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1.
Glia ; 68(1): 27-43, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31429156

RESUMO

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.

2.
J Neurochem ; 2019 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-31665810

RESUMO

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 (AC1 KO) mice. Integrative approaches were used to investigate possible changes of neuronal adenylyl cyclase 1 (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 upregulation of AC1 protein in the ACC. Furthermore, we found that AC1 is required for NMDA GluN2B receptor upregulation 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 upregulation 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.

3.
J Neuroinflammation ; 16(1): 132, 2019 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-31255170

RESUMO

BACKGROUND: Liver X receptors (LXRs), including LXRα and LXRß, are key regulators of transcriptional programs for both cholesterol homeostasis and inflammation in the brain. Here, the modes of action of LXRs and the epigenetic mechanisms regulating LXRß expression in anterior cingulate cortex (ACC) of chronic inflammatory pain (CIP) are investigated. METHODS: The deficit of LXR isoform and analgesic effect of LXR activation by GW3965 were evaluated using the mouse model of CIP induced by hindpaw injection of complete Freund's adjuvant (CFA). The mechanisms involved in GW-mediated analgesic effects were analyzed with immunohistochemical methods, ELISA, co-immunoprecipitation (Co-IP), Western blot, and electrophysiological recording. The epigenetic regulation of LXRß expression was investigated by chromatin immunoprecipitation, quantitative real-time PCR, and sequencing. RESULTS: We revealed that CFA insult led to LXRß reduction in ACC, which was associated with upregulated expression of histone deacetylase 5 (HDAC5), and knockdown of LXRß by shRNA led to thermal hyperalgesia. Co-IP showed that LXRß interacted with NF-κB p65 physically. LXRß activation by GW3965 exerted analgesic effects by inhibiting the nuclear translocation of NF-κB, reducing the phosphorylation of mitogen-activated protein kinases (MAPKs) in ACC, and decreasing the promoted input-output and enhanced mEPSC frequency in ACC neurons after CFA exposure. In vitro experiments confirmed that HDAC5 triggered histone deacetylation on the promoter region of Lxrß, resulting in downregulation of Lxrß transcription. CONCLUSION: These findings highlight an epigenetic mechanism underlying LXRß deficits linked to CIP, and LXRß activation may represent a potential novel target for the treatment of CIP with an alteration in inflammation responses and synaptic transmission in ACC.

4.
J Clin Invest ; 129(6): 2333-2350, 2019 05 06.
Artigo em Inglês | MEDLINE | ID: mdl-31063987

RESUMO

Hormone therapy (HT) is reported to be deficient in improving learning and memory in older postmenopausal women according to recent clinical studies; however, the reason for failure is unknown. A "window of opportunity" for estrogen treatment is proposed to explain this deficiency. Here, we found that facilitation of memory extinction and long-term depression by 17ß-estradiol (E2) was normal in mice 1 week after ovariectomy (OVXST), but it was impaired in mice 3 months after ovariectomy (OVXLT). High-throughput sequencing revealed a decrease of miR-221-5p, which promoted cannabinoid receptor 1 (CB1) ubiquitination by upregulation of Neurl1a/b in E2-treated OVXLT mice. Blood samples from postmenopausal women aged 56-65 indicated decreases of miR-221-5p and 2-arachidonoylglycerol compared with samples from perimenopausal women aged 46-55. Replenishing of miR-221-5p or treatment with a CB1 agonist rescued the impairment of fear extinction in E2-treated OVXLT mice. The present study demonstrates that an HT time window in mice can be prolonged by cotreatment with a CB1 agonist, implying a potential strategy for HT in long-term menopausal women.

5.
Mol Brain ; 12(1): 42, 2019 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-31053149

RESUMO

Clinical depression is frequently comorbid with chronic inflammatory disease, and neuroinflammation is currently proposed as a key mechanism in major depressive disorders. Different from unpredictable chronic stress, which is a well-established animal model for depression, predictable chronic mild stress (PCMS), a routine stress experienced in day-to-day life, has been demonstrated to improve mood and memory. In the present study, we assess the effects of PCMS (5 min of daily restrain stress for 4 weeks) on depressive-like behavior, neuroinflammation, oxidative stress, and pyrin domain containing three (NLRP3) activation in hippocampus of mice subjected to peripheral immune challenge by lipopolysaccharide (LPS). We found that PCMS facilitated the recovery from LPS-induced depressive- or anxiety-like behavior. Concurrent with the reversal of abnormal behavioral changes, PCMS suppressed LPS-induced proinflammatory cytokine expression, microglia activation, and oxidative stress in hippocampus. Correspondingly, PCMS inhibited LPS-induced overactivation of NLRP3 inflammasome components (NLRP3, ASC, and Caspase-1), and interleukin 1 beta (IL-1ß) maturation. Nrf2 (nuclear factor (erythroid-derived 2)-like 2) signaling was demonstrated to inhibit NLRP3 inflammasome overactivation and oxidative stress. PCMS activated Nrf2 signaling and inhibited thioredoxin (Trx)-interacting protein (TXNIP) expression in LPS-treated mice. Collectively, present data suggest that PCMS, contrary to severe and uncontrolled stress, alleviated impairments of the Nrf2-TXNIP-Trx system and may contribute to inflammatory brain damage and the imbalance of cellular redox homeostasis in depressed mice. This study provides a mechanistic link to the resilience of PCMS to LPS-induced behavioral deficits.

6.
Mol Brain ; 12(1): 36, 2019 04 08.
Artigo em Inglês | MEDLINE | ID: mdl-30961625

RESUMO

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 GABAA 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.


Assuntos
Ansiolíticos/uso terapêutico , Ansiedade/terapia , Inflamação/patologia , Isoflavonas/uso terapêutico , Animais , Ansiolíticos/farmacologia , Complexo Nuclear Basolateral da Amígdala/metabolismo , Comportamento Animal/efeitos dos fármacos , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Modelos Animais de Doenças , Adjuvante de Freund , Isoflavonas/química , Isoflavonas/farmacologia , Masculino , Camundongos Endogâmicos C57BL , Microglia/efeitos dos fármacos , Microglia/metabolismo , Microglia/patologia , Modelos Moleculares , NF-kappa B/metabolismo , NF-kappa B/farmacocinética , Dor/tratamento farmacológico , Receptores de GABA/metabolismo , Receptores de N-Metil-D-Aspartato/química , Receptores de N-Metil-D-Aspartato/metabolismo , Transdução de Sinais , Regulação para Cima/efeitos dos fármacos
7.
Brain Res ; 1712: 55-62, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-30731077

RESUMO

Patients with irritable bowel syndrome suffer from chronic visceral pain, and in some of them, this is accompanied by anxiety comorbidity. Cytoplasmic polyadenylation element binding protein 1 (CPEB1) mediates the cytoplasmic polyadenylation of mRNAs and facilitates their translation. Our previous studies have shown that CPEB1 knockdown in the amygdala exerts anxiolytic but not analgesic effects in a mouse model of inflammatory pain. However, the roles of CPEB1 in the anterior cingulate cortex (ACC) in visceral pain modulation remain unclear. In this study, a visceral pain mouse model was established by injecting zymosan into the colon of mice. Zymosan injection significantly induced visceral pain- and anxiety-like behaviors in mice and increased the levels of GluA1, phosphorylated GluA1 at S845 and S831, and CPEB1 in the ACC. CPEB1 knockdown in the ACC by AAV-CPEB1-shRNA reduced zymosan-induced pain- and anxiety-like behaviors in mice. This observation was closely correlated with reduced AMPA receptor, synaptophysin, and PSD95 levels. These data suggest that CPEB1 in the ACC is a potential therapeutic target for visceral pain and anxiety comorbidity.

8.
Toxicol Appl Pharmacol ; 368: 26-36, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30776389

RESUMO

Cardiac dysfunction is a vital complication during endotoxemia (ETM). Accumulating evidence suggests that enhanced glycolytic metabolism promotes inflammatory and myocardial diseases. In this study, we performed deep mRNA sequencing analysis on the hearts of control and lipopolysaccharide (LPS)-challenged mice (40 mg/kg, i.p.) and identified that the glycolytic enzyme, 6-phosphofructo-2-kinase (PFK-2)/fructose-2,6-bisphosphatase 3 (PFKFB3) might play an indispensable role in ETM-induced cardiac damage. Quantitative real-time PCR validated the transcriptional upregulation of PFKFB3 in the myocardium of LPS-challenged mice and immunoblotting and immunostaining assays confirmed that LPS stimulation markedly increased the expression of PFKFB3 at the protein level both in vivo and in vitro. The potent antagonist 3-(3pyridinyl)-1-(4-pyridinyl)-2-propen-1-one (3PO) was used to block PFKFB3 activity in vivo (50 mg/kg, i.p.) and in vitro (10 µM). Echocardiographic analysis and TUNEL staining showed that 3PO significantly alleviated LPS-induced cardiac dysfunction and apoptotic injury in vivo. 3PO also suppressed the LPS-induced secretion of tumor necrosis factor-α, interleukin (IL)-1ß, IL-6 and lactate in the serum, in addition to lactate in the myocardium. PFKFB3 inhibition also diminished the nuclear translocation and phosphorylation of transcription factor nuclear factor-κB (NF-κB) in both adult cardiomyocytes and HL-1 cells. Furthermore, immunoblotting analysis showed that 3PO inhibited LPS-induced apoptotic induction in cardiomyocytes. Taken together, these findings demonstrate that PFKFB3 participates in LPS-induced cardiac dysfunction via mediating inflammatory and apoptotic signaling pathway.

9.
Mol Pain ; 14: 1744806918814367, 2018 Jan-Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30380983

RESUMO

Tetrahydroxystilbene glucoside (THSG) is one of the active ingredients of Polygonum multiflorum. It has been shown to exert a variety of pharmacological effects, including antioxidant, anti-aging, and anti-atherosclerosis. Because of its prominent anti-inflammatory effect, we explored whether THSG had analgesic effect. In this study, we used a model of chronic inflammatory pain caused by injecting complete Freund's adjuvant into the hind paw of mice. We found THSG relieved swelling and pain in the hind paw of mice on a dose-dependent manner. In the anterior cingulate cortex, THSG suppressed the upregulation of GluN2B-containing N-methyl-D-aspartate receptors and the downregulation of GluN2A-containing N-methyl-D-aspartate receptors caused by chronic inflammation. In addition, THSG increased Bcl-2 and decreased Bax and Caspase-3 expression by protecting neuronal survival. Furthermore, THSG inhibited the phosphorylation of p38 and the increase of nuclear factor κB (NF-κB) and tumor necrosis factor α (TNF-α). Immunohistochemical staining revealed that THSG blocked the activation of microglia and reduced the release of proinflammatory cytokines TNF-α, interleukin 1ß (IL-1ß), and interleukin 6 (IL-6). In conclusion, this study demonstrated that THSG had a certain effect on alleviating complete Freund's adjuvant-induced chronic inflammatory pain.

10.
Metab Brain Dis ; 33(5): 1413-1420, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29948656

RESUMO

Targeting neuroinflammatory disturbances has been acknowledged as a potential strategy for treatment of depressive disorder in humans. Over-activation of tryptophan-degrading pathway by pro-inflammatory cytokines resulted in N-methyl-d-aspartate (NMDA)-mediated excitotoxicity, which is implicated in pathophysiology of depression. Gentiopicroside (Gent) has powerful anti-inflammatory property and exhibits promising antidepressant effect in an animal model of pain/depression dyad by down-regulating GluN2B-containing NMDA receptors. Therefore, the present study aimed to investigate the ability of Gent to abolish depressive-like behavior induced by lipopolysaccharide (LPS) in mice. Acute administration of LPS (0.5 mg/kg, i.p.) increased immobility time in both forced swimming test (FST) and tail suspension test (TST) without affecting spontaneous locomotor activity, indicative of depressive-like behavior. Gent (50 mg/kg, i.p.) administered once a day for three consecutive days prevented the development of depressive-like behavior induced by LPS. The antidepressant-like effect was paralleled with restoration of LPS-induced alterations in brain inflammatory mediators (i.e. IL-1ß and TNF-α). In addition, Gent prevented over-activation of indoleamine 2,3-double oxygen enzyme (IDO) and recovered GluN2B subunit expression in the PFC challenged by LPS. In conclusion, our results suggested that Gent pretreatment provided protection against LPS-induced depressive-like behavior and the effect appeared to be demonstrated, at least partially, by blocking various steps of tryptophan-degrading pathway.

11.
Neuroreport ; 29(13): 1114-1120, 2018 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-29958245

RESUMO

The effects of gentiopicroside (Gent), an active component derived from the traditional Chinese medicine Gentiana macrophylla, on lipopolysaccharide-induced astrocyte activation and subsequent neuronal damage were investigated. Gent significantly inhibited the release of tumor necrosis factor-α, interleukin-1ß, nitric oxide, and prostaglandin E, as well as expressions of inducible nitric oxide synthase and cyclooxygenase-2 in lipopolysaccharide-induced primary astrocytes. Furthermore, Gent relieved neurotoxicity from astrocyte-mediated inflammatory injury. Mechanism studies indicated that Gent significantly suppressed nuclear factor-κB nuclear translocation and down-regulated c-Jun-N-terminal kinase/stress-activated protein kinase mitogen-activated protein kinase phosphorylation levels with little influence on elevated p-p38 levels. Taken together, our findings suggested Gent could prevent the neurotoxicity related to astrocyte-mediated inflammatory injury by inhibition of nuclear factor-κB and mitogen-activated protein kinase signaling pathways. The study also indicated that neuronal injury could be prevented by promptly modulating inflammatory responses of astrocytes.

12.
Behav Brain Res ; 348: 184-191, 2018 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-29680784

RESUMO

Classic antidepressants benefit depression patients partially by improving neurogenesis and/or brain-derived neurotrophic factor (BDNF)/TrkB pathway which were impaired in depression. In this study, we demonstrated that Silibinin (SLB), a polyphenolic flavanoid from Silybum marianum, ameliorated reserpinized mouse depressant-like behaviors. The antidepressants of SLB administration was associated with increased neural stem cells (NSCs) proliferation and further confirmed in BDNF/TrkB signaling transduction. SLB treatment reversed the decreased expression levels of BDNF and its receptor TrkB, and the reduced activation of downstream target proteins including phosphorylated extracellular-regulated protein kinase (p-ERK) and phosphorylated cAMP-response element binding protein (p-CREB) in depressived hippocampus. Furthermore, intracerebroventricular injection of GNF5837, a TrkB antagonist, abrogated antidepressant-like effects of SLB in mice along with the improved NSC proliferation, as well as enhanced levels of p-ERK and p-CREB in mice hippocampus. Taken together, these results suggest that SLB may exert antidepressant effects through BDNF/TrkB signaling pathway to improve NSC proliferation in acute depression.


Assuntos
Silimarina/metabolismo , Silimarina/farmacologia , Animais , Antidepressivos , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Depressão/metabolismo , Transtorno Depressivo/tratamento farmacológico , Modelos Animais de Doenças , Masculino , Glicoproteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Células-Tronco Neurais/efeitos dos fármacos , Neurogênese/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Proteínas Tirosina Quinases/metabolismo , Transdução de Sinais/efeitos dos fármacos , Silibina , Estresse Psicológico/metabolismo
13.
Mol Brain ; 11(1): 12, 2018 03 05.
Artigo em Inglês | MEDLINE | ID: mdl-29506545

RESUMO

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.


Assuntos
Acetamidas/uso terapêutico , Antidepressivos/uso terapêutico , Depressão Pós-Parto/tratamento farmacológico , Purinonas/uso terapêutico , Acetamidas/farmacologia , Animais , Antidepressivos/farmacologia , Ansiedade/complicações , Ansiedade/tratamento farmacológico , Complexo Nuclear Basolateral da Amígdala/efeitos dos fármacos , Complexo Nuclear Basolateral da Amígdala/metabolismo , Complexo Nuclear Basolateral da Amígdala/patologia , Complexo Nuclear Basolateral da Amígdala/fisiopatologia , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Depressão Pós-Parto/complicações , Depressão Pós-Parto/patologia , Depressão Pós-Parto/fisiopatologia , Modelos Animais de Doenças , Feminino , Hormônios/metabolismo , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Sistema Hipotálamo-Hipofisário/metabolismo , Sistema Hipotálamo-Hipofisário/patologia , Ligantes , Camundongos Endogâmicos C57BL , Plasticidade Neuronal/efeitos dos fármacos , Purinonas/farmacologia , Receptores de GABA/metabolismo , Receptores de Glutamato/metabolismo , Receptores de Serotonina/metabolismo
14.
Exp Neurol ; 304: 21-29, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29447944

RESUMO

Chronic cerebral hypoperfusion (CCH), a leading cause of various cerebrovascular diseases, leads to cognitive dysfunction due to neuron loss and impaired neurogenesis. Liver X receptors (LXRs), including LXRα and LXRß isoforms, are crucial for cholesterol metabolism, synaptic plasticity as well as neurogenesis. However, it is not clear the potential roles of LXRs in the pathogenesis of cognitive impairment induced by CCH. In this study, we demonstrated that LXRß expression decreased in hippocampus of CCH mice. GW3965, a synthetic dual agonist for both LXRα and LXRß, ameliorated impairment of learning and memory in CCH mice by promoting neuronal survival and neural stem cells (NSCs) proliferation in dentate gyrus (DG) of CCH mice. The proliferative effects of GW3965 were further confirmed in cultured neural progenitor cells (NPCs) and showed in a concentration-dependent manner. Moreover, GW3965 phosphorylated protein kinase B (Akt) at Ser473 in a time- and concentration-dependent manner in NPCs. Furthermore, both LY294002, an inhibitor for phosphoinositide-3-kinase (PI3K), and short hairpin RNAs for LXRß knockdown, abrogated GW3965-induced Akt phosphorylation, and therefore abolished GW3965-mediated proliferation-promoting of NPCs. All the data suggested that GW3965 ameliorated impaired cognitive functions in CCH by promoting NSC proliferation through PI3K/Akt pathway followed LXRß activation. This study correlates a deficit of LXRß in cognitive dysfunction in CCH with impaired neurogenesis in hippocampus, and LXRs may serve as a potential therapeutic target for chronic cerebral ischemia.

15.
Brain Res Bull ; 137: 156-165, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29242136

RESUMO

Anxiety disorders are a category of mental disorders characterized by feelings of anxiety, stress, and fear attached to various sources. However, their pathogenesis is complicated and has not been fully elucidated. The amygdala is a vital brain region that regulates anxiety and mental disorders. Cytoplasmic polyadenylation element binding protein 1 (CPEB1) mediates the extension of the mRNA polyadenylation tail and facilitates the translation of target RNA. CPEB1 is closely related to neuronal diseases, such as Fragile X Syndrome, learning and memory disorders, and chronic pain. In this study, the role of CPEB1 in anxiety development was determined in a pain-mediated anxiety mouse model. The anxiety model was established in mice by injecting with Complete Freund's Adjuvant (CFA) into the hindpaw. CFA injection then led to anxiety-like behaviors and increased the CPEB1 levels in the mouse basolateral amygdala (BLA). CPEB1 enhancement facilitated the translation of GluA1, GluN2A, GluN2B, PSD95, and GABA receptors, which disturbed the E/I balance in the BLA as shown by enhanced excitatory presynaptic release and reduced inhibitory presynaptic release. CPEB1 knockdown with AAV-CPEB1-shRNA alleviated the anxiety-like behaviors but not the pain-like behaviors by enhancing inhibitory transmission in the BLA of model mice. The data suggest that CPEB1 participates in anxiety development by regulating excitatory/inhibitory synaptic transmission in the BLA.


Assuntos
Ansiedade/metabolismo , Complexo Nuclear Basolateral da Amígdala/metabolismo , Inflamação/metabolismo , Dor/metabolismo , Fatores de Transcrição/deficiência , Fatores de Poliadenilação e Clivagem de mRNA/deficiência , Animais , Células Cultivadas , Modelos Animais de Doenças , Proteína 4 Homóloga a Disks-Large/metabolismo , Adjuvante de Freund , Técnicas de Silenciamento de Genes , Vetores Genéticos , Membro Posterior , Inflamação/psicologia , Masculino , Camundongos Endogâmicos C57BL , Inibição Neural/fisiologia , Neurônios/metabolismo , Dor/psicologia , RNA Interferente Pequeno/administração & dosagem , RNA Interferente Pequeno/genética , Receptores de AMPA/metabolismo , Receptores de GABA/metabolismo , Transmissão Sináptica/fisiologia , Fatores de Transcrição/genética , Fatores de Poliadenilação e Clivagem de mRNA/genética
16.
Brain ; 140(12): 3215-3232, 2017 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-29096020

RESUMO

Fragile X syndrome is an inheritable form of intellectual disability caused by loss of fragile X mental retardation protein (FMRP, encoded by the FMR1 gene). Absence of FMRP caused overexpression of progranulin (PGRN, encoded by GRN), a putative tumour necrosis factor receptor ligand. In the present study, we found that progranulin mRNA and protein were upregulated in the medial prefrontal cortex of Fmr1 knock-out mice. In Fmr1 knock-out mice, elevated progranulin caused insufficient dendritic spine pruning and late-phase long-term potentiation in the medial prefrontal cortex of Fmr1 knock-out mice. Partial progranulin knock-down restored spine morphology and reversed behavioural deficits, including impaired fear memory, hyperactivity, and motor inflexibility in Fmr1 knock-out mice. Progranulin increased levels of phosphorylated glutamate ionotropic receptor GluA1 and nuclear factor kappa B in cultured wild-type neurons. Tumour necrosis factor receptor 2 antibody perfusion blocked the effects of progranulin on GluA1 phosphorylation; this result indicates that tumour necrosis factor receptor 2 is required for progranulin-mediated GluA1 phosphorylation and late-phase long-term potentiation expression. However, high basal level of progranulin in Fmr1 knock-out mice prevented further facilitation of synaptic plasticity by exogenous progranulin. Partial downregulation of progranulin or tumour necrosis factor receptor 2/nuclear factor kappa B signalling restored synaptic plasticity and memory deficits in Fmr1 knock-out mice. These findings suggest that elevated PGRN is linked to cognitive deficits of fragile X syndrome, and the progranulin/tumour necrosis factor receptor 2 signalling pathway may be a putative therapeutic target for improving cognitive deficits in fragile X syndrome.


Assuntos
Comportamento Animal , Proteína do X Frágil de Retardo Mental/genética , Peptídeos e Proteínas de Sinalização Intercelular/genética , Aprendizagem , Sinapses/metabolismo , Animais , Anticorpos Neutralizantes/farmacologia , Western Blotting , Células Cultivadas , Imunofluorescência , Técnicas de Silenciamento de Genes , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/farmacologia , Potenciação de Longa Duração/efeitos dos fármacos , Potenciação de Longa Duração/genética , Camundongos , Camundongos Knockout , NF-kappa B/efeitos dos fármacos , NF-kappa B/metabolismo , Plasticidade Neuronal/efeitos dos fármacos , Plasticidade Neuronal/genética , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Fosforilação/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , RNA Mensageiro/metabolismo , Receptores de AMPA/efeitos dos fármacos , Receptores de AMPA/metabolismo , Receptores Tipo II do Fator de Necrose Tumoral/imunologia , Transdução de Sinais
17.
Mol Brain ; 10(1): 38, 2017 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-28800762

RESUMO

The G protein-coupled receptor 55 (GPR55) is a novel cannabinoid receptor, whose exact role in anxiety remains unknown. The present study was conducted to explore the possible mechanisms by which GPR55 regulates anxiety and to evaluate the effectiveness of O-1602 in the treatment of anxiety-like symptoms. Mice were exposed to two types of acute stressors: restraint and forced swimming. Anxiety behavior was evaluated using the elevated plus maze and the open field test. We found that O-1602 alleviated anxiety-like behavior in acutely stressed mice. We used lentiviral shRNA to selective ly knockdown GPR55 in the medial orbital cortex and found that knockdown of GPR55 abolished the anxiolytic effect of O-1602. We also used Y-27632, a specific inhibitor of ROCK, and U73122, an inhibitor of PLC, and found that both inhibitors attenuated the effectiveness of O-1602. Western blot analysis revealed that O-1602 downregulated the expression of GluA1 and GluN2A in mice. Taken together, these results suggest that GPR55 plays an important role in anxiety and O-1602 may have therapeutic potential in treating anxiety-like symptoms.


Assuntos
Ansiedade/metabolismo , Ansiedade/psicologia , Córtex Pré-Frontal/metabolismo , Receptores de Canabinoides/metabolismo , Estresse Psicológico/metabolismo , Doença Aguda , Amidas/administração & dosagem , Amidas/farmacologia , Amidas/uso terapêutico , Animais , Ansiolíticos/administração & dosagem , Ansiolíticos/farmacologia , Ansiolíticos/uso terapêutico , Ansiedade/tratamento farmacológico , Doença Crônica , Cicloexanos/farmacologia , Cicloexanos/uso terapêutico , Estrenos/farmacologia , Técnicas de Silenciamento de Genes , Injeções Intraperitoneais , Masculino , Camundongos Endogâmicos C57BL , Piridinas/administração & dosagem , Piridinas/farmacologia , Piridinas/uso terapêutico , Pirrolidinonas/farmacologia , Resorcinóis/farmacologia , Resorcinóis/uso terapêutico , Restrição Física , Transdução de Sinais , Estresse Psicológico/tratamento farmacológico , Natação
18.
Mol Brain ; 10(1): 21, 2017 06 12.
Artigo em Inglês | MEDLINE | ID: mdl-28606116

RESUMO

Excitatory synaptic transmission in central synapses is modulated by serotonin (5-HT). The anterior cingulate cortex (ACC) is an important cortical region for pain perception and emotion. ACC neurons receive innervation of projecting serotonergic nerve terminals from raphe nuclei, but the possible effect of 5-HT on excitatory transmission in the ACC has not been investigated. In the present study, we investigated the role of 5-HT on glutamate neurotransmission in the ACC slices of adult mice. Bath application of 5-HT produced dose-dependent inhibition of evoked excitatory postsynaptic currents (eEPSCs). Paired pulse ratio (PPR) was significantly increased, indicating possible presynaptic effects of 5-HT. Consistently, bath application of 5-HT significantly decreased the frequency of spontaneous and miniature excitatory postsynaptic currents (sEPSCs and mEPSCs). By contrast, amplitudes of sEPSCs and mEPSCs were not significantly affected. After postsynaptic application of G protein inhibitor GDP-ß-S, 5-HT produced inhibition of eEPSCs was significantly reduced. Finally, NAN-190, an antagonist of 5-HT1A receptor, significantly reduced postsynaptic inhibition of 5-HT and abolished presynaptic inhibition. Our results strongly suggest that presynaptic as well as postsynaptic 5-HT receptor including 5-HT1A subtype receptor may contribute to inhibitory modulation of glutamate release as well as postsynaptic responses in the ACC.


Assuntos
Giro do Cíngulo/fisiologia , Serotonina/farmacologia , Transmissão Sináptica/fisiologia , Animais , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Proteínas de Ligação ao GTP/metabolismo , Guanosina Difosfato/análogos & derivados , Guanosina Difosfato/farmacologia , Giro do Cíngulo/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Piperazinas/farmacologia , Receptor 5-HT1A de Serotonina/metabolismo , Transmissão Sináptica/efeitos dos fármacos , Tionucleotídeos/farmacologia
19.
Sci Rep ; 7: 43594, 2017 03 16.
Artigo em Inglês | MEDLINE | ID: mdl-28300056

RESUMO

Sleep disorder is becoming a widespread problem in current society, and is associated with impaired cognition and emotional disorders. Progranulin (PGRN), also known as granulin epithelin precursor, promotes neurite outgrowth and cell survival, and is encoded by the GRN gene. It is a tumor necrosis factor α receptor (TNFR) ligand which is implicated in many central nervous system diseases. However, the role PGRN in sleep disorder remains unclear. In the present study, we found that sleep deprivation (S-DEP) impaired the memory and produced thigmotaxis/anxiety-like behaviors in mice. S-DEP increased the levels of TNFα but decreased PGRN levels in the hippocampus. The intracerebroventricular (ICV) injection of PGRN or intraperitoneal injection of TNFα synthesis blocker thalidomide (25 mg/kg), prevented the memory impairment and anxiety behaviors induced by S-DEP. PGRN treatment also restored dendritic spine density in the hippocampus CA1 region and neurogenesis in hippocampus dentate gyrus (DG). These results indicate that an imbalance between TNFα and PGRN contributes to memory impairment and thigmotaxis/anxiety caused by sleep deprivation.


Assuntos
Ansiedade/etiologia , Ansiedade/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Transtornos da Memória/etiologia , Transtornos da Memória/metabolismo , Privação do Sono , Fator de Necrose Tumoral alfa/metabolismo , Animais , Comportamento Animal , Espinhas Dendríticas , Hipocampo/metabolismo , Camundongos , Neurogênese , Transdução de Sinais
20.
Neuroreport ; 28(5): 259-267, 2017 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-28240721

RESUMO

Cucurbitacin IIa (CuIIa) is the major active component of the Helmseya amabilis root and is known to have antiviral and anti-inflammatory effects. In this study, we examined the antidepressant-like effects of CuIIa in a mouse model of chronic unpredictable mild stress (CUMS) and investigated the possible underlying mechanisms. To evaluate the antidepressant-like effects of CuIIa on depression-like behaviors, mice were subjected to the open-field test, the elevated plus-maze test, the forced-swimming test, and the tail-suspension test. We found that CuIIa treatment reversed the CUMS-induced behavioral abnormalities. Western blot analyses showed that CUMS significantly decreased brain-derived neurotrophic factor (BDNF) levels, cAMP-response element binding protein (CREB), and calcium/calmodulin-dependent protein kinase II (CaMKII) phosphorylation, and N-methyl-D-aspartate receptor subtype GluN2B and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor GluA1 expression in the amygdala; in addition, the expression of gamma-aminobutyric acid receptor A subunit α2 was upregulated in CUMS mice. These CUMS-induced changes were all normalized by CuIIa treatment and administration of the BDNF antagonist ANA-12 can block the antidepressant effect of CuIIa. Our findings suggest that the antidepressant-like effects of CuIIa may be exerted by regulation of the CaMKIIα-CREB-BDNF pathway and the balance between excitatory and inhibitory synaptic transmission in the amygdala.


Assuntos
Antidepressivos/uso terapêutico , Cucurbitacinas/uso terapêutico , Depressão/tratamento farmacológico , Depressão/etiologia , Estresse Psicológico/complicações , Tonsila do Cerebelo/efeitos dos fármacos , Tonsila do Cerebelo/metabolismo , Animais , Azepinas/uso terapêutico , Benzamidas/uso terapêutico , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Proteína de Ligação a CREB/metabolismo , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Doença Crônica , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Comportamento Exploratório/efeitos dos fármacos , Elevação dos Membros Posteriores , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , Receptores de N-Metil-D-Aspartato/metabolismo , Estresse Psicológico/tratamento farmacológico , Natação/psicologia
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