RESUMEN
Our previous study suggests that hippocampal cysteinyl leukotriene receptor 1 (CysLT1R) could be involved in depression. Herein we hypothesize that CysLT1R may regulate depression by affecting synaptic glutamate cycling based on existence of CysLT1R in the astrocytes that participate in occurrence of depression. We found that CysLT1R expression was significantly increased in the astrocyte of chronic unpredictable mild stress (CUMS)-induced depression-like mice, CysLT1R astrocyte-specific conditional knockout (AcKO) significantly improved depression-like behaviors, as indicated by decreased immobility time in the forced swimming test and tail suspension test and increased sucrose preference in the sucrose preference test, and knockdown of CysLT1R in the astrocyte of dentate gyrus (DG), the region with the most significant increase of CysLT1R in the astrocyte of depression-like mice, produced similar effects. Correspondingly, overexpression of CysLT1R in the astrocyte of DG induced depression-like behaviors in mice. The further study showed that CysLT1R AcKO ameliorated synaptic plasticity impairment, as reflected by increased synapse, LTP and PSD95, and promoted glutamate transporter 1 (GLT-1) expression by inhibiting NF-κB p65 nuclear translocation mediated by ß-arestin2 and clatrhin, subsequently decreased glutamate in synaptic cleft and GluN2B on postsynaptic membrane in depression-like mice. The present study also showed that GLT-1 agonist or NF-κB inhibitor ameliorated depressive-like behaviors induced by overexpression of the astrocyte CysLT1R of DG. Our study demonstrated that astrocyte CysLT1R regulated depression by modulating glutamate synaptic transmission, suggesting that CysLT1R could be a potential target for developing novel drugs of anti-depression.
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Astrocitos , Depresión , Ácido Glutámico , Receptores de Leucotrienos , Transmisión Sináptica , Animales , Ratones , Astrocitos/metabolismo , Ácido Glutámico/metabolismo , Hipocampo/metabolismo , FN-kappa B/metabolismo , Estrés Psicológico , Sacarosa/metabolismo , Sacarosa/farmacología , Receptores de Leucotrienos/metabolismo , Depresión/metabolismo , Depresión/patologíaRESUMEN
This study aimed to evaluate whether mogrol, a main bioactive ingredient of Siraitia grosvenorii, could attenuate LPS-induced memory impairment in mice. The behavioral tests and immunohistochemical analysis and Western blot were performed. The present results showed that oral administration of mogrol (20, 40, 80 mg/kg) significantly improved LPS-induced memory impairment in mice. The results also indicated that mogrol treatment significantly reduced the number of Iba1-positive cells, the nuclear NF-κB p65 and levels of TNF-α, IL-1ß and IL-6 both in the hippocampus and frontal cortex of LPS-challenged mice. [Formula: see text].
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Inflamación , Lipopolisacáridos , Animales , Hipocampo , Ratones , Estructura Molecular , FN-kappa B , Factor de Necrosis Tumoral alfaRESUMEN
Increasing evidence demonstrates that the neurotoxicity of amyloid-beta (Aß) deposition plays a causative role in Alzheimer's disease (AD). Herein, we evaluated the neuroprotective effects of 6α-ethyl-23(S)-methylcholic acid (S-EMCA, INT-777), a specific G-protein coupled bile acid receptor 1 (TGR5) agonist, in the Aß1-42-treated mouse model of acute neurotoxicity. Single intracerebroventricular (i.c.v.) injection of aggregated Aß1-42 (410â¯pmol/mouse; 5⯵l) into the mouse brain induced cognitive impairment, neuroinflammation, apoptosis, and synaptic dysfunction. In contrast, INT-777 (1.5 or 3.0⯵g/mouse, i.c.v.) significantly improved Aß1-42-induced cognitive impairment, as reflected by better performance in memory tests. Importantly, INT-777 treatment reversed Aß1-42-induced TGR5 down-regulation, suppressed the increase of nuclear NF-κB p65, and mitigated neuroinflammation, as evidenced by lower proinflammatory cytokines and less Iba1-positive cells in the hippocampus and frontal cortex. INT-777 treatment also pronouncedly suppressed apoptosis through the reduction of TUNEL-positive cells, decreased caspase-3 activation, increased the ratio of Bcl-2/Bax, and ameliorated synaptic dysfunction by promoting dendritic spine generation with the upregulation of postsynaptic and presynaptic proteins (PSD95 and synaptophysin) in Aß1-42-treated mice. Our results indicate that INT-777 has potent neuroprotective effects against Aß1-42-induced neurotoxicity. Taken together, these findings suggest that the activation of TGR5 could be a novel and promising strategy for the treatment of AD.
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Ácidos Cólicos/farmacología , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/efectos adversos , Péptidos beta-Amiloides/metabolismo , Animales , Apoptosis/efectos de los fármacos , Encéfalo/metabolismo , Caspasa 3/metabolismo , Ácidos Cólicos/metabolismo , Disfunción Cognitiva/tratamiento farmacológico , Modelos Animales de Enfermedad , Hipocampo/metabolismo , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Memoria/efectos de los fármacos , Trastornos de la Memoria/metabolismo , Ratones , Ratones Endogámicos ICR , Neuroinmunomodulación/efectos de los fármacos , Neuronas/metabolismo , Fármacos Neuroprotectores/metabolismo , Fármacos Neuroprotectores/farmacología , Fragmentos de Péptidos/efectos adversos , Fragmentos de Péptidos/metabolismoRESUMEN
Estrogen receptors (ERs) are thought to be associated with the onset and progression of neurodegenerative injuries and diseases, but the relationship and mechanisms underlying between ERs and cognition in type 1 diabetes remain elusive. In the current study, we investigated the effects of ERα and ERß on the memory impairment and apoptosis in streptozotocin-induced diabetic mice. We found that ERα and/or ERß activation using their agonists (0.5â¯mg/kg E2, PPT or DPN) ameliorate memory impairment in the Morris water maze (MWM) and Y-maze tests and suppress apoptosis as evidenced by decreased caspase-3 activity and increased ratio of Bcl-2/Bax. Importantly, treatment with the pharmacologic ERs agonists caused significant increases in the membrane ERα and ERß expression and subsequent PI3K/Akt, CREB and BDNF activation in the hippocampus of diabetic mice. Our data indicate that ERα and ERß are involved in the cognitive impairment of type 1 diabetes and that activation of ERs via administration of ERs agonists could be a novel and promising strategy for the treatment of diabetic cognitive impairment.
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Disfunción Cognitiva/tratamiento farmacológico , Diabetes Mellitus Experimental/tratamiento farmacológico , Fármacos Neuroprotectores/uso terapéutico , Animales , Apoptosis/efectos de los fármacos , Disfunción Cognitiva/etiología , Diabetes Mellitus Experimental/inducido químicamente , Diabetes Mellitus Experimental/complicaciones , Diabetes Mellitus Experimental/psicología , Estradiol/farmacología , Estradiol/uso terapéutico , Receptor alfa de Estrógeno/agonistas , Receptor alfa de Estrógeno/metabolismo , Receptor beta de Estrógeno/agonistas , Receptor beta de Estrógeno/metabolismo , Femenino , Hipocampo/efectos de los fármacos , Aprendizaje por Laberinto/efectos de los fármacos , Ratones , Ratones Endogámicos ICR , Fármacos Neuroprotectores/farmacología , Nitrilos/farmacología , Nitrilos/uso terapéutico , Ovariectomía , Fenoles/farmacología , Fenoles/uso terapéutico , Pirazoles/farmacología , Pirazoles/uso terapéutico , EstreptozocinaRESUMEN
Mounting evidence suggests that diabetes mellitus (DM) is associated with mild cognitive impairment (MCI), vascular dementia and Alzheimer's disease (AD). Biological, clinical and epidemiological data support a close link between DM and AD. Increasingly, studies have found that several antidiabetic agents can promote neurogenesis, and clinically ameliorate cognitive and memory impairments in different clinical settings. Data has shown that these antidiabetic drugs positively affect mitochondrial and synaptic function, neuroinflammation, and brain metabolism. Evidence to date strongly suggests that these antidiabetic drugs could be developed as disease-modifying therapies for MCI and AD in patients with and without diabetes.
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Enfermedad de Alzheimer/tratamiento farmacológico , Disfunción Cognitiva/tratamiento farmacológico , Hipoglucemiantes/uso terapéutico , Enfermedad de Alzheimer/prevención & control , Disfunción Cognitiva/prevención & control , HumanosRESUMEN
Evidence suggests that neuroinflammation is involved in depression and that the cysteinyl leukotriene receptor 1 (CysLT1R) plays a potential pathophysiological role in several types of CNS disorders. Our previous study has shown that knockdown of hippocampal CysLT1R in mice prevents the depressive-like phenotype and neuroinflammation induced by chronic mild stress (CMS). Here, we examined the effects of hippocampal CysLT1R knockdown and CysLT1R blockade on LPS-induced depressive-like behavior in mice. We found that injection of LPS (0.5 mg/kg, ip) caused marked increase in hippocampal CysLT1R expression, which was reversed by pretreatment with fluoxetine (20 mg·kg-1·d-1 for 7 d, ig). Knockdown of hippocampal CysLT1R or blockade of CysLT1R by pretreatment with pranlukast (0.5 mg/kg, ip) significantly suppressed LPS-induced depressive behaviors, as evidenced by decreases in mouse immobility time in the forced swimming test (FST) and tail suspension test (TST) and latency to feed in the novelty-suppressed feeding (NSF) test. Moreover, both CysLT1R knockdown and CysLT1R blockade markedly prevented LPS-induced neuroinflammation, as shown by the suppressed activation of microglia and NF-κB signaling as well as the hippocampal levels of TNF-α and IL-1ß in mice. Our results suggest that CysLT1R may be involved in LPS-induced depressive-like behaviors and neuroinflammation, and that downregulation of CysLT1R could be a novel and potential therapeutic strategy for the treatment of depression, at least partially due to its role in neuroinflammation.
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Depresión/tratamiento farmacológico , Hipocampo/metabolismo , Lipopolisacáridos/farmacología , Receptores de Leucotrienos/genética , Animales , Cromonas/uso terapéutico , Depresión/metabolismo , Depresión/psicología , Fluoxetina/uso terapéutico , Técnicas de Silenciamiento del Gen , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Antagonistas de Leucotrieno/uso terapéutico , Masculino , Ratones Endogámicos ICR , Receptores de Leucotrienos/metabolismo , Transducción de SeñalRESUMEN
Amyloid-ß deposition is thought to be associated with memory deficits, neuroinflammation, apoptotic responses, and progressive neuronal death manifested in Alzheimer's disease. Peroxisome proliferator-activated receptor δ (PPARδ) is a transcription factor with potent anti-inflammatory effect. In the current study, the effect of GW0742, a selective PPARδ agonist, on Aß1-42-induced neurotoxicity was investigated in the hippocampus of mice. Intra-hippocampal infusion of aggregated Aß1-42 oligomer (410pmol/mouse) remarkably damaged learning and memory in the Morris water maze (MWM) and Y-maze tests, accompanied by decreased expression of PPARδ in the hippocampus as confirmed by Western blot. Intra-hippocampal infusion of GW0742 (1.06 mM/mouse) significantly improved Aß1-42-induced memory deficits in mice, reversed Aß1-42-induced hippocampal PPARδ down-regulation and repressed Aß1-42-triggered neuroinflammatory and apoptotic responses, indicated by decreased nuclear NF-κB p65, TNF-α, IL-1ß as well as a decrease in cleaved caspase-3 and increased ratio of Bcl-2/Bax in the hippocampus. These results suggest that PPARδ activation ameliorates Aß1-42-induced hippocampal neurotoxicity, and it might play a crucial role in Alzheimer's disease.
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Péptidos beta-Amiloides/toxicidad , Hipocampo/efectos de los fármacos , Aprendizaje por Laberinto/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , PPAR delta/agonistas , Fragmentos de Péptidos/toxicidad , Tiazoles/farmacología , Animales , Apoptosis/efectos de los fármacos , Caspasa 3/metabolismo , Hipocampo/metabolismo , Interleucina-1beta/metabolismo , Masculino , Trastornos de la Memoria/tratamiento farmacológico , Trastornos de la Memoria/metabolismo , Ratones , Ratones Endogámicos ICR , FN-kappa B/metabolismo , Neuronas/efectos de los fármacos , Neuronas/metabolismo , PPAR delta/metabolismo , Tiazoles/uso terapéutico , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
BACKGROUND: Emerging data have demonstrated that peroxisome proliferator-activated receptor δ (PPARδ) activation confers a potentially neuroprotective role in some neurodegenerative diseases. However, whether PPARδ is involved in depression is unknown. METHODS: In this study, PPARδ was firstly investigated in the chronic mild stress (CMS) and learned helplessness (LH) models of depression. The changes in depressive behaviors and hippocampal neurogenesis were investigated after PPARδ overexpression by microinfusion of the lentiviral vector, containing the coding sequence of mouse PPARδ (LV-PPARδ), into the bilateral dentate gyri of the hippocampus or PPARδ activation by repeated systemic administration of PPARδ agonist GW0742 (5 or 10mg/kg.d, i.p., for 21 d). RESULTS: We found that both CMS and LH resulted in a significant decrease in the PPARδ expression in the hippocampi of mice, and this change was reversed by treatment with the antidepressant fluoxetine. PPARδ overexpression and PPARδ activation each suppressed the CMS- and LH-induced depressive-like behavior and produced an antidepressive effect. In vivo or in vitro studies also showed that both overexpression and activation of PPARδ enhanced proliferation or differentiation of neural stem cells in the hippocampi of mice. CONCLUSIONS: These results suggest that hippocampal PPARδ upregulation represses stress-induced depressive behaviors, accompanied by enhancement of neurogenesis.
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Depresión/complicaciones , Depresión/patología , Hipocampo/metabolismo , Neurogénesis/fisiología , PPAR delta/metabolismo , Estrés Psicológico/complicaciones , Animales , Diferenciación Celular , Modelos Animales de Enfermedad , Regulación de la Expresión Génica/fisiología , Proteína Ácida Fibrilar de la Glía/metabolismo , Suspensión Trasera , Masculino , Ratones , Ratones Endogámicos ICR , Células-Madre Neurales/fisiología , PPAR delta/genética , Fosfopiruvato Hidratasa/metabolismo , Sincalida/metabolismo , Tiazoles/farmacología , Factores de Tiempo , Transducción GenéticaRESUMEN
Deposition of extracellular amyloid-ß (Aß) peptide is one of the pathological hallmarks of Alzheimer's disease (AD). Accumulation of Aß is thought to associate with cognition deficits, neuroinflammation and apoptosis observed in AD. However, effective neuroprotective approaches against Aß neurotoxicity are unavailable. In the present study, we analysed the effects of pranlukast, a selective cysteinyl leukotriene receptor 1 (CysLT1R) antagonist, on the impairment of learning and memory formation induced by Aß and the probable underlying electrophysiological and molecular mechanisms. We found that bilateral intrahippocampal injection of Aß1â42 resulted in a significant decline of spatial learning and memory of mice in the Morris water maze (MWM) and Y-maze tests, together with a serious depression of in vivo hippocampal long-term potentiation (LTP) in the CA1 region of the mice. Importantly, this treatment caused significant increases in CysLT1R expression and subsequent NF-κB signaling, caspase-3 activation and Bcl-2 downregulation in the hippocampus or prefrontal cortex. Oral administration of pranlukast at 0.4 or 0.8 mg/kg for 4 wk significantly reversed Aß1â42-induced impairments of cognitive function and hippocampal LTP in mice. Furthermore, pranlukast reversed Aß1â42-induced CysLT1R upregulation, and markedly suppressed the Aß1â42-triggered NF-κB pathway, caspase-3 activation and Bcl-2 downregulation in the hippocampus and prefrontal cortex in mice. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay confirmed its presence in the brain after oral administration of pranlukast in mice. These data disclose novel findings about the therapeutic potential of pranlukast, revealing a previously unknown therapeutic possibility to treat memory deficits associated with AD.
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Péptidos beta-Amiloides/farmacología , Cromonas/farmacología , Trastornos del Conocimiento/tratamiento farmacológico , Hipocampo/efectos de los fármacos , Antagonistas de Leucotrieno/farmacología , Fragmentos de Péptidos/farmacología , Péptidos beta-Amiloides/administración & dosificación , Animales , Conducta Animal/efectos de los fármacos , Región CA1 Hipocampal/efectos de los fármacos , Región CA1 Hipocampal/fisiopatología , Cromonas/administración & dosificación , Trastornos del Conocimiento/inducido químicamente , Trastornos del Conocimiento/fisiopatología , Modelos Animales de Enfermedad , Regulación hacia Abajo/efectos de los fármacos , Regulación hacia Abajo/fisiología , Hipocampo/fisiopatología , Aprendizaje/efectos de los fármacos , Antagonistas de Leucotrieno/administración & dosificación , Potenciación a Largo Plazo/efectos de los fármacos , Potenciación a Largo Plazo/fisiología , Masculino , Memoria/efectos de los fármacos , Ratones Endogámicos ICR , Fragmentos de Péptidos/administración & dosificación , Corteza Prefrontal/efectos de los fármacos , Corteza Prefrontal/fisiopatología , Receptores de Leucotrienos/efectos de los fármacosRESUMEN
Although bile acids play a notable role in depression, the pathological significance of the bile acid TGR5 membrane-type receptor in this disorder remains elusive. Using depression models of chronic social defeat stress and chronic restraint stress in male mice, we found that TGR5 in the lateral hypothalamic area (LHA) predominantly decreased in GABAergic neurons, the excitability of which increased in depressive-like mice. Upregulation of TGR5 or inhibition of GABAergic excitability in LHA markedly alleviated depressive-like behavior, whereas down-regulation of TGR5 or enhancement of GABAergic excitability facilitated stress-induced depressive-like behavior. TGR5 also bidirectionally regulated excitability of LHA GABAergic neurons via extracellular regulated protein kinases-dependent Kv4.2 channels. Notably, LHA GABAergic neurons specifically innervated dorsal CA3 (dCA3) CaMKIIα neurons for mediation of depressive-like behavior. LHA GABAergic TGR5 exerted antidepressant-like effects by disinhibiting dCA3 CaMKIIα neurons projecting to the dorsolateral septum (DLS). These findings advance our understanding of TGR5 and the LHAGABAâdCA3CaMKIIαâDLSGABA circuit for the development of potential therapeutic strategies in depression.
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Depresión , Neuronas GABAérgicas , Área Hipotalámica Lateral , Receptores Acoplados a Proteínas G , Animales , Masculino , Ratones , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/metabolismo , Depresión/metabolismo , Modelos Animales de Enfermedad , Neuronas GABAérgicas/metabolismo , Neuronas GABAérgicas/fisiología , Área Hipotalámica Lateral/metabolismo , Ratones Endogámicos C57BL , Vías Nerviosas/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Receptores Acoplados a Proteínas G/genética , Núcleos Septales/metabolismo , Derrota Social , Estrés Psicológico/metabolismoRESUMEN
Clinical and experimental studies have shown that the sharp reduction of estrogen is one of the important reasons for the high incidence of Alzheimer's disease (AD) in elderly women, but there is currently no such drug for treatment of AD. Our group first designed and synthesized a novel compound R-9-(4fluorophenyl)-3-methyl-10,10,-Hydrogen-6-hydrogen-benzopyran named FMDB. In this study, our aim is to investigate the neuroprotective effects and mechanism of FMDB in APP/PS1 transgenic mice. 6 months old APP/PS1 transgenic mice were intragastrical administered with FMDB (1.25, 2.5 and 5 mg/kg) every other day for 8 weeks. LV-ERß-shRNA was injected bilaterally into the hippocampus of APP/PS1 mice to knockdown estrogen receptor ß (ERß). We found that FMDB ameliorated cognitive impairment in the Morris water maze and novel object recognition tests, increased hippocampal neurogenesis and prevented hippocampal apoptotic responses in APP/PS1 mice. Importantly, FMDB activated nuclear ERß mediated CBP/p300, CREB and brain-derived neurotrophic factor (BDNF) signaling, and membrane ERß mediated PI3K/Akt, CREB and BDNF signaling in the hippocampus. Our study demonstrated the contributions and mechanism of FMDB to cognition, neurogenesis and apoptosis in APP/PS1 mice. These lay the experimental foundation for the development of new anti-AD drugs.
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Enfermedad de Alzheimer , Fármacos Neuroprotectores , Ratones , Animales , Femenino , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/genética , Ratones Transgénicos , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Fosfatidilinositol 3-Quinasas , Receptor beta de Estrógeno , Cognición , Hipocampo/metabolismo , Modelos Animales de Enfermedad , Neurogénesis , Apoptosis , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Presenilina-1/genéticaRESUMEN
BACKGROUND: Cognitive impairment is a serious complication of diabetes that manifests as an impairment of spatial memory and learning ability. Its pathogenesis is unclear, and effective therapeutic drugs are very limited. Our group designed and synthesized a novel compound named 3-p-tolyl-9H-xanthen-9-one (Tozan). In this study, we sought to investigate the effects and mechanism of Tozan on diabetic cognitive impairment. METHODS: Methylglyoxal (MG)-induced SH-SY5Y cells and streptozotocin (STZ)-induced type 1 diabetic mice were treated with Tozan. Methyl thiazolul tetrazolium (MTT) and lactate dehydrogenase (LDH) were used to test cytotoxicity. Morris water maze (MWM) and Y-maze tests were used to evaluate cognitive function. Immunofluorescence and western blot analyses were used to evaluate neurogenesis, apoptosis, and signal transduction pathway-related proteins. In addition, Lentivirus (LV)-estrogen receptor beta (ERß)-ribonucleic acid interference (RNAi) was used to knockdown the ERß gene in SH-SY5Y cells. RESULTS: We found that Tozan ameliorated MG-induced cytotoxicity in SH-SY5Y cells, improved cognitive dysfunction in STZ-induced type 1 diabetic mice, increased neurogenesis, and prevented apoptotic responses in vitro and in vivo. Importantly, Tozan (2, 4, and 8 mg/kg) mediated phosphatidylinositol-3-kinase and protein kinase B cAMP-response element binding protein (PI3K/Akt-CREB) signaling by activating membrane ERß, and a high dose of Tozan (8 mg/kg) mediated CREB signaling by activating nuclear ERß in the hippocampus. Notably, Tozan did not have an anti-apoptosis and regeneration protective role in ERß gene knockdown cells. CONCLUSIONS: Our study demonstrates Tozan's contributions to and role in cognition, neurogenesis, and apoptosis in diabetes, and lays an experimental foundation for the development of new anti-diabetic cognitive impairment drugs.
RESUMEN
BACKGROUND: Our previous studies demonstrated that cysteinyl leukotrienes receptor 1 (CysLT1R) knockout, pharmacological blockade, or hippocampus knockdown produced beneficial effects against Alzheimer's disease (AD); however, whether CysLT1R upregulation has deleterious effects on AD remains elusive. METHODS: In this study, we investigated the changes in behaviors, hippocampal amyloidogenesis, and synapse plasticity after CysLT1R overexpression by microinfusion of the lentiviral vector, containing its coding sequence of mouse (LV-CysLT1R), into the bilateral dentate gyri (DG) of the hippocampus or CysLT1R activation by repeated systemic administration of its agonist YM-17690 (0.1 mg/kg, once a day, i.p., for 28 d). RESULTS: The behavior data showed that overexpression of CysLT1R in hippocampal DG or administration of YM-17690 deteriorated behavioral performance in Morris water maze (MWM), Y-maze tests, and novel object recognition (NOR) in young APP/PS1 mice. The further studies showed that these treatments significantly destroyed synaptic function, as evidenced by impaired hippocampal long-term potentiation (LTP), decreased spine density, low number of synapses, and decreased postsynaptic protein (PSD95), and promoted the generation of amyloid ß (Aß) through increased expression of BACE1 and PS1 in the hippocampus of young APP/PS1 mice. CONCLUSIONS: Together, our results indicate that CysLT1R upregulation accelerates memory impairment in young APP/PS1 mice, which is associated with promoting synaptic dysfunction and amyloidogenesis in the hippocampus.
RESUMEN
BACKGROUND: Takeda G protein-coupled receptor 5 (TGR5) is recognized as a promising target for type 2 diabetes and metabolic syndrome; its expression has been demonstrated in the brain and is thought to be neuroprotective. Here, we hypothesize that dysfunction of central TGR5 may contribute to the pathogenesis of depression. METHODS: In well-established chronic social defeat stress (CSDS) and chronic restraint stress (CRS) models of depression, we investigated the functional roles of TGR5 in CA3 pyramidal neurons (PyNs) and underlying mechanisms of the neuronal circuit in depression (for in vivo studies, n = 10; for in vitro studies, n = 5-10) using fiber photometry; optogenetic, chemogenetic, pharmacological, and molecular profiling techniques; and behavioral tests. RESULTS: Both CSDS and CRS most significantly reduced TGR5 expression of hippocampal CA3 PyNs. Genetic overexpression of TGR5 in CA3 PyNs or intra-CA3 infusion of INT-777, a specific agonist, protected against CSDS and CRS, exerting significant antidepressant-like effects that were mediated via CA3 PyN activation. Conversely, genetic knockout or TGR5 knockdown in CA3 facilitated stress-induced depression-like behaviors. Re-expression of TGR5 in CA3 PyNs rather than infusion of INT-777 significantly improved depression-like behaviors in Tgr5 knockout mice exposed to CSDS or CRS. Silencing and stimulation of CA3 PyNsâsomatostatin-GABAergic (gamma-aminobutyric acidergic) neurons of the dorsolateral septum circuit bidirectionally regulated depression-like behaviors, and blockade of this circuit abrogated the antidepressant-like effects from TGR5 activation of CA3 PyNs. CONCLUSIONS: These findings indicate that TGR5 can regulate depression via CA3 PyNsâsomatostatin-GABAergic neurons of dorsolateral septum transmission, suggesting that TGR5 could be a novel target for developing antidepressants.
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Depresión , Células Piramidales/fisiología , Receptores Acoplados a Proteínas G/fisiología , Animales , Región CA3 Hipocampal/fisiología , RatonesRESUMEN
Our previous study has found that zileuton, a selective 5-lipoxygenase (5LO) inhibitor, abrogated lipopolysaccharide-induced depressive-like behaviors and hippocampal neuroinflammation. Herein, we further extended our curiosity to investigate effects of zileuton on stress-induced depressive-like behaviors. Our data indicated that zileuton significantly ameliorated depressive-like behaviors in mice subjected to chronic mild stress (CMS), as shown in the tail suspension test, forced swimming test and novelty-suppressed feeding test. The further studies indicated that zileuton suppressed hippocampal neuroinflammation, evidenced by lower levels of TNF-α, IL-1ß and nuclear NF-κB p65 as well as decreased number of Iba1-positive cells. It also significantly ameliorated hippocampal apoptosis, indicated by deceased number of TUNEL-positive cells, deceased ratio of cleaved caspase-3/procaspase-3 and increased ratio of Bcl-2/Bax. More importantly, zileuton increased the level of synaptic proteins PSD-95 and SYN and the number of NeuN+/BrdU+ cells in the hippocampus. Over all, zileuton alleviated CMS-induced depressive-like behaviors, neuroinflammatory and apoptotic responses, abnormalities of synapse and neurogenesis in the hippocampus, suggesting that it might has beneficial effects on depression.
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Antiinflamatorios/uso terapéutico , Antidepresivos/uso terapéutico , Depresión/tratamiento farmacológico , Encefalitis/tratamiento farmacológico , Hidroxiurea/análogos & derivados , Fármacos Neuroprotectores/uso terapéutico , Estrés Psicológico/tratamiento farmacológico , Animales , Antiinflamatorios/farmacología , Antidepresivos/farmacología , Apoptosis/efectos de los fármacos , Conducta Animal/efectos de los fármacos , Depresión/metabolismo , Depresión/patología , Encefalitis/metabolismo , Encefalitis/patología , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Hipocampo/patología , Hidroxiurea/farmacología , Hidroxiurea/uso terapéutico , Interleucina-1beta/metabolismo , Masculino , Ratones Endogámicos ICR , Neurogénesis/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Estrés Psicológico/metabolismo , Estrés Psicológico/patología , Sinapsis/efectos de los fármacos , Factor de Transcripción ReIA/metabolismo , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Estrogen receptors (ERs) are thought to be associated with the onset and progression of neurodegenerative injuries and diseases, but the relationship and mechanisms underlying between ERs and cognition in type 2 diabetes remain elusive. In the current study, we investigated the effects of ERα and ERß on the cognition, neurogenesis and apoptosis in high-fat diet and streptozocin-induced diabetic mice. We found that ERα and/or ERß activation using their agonists (0.5â¯mg/kg E2, PPT or DPN) ameliorate memory impairment in the Morris water maze and Y-maze tests, increase hippocampal neurogenesis and prevent hippocampal apoptotic responses. Importantly, treatment with the pharmacologic ERs agonists caused significant increases in the membrane ERα and ERß expression and subsequent PI3K/Akt, CREB and BDNF activation in the hippocampus of type 2 diabetes mellitus mice. Our data indicate that ERα and ERß are involved in the cognitive impairment in type 2 diabetes, and that activated ERs, such as application of ERs agonists, could be a novel and promising strategy for the treatment of diabetic cognitive impairment.
Asunto(s)
Apoptosis/fisiología , Disfunción Cognitiva/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Receptor alfa de Estrógeno/metabolismo , Receptor beta de Estrógeno/metabolismo , Neurogénesis/fisiología , Animales , Apoptosis/efectos de los fármacos , Disfunción Cognitiva/tratamiento farmacológico , Disfunción Cognitiva/psicología , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/psicología , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/psicología , Estradiol/farmacología , Estradiol/uso terapéutico , Receptor alfa de Estrógeno/agonistas , Receptor beta de Estrógeno/agonistas , Femenino , Aprendizaje por Laberinto/efectos de los fármacos , Aprendizaje por Laberinto/fisiología , Ratones , Ratones Endogámicos ICR , Neurogénesis/efectos de los fármacos , Distribución AleatoriaRESUMEN
Alzheimer's disease (AD) is a neurodegenerative disease that affects cognition and behavior. The neuroinflammatory response in the brain is an important pathological characteristic in AD. In this study, we investigated the neuroprotective effects of 1-Methylnicotinamide (MNA), known as the main metabolite of nicotinamide, on reducing lipopolysaccharide (LPS)-induced cognitive deficits via targeting neuroinflammation and neuronal apoptosis. We found that the mice treated with LPS exhibited cognitive deficits in the novel object recognition, Morris water maze and Y-maze avoidance tests. However, intragastric administration of MNA (100 or 200â¯mg/kg) for 3â¯weeks significantly attenuated LPS-induced cognitive deficits in mice. Importantly, MNA treatment suppressed the protein expression of nuclear factor-kappa B p65 (NF-κB p65), pro-inflammatory cytokines (TNF-α, IL-6) and decreased the activation of microglia and astrocytes in the hippocampus and frontal cortex of LPS-induced mice. In addition, MNA treatment suppressed neuronal apoptosis by reducing the number of TUNEL-positive cells, caspase-3 activation and increasing the level of Bcl-2/Bax ratio in the hippocampus and frontal cortex. These findings indicate that MNA could be a potential neuroprotective drug in neurodegenerative diseases such as AD.
Asunto(s)
Antiinflamatorios/uso terapéutico , Trastornos del Conocimiento/tratamiento farmacológico , Trastornos de la Memoria/tratamiento farmacológico , Fármacos Neuroprotectores/uso terapéutico , Niacinamida/análogos & derivados , Animales , Antiinflamatorios/farmacología , Apoptosis/efectos de los fármacos , Trastornos del Conocimiento/inducido químicamente , Trastornos del Conocimiento/inmunología , Lóbulo Frontal/efectos de los fármacos , Hipocampo/efectos de los fármacos , Interleucina-6/inmunología , Lipopolisacáridos , Masculino , Trastornos de la Memoria/inducido químicamente , Trastornos de la Memoria/inmunología , Ratones Endogámicos ICR , Neuronas/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Niacinamida/farmacología , Niacinamida/uso terapéutico , Factor de Transcripción ReIA/inmunología , Factor de Necrosis Tumoral alfa/inmunologíaRESUMEN
Accumulating evidence has shown that tauroursodeoxycholic acid (TUDCA) is neuroprotective in different animal models of neurological diseases. However, whether TGR5 agonist TUDCA can improve lipopolysaccharide (LPS)-induced cognitive impairment in mice is less clear. Using a model of cognitive impairment with LPS (2.0⯵g) we investigated the effects of TUDCA (200 or 400⯵g) on cognitive dysfunction and neurotoxicity in mice. Both Morris water maze and Y-maze avoidance tests showed that TUDCA treatment significantly alleviated LPS-induced behavioral impairments. More importantly, we found that TUDCA treatment reversed TGR5 down-regulation, prevented neuroinflammation via inhibiting NF-κB signaling in the hippocampus of LPS-treated mice. Additionally, TUDCA treatment decreased LPS-induced apoptosis through decreasing TUNEL-positive cells and the overexpression of caspase-3, increasing the ratio of Bcl-2/Bax. TUDCA treatment also ameliorated synaptic plasticity impairments by increasing the ratio of mBDNF/proBDNF, the number of dendritic spines and the expression of synapse-associated proteins in the hippocampus. Our results indicated that TUDCA can improve cognitive impairment and neurotoxicity induced by LPS in mice, which is involved in TGR5-mediated NF-κB signaling.
Asunto(s)
Disfunción Cognitiva/tratamiento farmacológico , Fármacos Neuroprotectores/uso terapéutico , Ácido Tauroquenodesoxicólico/uso terapéutico , Animales , Apoptosis/efectos de los fármacos , Disfunción Cognitiva/metabolismo , Disfunción Cognitiva/fisiopatología , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Lipopolisacáridos , Ratones , Microglía/efectos de los fármacos , FN-kappa B/metabolismo , Neuronas/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Receptores Acoplados a Proteínas G/agonistas , Sinapsis/efectos de los fármacos , Sinapsis/fisiología , Ácido Tauroquenodesoxicólico/farmacologíaRESUMEN
Neuroinflammation plays an important role in the pathophysiology of Alzheimer's disease (AD) and memory impairment. Herein, we evaluated the neuroprotective effects of 6-ethyl-23(S)-methyl-cholic acid (INT-777), a specific G-protein coupled bile acid receptor 1 (TGR5) agonist, in the LPS-treated mouse model of acute neurotoxicity. Single intracerebroventricular (i.c.v.) injection of LPS remarkably induced mouse behavioral impairments in Morris water maze, novel object recognition, and Y-maze avoidance tests, which were ameliorated by INT-777 (1.5 or 3.0⯵g/mouse, i.c.v.) treatment. Importantly, INT-777 treatment reversed LPS-induced TGR5 down-regulation, suppressed the increase of nuclear NF-κB p65, and mitigated neuroinflammation, evidenced by lower proinflammatory cytokines, less activation of microglia, and increased the ratio of p-CREB/CREB or mBDNF/proBDNF in the hippocampus and frontal cortex. In addition, INT-777 treatment also suppressed neuronal apoptosis, as indicated by the reduction of TUNEL-positive cells, decreased activation of caspase-3, increased the ratio of Bcl-2/Bax, and ameliorated synaptic dysfunction as evidenced by the upregulation of PSD95 and synaptophysin in the hippocampus and frontal cortex. Taken together, this study showed the potential neuroprotective effects of INT-777 against LPS-induced cognitive impairment, neuroinflammation, apoptosis, and synaptic dysfunction in mice.
Asunto(s)
Antiinflamatorios/uso terapéutico , Apoptosis/efectos de los fármacos , Ácidos Cólicos/uso terapéutico , Trastornos del Conocimiento/tratamiento farmacológico , Encefalitis/tratamiento farmacológico , Sinapsis/efectos de los fármacos , Animales , Proteínas de Unión al Calcio/metabolismo , Trastornos del Conocimiento/inducido químicamente , Citocinas/metabolismo , Modelos Animales de Enfermedad , Interacciones Farmacológicas , Encefalitis/inducido químicamente , Conducta Exploratoria/efectos de los fármacos , Lipopolisacáridos/toxicidad , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Ratones , Ratones Endogámicos ICR , Proteínas de Microfilamentos/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Reconocimiento en Psicología/efectos de los fármacos , Sinapsis/patología , Proteína X Asociada a bcl-2/metabolismoRESUMEN
AIMS: To investigate restorative effects of the receptor for advanced glycation end products (RAGE)-specific inhibitor FPS-ZM1 on abnormal amyloid ß (Aß) influx across the blood brain-barrier (BBB) and cognitive deficits in db/db mice. METHODS: Aß influx across the BBB was determined by intra-arterial infusion of 125I-Aß1-40. Receptor for advanced glycation end products (RAGE), Aß, NF-κB p65, caspase-3, Bax, Bcl-2, PSD-95 and synaptophysin were assayed by Western blot, immunohistochemistry or RT-PCR. Apoptosis was quantified by TUNEL assay. In vivo hippocampal long term potentiation (LTP) recording, Golgi Staining, Morris water maze (MWM) task and Y-maze test were performed. RESULTS: FPS-ZM1 (1.0â¯mg/kg i.p.) inhibited Aß influx across the BBB and expression of RAGE participating in Aß influx, consequently decreased hippocampal Aß1-40 and Aß1-42 in db/db mice. After FPS-ZM1 treatment, NF-κB signaling was inhibited, and neuronal apoptosis was reduced, which revealed by less TUNEL + cells, reduced caspase-3 activity and higher ratio of Bcl-2/Bax. In addition, FPS-ZM1 improved hippocampal plasticity evidenced by enhanced in vivo LTP and the restoration of spine deficit and increased PSD-95 expression in hippocampal neuron. Further studies found that FPS-ZM1 treatment alleviated cognitive deficits shown by better performance in behavioral tests, without significant metabolic effects on blood glucose, insulin and cerebral AGEs. CONCLUSION: Downregulation of abnormal Aß influx across the BBB by FPS-ZM1 at higher dosage contributes to reduced neuronal apoptosis, improved hippocampal plasticity and cognitive impairment in db/db mice.