiety disorder.
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