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1.
Life Sci ; 276: 119407, 2021 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-33794254

RESUMEN

AIMS: The aim of the study was to investigate the interaction between cannabinoid CB1/CB2 and lysophosphatidic acid (LPA) receptors in controlling neuronal signaling and fate. METHODS: HT22 hippocampal cells were treated with different cannabinoid and LPA receptor agonists and antagonists. Western blot and immunofluorescence microscopy were used to study intracellular signaling and the expression of apoptotic markers. Cell viability was determined by a luminescence assay. KEY FINDINGS: Cannabinoid agonists induced activation of both ERK1/2 and p38 MAP kinases. The effects of the CB1/CB2 receptor agonist HU210 were antagonized by the CB1 antagonist rimonabant, whereas the responses to the CB2 agonist JWH133 were blocked by the CB2 antagonist SR144528. HU210 reduced the apoptotic cell death induced by the pro-inflammatory cytokine TNF-α, whereas JWH133 enhanced the cytokine cytotoxicity. Blockade of ERK1/2 and p38 MAPK activation abrogated the HU210 pro-survival and the JWH133 pro-apoptotic effects, respectively. HU210 and the endocannabinoid anandamide, but not JWH133, potentiated ERK1/2 stimulation by LPA and the tricyclic antidepressant amitriptyline acting through the LPA1 receptor. HU210 enhanced amitriptyline-stimulated CREB phosphorylation and protection against TNF-α-induced apoptosis, whereas JWH133 had no effect. ERK1/2 stimulation by either HU210 or amitriptyline was dependent on fibroblast growth factor receptor (FGF-R) kinase activity and the combination of the two stimulants induced FGF-R phosphorylation. Moreover, the CB1 receptor was found to co-immunoprecipitate with the LPA1 receptor. CONCLUSIONS: In HT22 hippocampal cells CB1 and CB2 receptors differentially regulate TNF-α-induced apoptosis and CB1 receptors positively interact with amitriptyline-stimulated LPA1 in promoting FGF-R-mediated ERK1/2 signaling and neuroprotection.


Asunto(s)
Apoptosis , Agonistas de Receptores de Cannabinoides/farmacología , Hipocampo/patología , Receptor Cannabinoide CB1/metabolismo , Receptor Cannabinoide CB2/metabolismo , Receptores del Ácido Lisofosfatídico/metabolismo , Factor de Necrosis Tumoral alfa/farmacología , Inhibidores de Captación Adrenérgica/farmacología , Amitriptilina/farmacología , Animales , Supervivencia Celular , Células Cultivadas , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Ratones , Proteína Quinasa 1 Activada por Mitógenos/genética , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos/genética , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Fosforilación , Receptor Cannabinoide CB1/agonistas , Receptor Cannabinoide CB2/agonistas , Receptores del Ácido Lisofosfatídico/genética , Transducción de Señal
2.
Int J Mol Sci ; 22(6)2021 Mar 22.
Artículo en Inglés | MEDLINE | ID: mdl-33810180

RESUMEN

Status epilepticus (SE) is a frequent medical emergency that can lead to a variety of neurological disorders, including cognitive impairment and abnormal neurogenesis. The aim of the presented study was the in vitro evaluation of potential neuroprotective properties of a new pyrrolidine-2,5-dione derivatives compound C11, as well as the in vivo assessment of the impact on the neurogenesis and cognitive functions of C11 and levetiracetam (LEV) after pilocarpine (PILO)-induced SE in mice. The in vitro results indicated a protective effect of C11 (500, 1000, and 2500 ng/mL) on astrocytes under trophic stress conditions in the MTT (3-[4,5-dimethylthiazole-2-yl]-2,5-diphenyltetrazolium bromide) test. The results obtained from the in vivo studies, where mice 72 h after PILO SE were treated with C11 (20 mg/kg) and LEV (10 mg/kg), indicated markedly beneficial effects of C11 on the improvement of the neurogenesis compared to the PILO control and PILO LEV mice. Moreover, this beneficial effect was reflected in the Morris Water Maze test evaluating the cognitive functions in mice. The in vitro confirmed protective effect of C11 on astrocytes, as well as the in vivo demonstrated beneficial impact on neurogenesis and cognitive functions, strongly indicate the need for further advanced molecular research on this compound to determine the exact neuroprotective mechanism of action of C11.


Asunto(s)
Anticonvulsivantes/farmacología , Cognición/efectos de los fármacos , Neurogénesis/efectos de los fármacos , Pilocarpina/efectos adversos , Estado Epiléptico/etiología , Animales , Anticonvulsivantes/administración & dosificación , Astrocitos/efectos de los fármacos , Astrocitos/metabolismo , Biomarcadores , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Masculino , Ratones , Fármacos Neuroprotectores/farmacología , Estado Epiléptico/diagnóstico , Estado Epiléptico/tratamiento farmacológico
3.
Int J Mol Sci ; 22(4)2021 Feb 19.
Artículo en Inglés | MEDLINE | ID: mdl-33669795

RESUMEN

AdipoRon, an adiponectin receptor agonist, elicits similar antidiabetic, anti-atherogenic, and anti-inflammatory effects on mouse models as adiponectin does. Since AdipoRon can cross the blood-brain barrier, its chronic effects on regulating hippocampal function are yet to be examined. This study investigated whether AdipoRon treatment promotes hippocampal neurogenesis and spatial recognition memory in a dose-dependent manner. Adolescent male C57BL/6J mice received continuous treatment of either 20 mg/kg (low dose) or 50 mg/kg (high dose) AdipoRon or vehicle intraperitoneally for 14 days, followed by the open field test to examine anxiety and locomotor activity, and the Y maze test to examine hippocampal-dependent spatial recognition memory. Immunopositive cell markers of neural progenitor cells, immature neurons, and newborn cells in the hippocampal dentate gyrus were quantified. Immunosorbent assays were used to measure the serum levels of factors that can regulate hippocampal neurogenesis, including adiponectin, brain-derived neurotrophic factor (BDNF), and corticosterone. Our results showed that 20 mg/kg AdipoRon treatment significantly promoted hippocampal cell proliferation and increased serum levels of adiponectin and BDNF, though there were no effects on spatial recognition memory and locomotor activity. On the contrary, 50 mg/kg AdipoRon treatment impaired spatial recognition memory, suppressed cell proliferation, neuronal differentiation, and cell survival associated with reduced serum levels of BDNF and adiponectin. The results suggest that a low-dose AdipoRon treatment promotes hippocampal cell proliferation, while a high-dose AdipoRon treatment is detrimental to the hippocampus function.


Asunto(s)
Envejecimiento/fisiología , Hipocampo/fisiología , Neurogénesis/efectos de los fármacos , Piperidinas/farmacología , Adiponectina/sangre , Animales , Glucemia/metabolismo , Factor Neurotrófico Derivado del Encéfalo/sangre , Diferenciación Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Corticosterona/sangre , Giro Dentado/efectos de los fármacos , Giro Dentado/fisiología , Hipocampo/efectos de los fármacos , Masculino , Ratones Endogámicos C57BL , Modelos Biológicos , Células-Madre Neurales/efectos de los fármacos , Células-Madre Neurales/metabolismo , Neuronas/metabolismo , Memoria Espacial/efectos de los fármacos
4.
Int J Mol Sci ; 22(5)2021 Feb 25.
Artículo en Inglés | MEDLINE | ID: mdl-33668718

RESUMEN

BACKGROUND: Status epilepticus (SE) is a neurological disorder characterized by a prolonged epileptic activity followed by subsequent epileptogenic processes. The aim of the present study was to evaluate the early effects of topiramate (TPM) and lacosamide (LCM) treatment on oxidative stress and inflammatory damage in a model of pilocarpine-induced SE. METHODS: Male Wistar rats were randomly divided into six groups and the two antiepileptic drugs (AEDs), TPM (40 and 80 mg/kg, i.p.) and LCM (10 and 30 mg/kg, i.p.), were injected three times repeatedly after pilocarpine administration. Rats were sacrificed 24 h post-SE and several parameters of oxidative stress and inflammatory response have been explored in the hippocampus. RESULTS: The two drugs TPM and LCM, in both doses used, succeeded in attenuating the number of motor seizures compared to the SE-veh group 30 min after administration. Pilocarpine-induced SE decreased the superoxide dismutase (SOD) activity and reduced glutathione (GSH) levels while increasing the catalase (CAT) activity, malondialdehyde (MDA), and IL-1ß levels compared to the control group. Groups with SE did not affect the TNF-α levels. The treatment with a higher dose of 30 mg/kg LCM restored to control level the SOD activity in the SE group. The two AEDs, in both doses applied, also normalized the CAT activity and MDA levels to control values. In conclusion, we suggest that the antioxidant effect of TPM and LCM might contribute to their anticonvulsant effect against pilocarpine-induced SE, whereas their weak anti-inflammatory effect in the hippocampus is a consequence of reduced SE severity.


Asunto(s)
Anticonvulsivantes/uso terapéutico , Inflamación/patología , Lacosamida/uso terapéutico , Especies Reactivas de Oxígeno/metabolismo , Estado Epiléptico/inducido químicamente , Estado Epiléptico/tratamiento farmacológico , Topiramato/uso terapéutico , Animales , Anticonvulsivantes/farmacología , Biomarcadores/metabolismo , Hipocampo/efectos de los fármacos , Hipocampo/patología , Hipocampo/fisiopatología , Interleucina-1beta/metabolismo , Lacosamida/farmacología , Masculino , Actividad Motora/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Pilocarpina , Ratas Wistar , Convulsiones/fisiopatología , Estado Epiléptico/fisiopatología , Topiramato/farmacología , Factor de Necrosis Tumoral alfa/metabolismo
5.
Toxicol Lett ; 344: 11-17, 2021 Jun 15.
Artículo en Inglés | MEDLINE | ID: mdl-33675918

RESUMEN

Acrolein is a universal contaminant with high nucleophilicity in environment and also an endogenous product from lipid peroxidation or polyamine metabolism. Acrolein can react with nucleophilic amino acids, such as cysteines, lysines and histidines via Michael addition. Also, Schiff base products can be formed between acrolein and free amine of lysines. Accumulating evidences demonstrated that acrolein is involved in many diseases, including Alzheimer's disease (AD). Previously we found that oral exposure of acrolein induced AD-like pathology in rats. Here we investigated the acrolein-conjugated proteins in the hippocampus of acrolein-treated mice (3.0 mg/kg/d by gavage for 4 weeks) and aged APP/PS1 mice (the age of 22 months). Acrolein-conjugated proteins were enriched by an aniline-based aldehyde-directed probe, meta-aminophenylacetylene (m-APA). Combined with a quantitative chemoproteomic strategy, 912 proteins were finally identified. Gene ontology analysis revealed several acrolein affected pathways including glycolysis, tricarboxylic acid (TCA) cycle and carbon metabolism. Acrolein are mainly conjugated with 14-3-3 protein and members of small GTPase family in hippocampus. Taken together, our results provide new evidences for the roles of acrolein in AD.


Asunto(s)
Acroleína/toxicidad , Envejecimiento , Enfermedad de Alzheimer , Hipocampo/metabolismo , Proteómica/métodos , Precursor de Proteína beta-Amiloide , Animales , Hipocampo/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos
6.
Life Sci ; 273: 119310, 2021 May 15.
Artículo en Inglés | MEDLINE | ID: mdl-33667517

RESUMEN

AIMS: Alzheimer's disease (AD) is a leading health problem in which increased amyloid ß (Aß) accumulation may occur due to abnormal Aß precursor protein processing by ß-secretase 1 (BACE1) enzyme. Lately, neuro-inflammation was recognized as a significant contributor to its pathogenesis. Although the causes of AD are not yet well understood, much evidence has suggested that dyslipidemia has harmful effects on cognitive function and is inextricably involved in AD pathogenesis. Cholesterol is a vital molecule involved in neuronal development. Alteration in neuronal cholesterol levels affects Aß metabolism and results in neurodegeneration. Proprotein-convertase-subtilisin/kexin type-9 (PCSK9) was found to decrease neuronal cholesterol uptake by degradation of LDL-receptor related protein 1 (LRP-1) responsible for neuronal cholesterol uptake. Accordingly, this study was designed to evaluate the effect of PCSK9-inhibition by alirocumab (Aliro) in high-fat-cholesterol-diet (HFCD)-induced-AD-like condition. MAIN METHODS: Wistar Rats were divided into six groups; control; HFCD; HFCD and Memantine; HFCD and Aliro (4, 8 and 16 mg/kg/week) to test for ability of Aliro to modulate cognitive impairment, amyloidosis, brain cholesterol homeostasis and neuro-inflammation in HFCD-induced-AD-like condition. KEY FINDINGS: Our results demonstrated an association between PCSK9 inhibition by Aliro and amelioration of cognitive deficit, cholesterol hemostasis and reduction of neuro-inflammation. Aliro was able to alleviate hippocampal LRP-1expression levels and reduce brain cholesterol, hippocampal BACE1, Aß42, high-mobility-group-box-1 protein, receptor for advanced-glycation-end-products and toll like receptor-4 with subsequent decrease of different inflammatory mediators as nuclear-factor-kappa-B (NF-κB), tumor-necrosis-factor-alpha (TNF-α), interleukin-1beta (IL-1ß) and IL-6. SIGNIFICANCE: PCSK9-inhibition may represent a new therapeutic target in AD especially for HFCD-induced-AD-like condition.


Asunto(s)
Amiloidosis/tratamiento farmacológico , Anticuerpos Monoclonales Humanizados/farmacología , Colesterol/toxicidad , Disfunción Cognitiva/tratamiento farmacológico , Dieta Alta en Grasa/efectos adversos , Memantina/farmacología , Proproteína Convertasa 9/antagonistas & inhibidores , Amiloidosis/etiología , Amiloidosis/metabolismo , Amiloidosis/patología , Animales , Disfunción Cognitiva/etiología , Disfunción Cognitiva/metabolismo , Disfunción Cognitiva/patología , Antagonistas de Aminoácidos Excitadores/farmacología , Ácido Glutámico/metabolismo , Proteína HMGB1/genética , Proteína HMGB1/metabolismo , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Hipocampo/patología , Masculino , Ratas , Ratas Wistar , Receptor para Productos Finales de Glicación Avanzada/genética , Receptor para Productos Finales de Glicación Avanzada/metabolismo , Receptor Toll-Like 4/genética , Receptor Toll-Like 4/metabolismo
7.
Int J Mol Sci ; 22(3)2021 Jan 26.
Artículo en Inglés | MEDLINE | ID: mdl-33530349

RESUMEN

Tauopathies are a group of more than twenty known disorders that involve progressive neurodegeneration, cognitive decline and pathological tau accumulation. Current therapeutic strategies provide only limited, late-stage symptomatic treatment. This is partly due to lack of understanding of the molecular mechanisms linking tau and cellular dysfunction, especially during the early stages of disease progression. In this study, we treated early stage tau transgenic mice with a multi-target kinase inhibitor to identify novel substrates that contribute to cognitive impairment and exhibit therapeutic potential. Drug treatment significantly ameliorated brain atrophy and cognitive function as determined by behavioral testing and a sensitive imaging technique called manganese-enhanced magnetic resonance imaging (MEMRI) with quantitative R1 mapping. Surprisingly, these benefits occurred despite unchanged hyperphosphorylated tau levels. To elucidate the mechanism behind these improved cognitive outcomes, we performed quantitative proteomics to determine the altered protein network during this early stage in tauopathy and compare this model with the human Alzheimer's disease (AD) proteome. We identified a cluster of preserved pathways shared with human tauopathy with striking potential for broad multi-target kinase intervention. We further report high confidence candidate proteins as novel therapeutically relevant targets for the treatment of tauopathy. Proteomics data are available via ProteomeXchange with identifier PXD023562.


Asunto(s)
Neuronas/efectos de los fármacos , Neuronas/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Tauopatías/etiología , Tauopatías/metabolismo , Animales , Encéfalo/metabolismo , Encéfalo/patología , Modelos Animales de Enfermedad , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Hipocampo/patología , Humanos , Ratones , Ratones Transgénicos , Enfermedades Neurodegenerativas/diagnóstico , Enfermedades Neurodegenerativas/tratamiento farmacológico , Enfermedades Neurodegenerativas/etiología , Enfermedades Neurodegenerativas/metabolismo , Fosforilación , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteoma , Proteómica/métodos , Índice de Severidad de la Enfermedad , Tauopatías/diagnóstico , Tauopatías/tratamiento farmacológico , Respuesta de Proteína Desplegada , eIF-2 Quinasa/metabolismo , Proteínas tau/metabolismo
8.
Nat Neurosci ; 24(3): 326-330, 2021 03.
Artículo en Inglés | MEDLINE | ID: mdl-33603228

RESUMEN

By investigating the topology of neuronal co-activity, we found that mnemonic information spans multiple operational axes in the mouse hippocampus network. High-activity principal cells form the core of each memory along a first axis, segregating spatial contexts and novelty. Low-activity cells join co-activity motifs across behavioral events and enable their crosstalk along two other axes. This reveals an organizational principle for continuous integration and interaction of hippocampal memories.


Asunto(s)
Condicionamiento Operante/fisiología , Hipocampo/fisiología , Memoria/fisiología , Red Nerviosa/fisiología , Neuronas/fisiología , Sacarosa/administración & dosificación , Potenciales de Acción/efectos de los fármacos , Potenciales de Acción/fisiología , Animales , Condicionamiento Operante/efectos de los fármacos , Hipocampo/efectos de los fármacos , Memoria/efectos de los fármacos , Ratones , Red Nerviosa/efectos de los fármacos , Neuronas/efectos de los fármacos
9.
Toxicol Lett ; 341: 68-79, 2021 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-33548343

RESUMEN

BACKGROUND: General anesthetics such as sevoflurane interfere with dendritic development and synaptogenesis, resulting in cognitive impairment. The collapsin response mediator protein2 (CRMP2) plays important roles in dendritic development and synaptic plasticity and its phosphorylation is regulated by cycline dependent kinase-5 (Cdk5) and glycogen synthase kinase-3ß (GSK-3ß). Here we investigated whether Cdk5/CRMP2 or GSK-3ß/CRMP2 pathway is involved in sevoflurane-induced developmental neurotoxicity. METHODS: Rats at postnatal day 7 (PND7) were i.p. injected with Cdk5 inhibitor roscovitine, GSK-3ß inhibitor SB415286 or saline 20 min. before exposure to 2.8% sevoflurane for 4 h. Western-blotting was applied to measure the expression of Cdk5/CRMP2 and GSK-3ß/CRMP2 pathway proteins in the hippocampus 6 h after the sevoflurane exposure. When rats grew to adolescence (from PND25), they were tested for open-field and contextual fear conditioning, and then long term potentiation (LTP) from hippocampal slices was recorded, and morphology of pyramidal neuron was examined by Golgi staining and synaptic plasticity-related proteins expression in hippocampus were measured by western-blotting. In another batch of experiment, siRNA-CRMP2 or vehicle control was injected into hippocampus on PND5. RESULTS: Sevoflurane activated Cdk5/CRMP2 and GSK-3ß/CRMP2 pathways in the hippocampus of neonatal rats, reduced dendritic length, branches and the density of dendritic spine in pyramidal neurons. It also reduced the expressions of PSD-95, drebrin and synaptophysin in hippocampus, impaired memory ability of rats and inhibited LTP in hippocampal slices. All the impairment effects by sevoflurane were attenuated by pretreatment with inhibitor of Cdk5 or GSK-3ß. Furthermore, rat transfected with siRNA-CRMP2 eliminated the neuroprotective effects of Cdk5 or GSK-3ß blocker in neurobehavioral and LTP tests. CONCLUSION: Cdk5/CRMP2 and GSK-3ß/CRMP2 pathways participate in sevoflurane-induced dendritic development abnormalities and cognitive dysfunction in developing rats.


Asunto(s)
Disfunción Cognitiva/inducido químicamente , Quinasa 5 Dependiente de la Ciclina/metabolismo , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Sevoflurano/toxicidad , Aminofenoles/farmacología , Animales , Quinasa 5 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 5 Dependiente de la Ciclina/genética , Dendritas/efectos de los fármacos , Regulación del Desarrollo de la Expresión Génica/efectos de los fármacos , Glucógeno Sintasa Quinasa 3 beta/antagonistas & inhibidores , Glucógeno Sintasa Quinasa 3 beta/genética , Hipocampo/citología , Hipocampo/efectos de los fármacos , Péptidos y Proteínas de Señalización Intercelular/genética , Maleimidas/farmacología , Proteínas del Tejido Nervioso/genética , Inhibidores de Proteínas Quinasas/farmacología , Células Piramidales/efectos de los fármacos , Ratas , Roscovitina/farmacología
10.
Mol Pharmacol ; 99(5): 308-318, 2021 05.
Artículo en Inglés | MEDLINE | ID: mdl-33632781

RESUMEN

Celecoxib, or Celebrex, a nonsteroidal anti-inflammatory drug, is one of the most common medicines for treating inflammatory diseases. Recently, it has been shown that celecoxib is associated with implications in complex diseases, such as Alzheimer disease and cancer as well as with cardiovascular risk assessment and toxicity, suggesting that celecoxib may affect multiple unknown targets. In this project, we detected targets of celecoxib within the nervous system using a label-free thermal proteome profiling method. First, proteins of the rat hippocampus were treated with multiple drug concentrations and temperatures. Next, we separated the soluble proteins from the denatured and sedimented total protein load by ultracentrifugation. Subsequently, the soluble proteins were analyzed by nano-liquid chromatography tandem mass spectrometry to determine the identity of the celecoxib-targeted proteins based on structural changes by thermal stability variation of targeted proteins toward higher solubility in the higher temperatures. In the analysis of the soluble protein extract at 67°C, 44 proteins were uniquely detected in drug-treated samples out of all 478 identified proteins at this temperature. Ras-associated binding protein 4a, 1 out of these 44 proteins, has previously been reported as one of the celecoxib off targets in the rat central nervous system. Furthermore, we provide more molecular details through biomedical enrichment analysis to explore the potential role of all detected proteins in the biologic systems. We show that the determined proteins play a role in the signaling pathways related to neurodegenerative disease-and cancer pathways. Finally, we fill out molecular supporting evidence for using celecoxib toward the drug-repurposing approach by exploring drug targets. SIGNIFICANCE STATEMENT: This study determined 44 off-target proteins of celecoxib, a nonsteroidal anti-inflammatory and one of the most common medicines for treating inflammatory diseases. It shows that these proteins play a role in the signaling pathways related to neurodegenerative disease and cancer pathways. Finally, the study provides molecular supporting evidence for using celecoxib toward the drug-repurposing approach by exploring drug targets.


Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Celecoxib/farmacología , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Proteínas/metabolismo , Proteoma/metabolismo , Animales , Cromatografía Liquida/métodos , Perfilación de la Expresión Génica/métodos , Humanos , Masculino , Enfermedades Neurodegenerativas/tratamiento farmacológico , Enfermedades Neurodegenerativas/metabolismo , Ratas , Solubilidad/efectos de los fármacos , Espectrometría de Masas en Tándem/métodos , Temperatura
11.
Int J Mol Sci ; 22(3)2021 Feb 02.
Artículo en Inglés | MEDLINE | ID: mdl-33540803

RESUMEN

Distinct from ovarian estradiol, the steroid hormone 17ß-estradiol (E2) is produced in the brain and is involved in numerous functions, particularly acting as a neurosteroid. However, the physiological role of E2 and the mechanism of its effects are not well known. In hippocampal slices, 17ß-estradiol has been found to cause a modest increase in fast glutamatergic transmission; because some of these effects are rapid and acute, they might be mediated by membrane-associated receptors via nongenomic action. Moreover, activation of membrane estrogen receptors can rapidly modulate neuron function in a sex-specific manner. To further investigate the neurological role of E2, we examined the effect of E2, as an estrogen receptor (ER) agonist, on synaptic transmission in slices of the prefrontal cortex (PFC) and hippocampus in both male and female mice. Whole-cell recordings of spontaneous excitatory postsynaptic currents (sEPSC) in the PFC showed that E2 acts as a neuromodulator in glutamatergic transmission in the PFC in both sexes, but often in a cell-specific manner. The sEPSC amplitude and/or frequency responded to E2 in three ways, namely by significantly increasing, decreasing or having no response. Additional experiments using an agonist selective for ERß, diarylpropionitrile (DPN) showed that in males the sEPSC and spontaneous inhibitory postsynaptic currents sIPSC responses were similar to their E2 responses, but in females the estrogen receptor ß (ERß) agonist DPN did not influence excitatory transmission in the PFC. In contrast, in the hippocampus of both sexes E2 potentiated the gluatmatergic synaptic transmission in a subset of hippocampal cells. These data indicate that activation of E2 targeting probably a estrogen subtypes or different downstream signaling affect synaptic transmission in the brain PFC and hippocampus between males versus females mice.


Asunto(s)
Estradiol/farmacología , Receptor alfa de Estrógeno/fisiología , Hipocampo/metabolismo , Corteza Prefrontal/metabolismo , Transmisión Sináptica/fisiología , Animales , Receptor alfa de Estrógeno/agonistas , Fármacos actuantes sobre Aminoácidos Excitadores/farmacología , Potenciales Postsinápticos Excitadores/efectos de los fármacos , Femenino , GABAérgicos/farmacología , Hipocampo/efectos de los fármacos , Potenciales Postsinápticos Inhibidores/efectos de los fármacos , Cinética , Masculino , Ratones , Ratones Endogámicos C57BL , Nitrilos/farmacología , Técnicas de Placa-Clamp , Corteza Prefrontal/efectos de los fármacos , Propionatos/farmacología , Caracteres Sexuales , Transmisión Sináptica/efectos de los fármacos
12.
Int J Mol Sci ; 22(4)2021 Feb 04.
Artículo en Inglés | MEDLINE | ID: mdl-33557113

RESUMEN

Multiple lines of evidence support the pathogenic role of maternal immune activation (MIA) in the occurrence of the schizophrenia-like disturbances in offspring. While in the brain the homeostatic role of neuron-microglia protein systems is well documented, the participation of the CX3CL1-CX3CR1 and CD200-CD200R dyads in the adverse impact of MIA often goes under-recognized. Therefore, in the present study, we examined the effect of MIA induced by polyinosinic:polycytidylic acid (Poly I:C) on the CX3CL1-CX3CR1 and CD200-CD200R axes, microglial trajectory (MhcII, Cd40, iNos, Il-1ß, Tnf-α, Il-6, Arg1, Igf-1, Tgf-ß and Il-4), and schizophrenia-like behaviour in adult male offspring of Sprague-Dawley rats. Additionally, according to the "two-hit" hypothesis of schizophrenia, we evaluated the influence of acute challenge with Poly I:C in adult prenatally MIA-exposed animals on the above parameters. In the present study, MIA evoked by Poly I:C injection in the late period of gestation led to the appearance of schizophrenia-like disturbances in adult offspring. Our results revealed the deficits manifested as a diminished number of aggressive interactions, presence of depressive-like episodes, and increase of exploratory activity, as well as a dichotomy in the sensorimotor gating in the prepulse inhibition (PPI) test expressed as two behavioural phenotypes (MIAPPI-low and MIAPPI-high). Furthermore, in the offspring rats subjected to a prenatal challenge (i.e., MIA) we noticed the lack of modulation of behavioural changes after the additional acute immune stimulus (Poly I:C) in adulthood. The important finding reported in this article is that MIA affects the expression and levels of the neuron-microglia proteins in the frontal cortex and hippocampus of adult offspring. We found that the changes in the CX3CL1-CX3CR1 axis could affect microglial trajectory, including decreased hippocampal mRNA level of MhcII and elevated cortical expression of Igf-1 in the MIAPPI-high animals and/or could cause the up-regulation of an inflammatory response (Il-6, Tnf-α, iNos) after the "second hit" in both examined brain regions and, at least in part, might differentiate behavioural disturbances in adult offspring. Consequently, the future effort to identify the biological background of these interactions in the Poly I:C-induced MIA model in Sprague-Dawley rats is desirable to unequivocally clarify this issue.


Asunto(s)
Inmunomodulación/efectos de los fármacos , Microglía/efectos de los fármacos , Microglía/inmunología , Poli I-C/farmacología , Esquizofrenia/etiología , Animales , Conducta Animal , Biomarcadores , Modelos Animales de Enfermedad , Susceptibilidad a Enfermedades , Hipocampo/efectos de los fármacos , Hipocampo/inmunología , Hipocampo/metabolismo , Masculino , Microglía/metabolismo , Microglía/patología , Trastornos del Neurodesarrollo/etiología , Trastornos del Neurodesarrollo/metabolismo , Fotoperiodo , ARN Mensajero/genética , Ratas , Receptores CXCR3/metabolismo , Esquizofrenia/metabolismo , Conducta Social
13.
Radiat Res ; 195(4): 355-365, 2021 04 01.
Artículo en Inglés | MEDLINE | ID: mdl-33544844

RESUMEN

Radiation-induced brain injury (RBI) is a serious complication in patients who have received radiotherapy for head and neck tumors. Currently, there is a scarcity of information on early diagnostic and preventive methods of RBI. Accumulating evidence suggests that microRNAs are involved in the regulation of radiation injury, but the molecular biological mechanism of miRNAs in RBI is largely unknown. Therefore, in our study, microRNA sequencing was used to discover differential miRNAs in the hippocampus of RBI-modeled mice, which suggested that miR-741-3p was most significantly upregulated. To clarify the underlying mechanism of miR-741-3p in RBI-modeled mice, an inhibitor of miR-741-3p (antagomiR-741) was delivered into the brain via the nasal passage before irradiation. The delivery of antagomiR-741 significantly reduced miR-741-3p levels in the hippocampus of RBI-modeled mice, and the cognitive dysfunction and neuronal apoptosis induced by radiation were also alleviated at 6 weeks postirradiation. Downregulation of miR-741-3p was found to improve the protrusion and branching status of microglia after irradiation and reduced the number of GFAP-positive astrocytes. Additionally, antagomiR-741 suppressed the radiation-induced production of pro-inflammatory cytokines IL-6 and TNF-α in the hippocampus and S100B in the serum. Furthermore, Ddr2, PKCα and St8sia1 were revealed as target genes of miR-741-3p and as potential regulatory targets for RBI. Overall, our study provides identification and functional evaluation of miRNA in RBI and lays the foundation for improving the prevention strategy for RBI based on the delivery of miRNA via the nose-brain pathway.


Asunto(s)
Antagomirs/farmacología , Lesiones Encefálicas/tratamiento farmacológico , Neoplasias de Cabeza y Cuello/radioterapia , MicroARNs/farmacología , Traumatismos por Radiación/tratamiento farmacológico , Animales , Apoptosis/efectos de los fármacos , Encéfalo/efectos de los fármacos , Encéfalo/patología , Encéfalo/efectos de la radiación , Lesiones Encefálicas/etiología , Lesiones Encefálicas/genética , Lesiones Encefálicas/patología , Modelos Animales de Enfermedad , Neoplasias de Cabeza y Cuello/complicaciones , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Neoplasias de Cabeza y Cuello/patología , Hipocampo/efectos de los fármacos , Hipocampo/patología , Humanos , Inflamación/tratamiento farmacológico , Inflamación/genética , Inflamación/patología , Ratones , MicroARNs/genética , Traumatismos por Radiación/genética , Traumatismos por Radiación/patología , Transducción de Señal/efectos de los fármacos
14.
Int J Mol Sci ; 22(2)2021 Jan 08.
Artículo en Inglés | MEDLINE | ID: mdl-33435576

RESUMEN

A synthetic cathinone, mephedrone is widely abused by adolescents and young adults. Despite its widespread use, little is known regarding its long-term effects on cognitive function. Therefore, we assessed, for the first time, whether (A) repeated mephedrone (30 mg/kg, i.p., 10 days, once a day) exposure during adolescence (PND 40) induces deleterious effects on spatial memory and reversal learning (Barnes maze task) in adult (PND 71-84) rats and whether (B) these effects were comparable to amphetamine (2.5 mg/kg, i.p.). Furthermore, the influence of these drugs on MMP-9, NMDA receptor subunits (GluN1, GluN2A/2B) and PSD-95 protein expression were assessed in adult rats. The drug effects were evaluated at doses that per se induce rewarding/reinforcing effects in rats. Our results showed deficits in spatial memory (delayed effect of amphetamine) and reversal learning in adult rats that received mephedrone/amphetamine in adolescence. However, the reversal learning impairment may actually have been due to spatial learning rather than cognitive flexibility impairments. Furthermore, mephedrone, but not amphetamine, enhanced with delayed onset, MMP-9 levels in the prefrontal cortex and the hippocampus. Mephedrone given during adolescence induced changes in MMP-9 level and up-regulation of the GluN2B-containing NMDA receptor (prefrontal cortex and hippocampus) in young adult (PND 63) and adult (PND 87) rats. Finally, in adult rats, PSD-95 expression was increased in the prefrontal cortex and decreased in the hippocampus. In contrast, in adult rats exposed to amphetamine in adolescence, GluN2A subunit and PSD-95 expression were decreased (down-regulated) in the hippocampus. Thus, in mephedrone-but not amphetamine-treated rats, the deleterious effects on spatial memory were associated with changes in MMP-9 level. Because the GluN2B-containing NMDA receptor dominates in adolescence, mephedrone seems to induce more harmful effects on cognition than amphetamine does during this period of life.


Asunto(s)
Anfetamina/farmacología , Hipocampo/efectos de los fármacos , Aprendizaje por Laberinto/efectos de los fármacos , Metanfetamina/análogos & derivados , Corteza Prefrontal/efectos de los fármacos , Memoria Espacial/efectos de los fármacos , Factores de Edad , Animales , Estimulantes del Sistema Nervioso Central/farmacología , Cognición/efectos de los fármacos , Homólogo 4 de la Proteína Discs Large/metabolismo , Hipocampo/metabolismo , Masculino , Metaloproteinasa 9 de la Matriz/metabolismo , Metanfetamina/farmacología , Actividad Motora/efectos de los fármacos , Corteza Prefrontal/metabolismo , Ratas Wistar , Receptores de N-Metil-D-Aspartato/metabolismo
15.
Int J Mol Sci ; 22(2)2021 Jan 12.
Artículo en Inglés | MEDLINE | ID: mdl-33445535

RESUMEN

This study aimed to investigate whether the Protaetia brevitarsis seulensis (PB)' water extract (PBWE) ameliorates trimethyltin (TMT)-induced seizures and hippocampal neurodegeneration. To investigate the potential neuroprotective effect of the PBWE in vitro, a lactate dehydrogenase (LDH) assay was conducted in TMT-treated primary cultures of mouse hippocampal neurons. In TMT-treated adult C57BL/6 mice, behavioral and histopathological changes were evaluated by seizure scoring and Fluoro-Jade C staining, respectively. In our in vitro assay, we observed that pretreating mice hippocampal neuron cultures with the PBWE reduced TMT-induced cytotoxicity, as indicated by the decreased LDH release. Furthermore, pretreatment with the PBWE alleviated seizures and hippocampal neurodegeneration in TMT-treated mice. The antioxidant activity of the PBWE increased in a dose-dependent manner; moreover, pretreatment with the PBWE mitigated the TMT-induced Nrf2 stimulation. In addition, six major compounds, including adenine, hypoxanthine, uridine, adenosine, inosine, and benzoic acid, were isolated from the PBWE, and among them, inosine and benzoic acid have been confirmed to have an essential antioxidative activity. In conclusion, the PBWE ameliorated TMT-induced toxicity in hippocampal neurons in both in vitro and in vivo assays, through a potential antioxidative effect. Our findings suggest that the PBWE may have pharmacotherapeutic potential in neurodegenerative diseases such as seizures or epilepsy.


Asunto(s)
Productos Biológicos/química , Productos Biológicos/farmacología , Escarabajos/química , Hipocampo/efectos de los fármacos , Fármacos Neuroprotectores/química , Fármacos Neuroprotectores/farmacología , Animales , Productos Biológicos/aislamiento & purificación , Biomarcadores , Cromatografía Líquida de Alta Presión , Escarabajos/anatomía & histología , Escarabajos/clasificación , Escarabajos/genética , Modelos Animales de Enfermedad , Técnica del Anticuerpo Fluorescente , Genes de Insecto , Pruebas Genéticas , Hipocampo/metabolismo , Hipocampo/patología , Degeneración Nerviosa/tratamiento farmacológico , Degeneración Nerviosa/etiología , Degeneración Nerviosa/metabolismo , Degeneración Nerviosa/patología , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Fármacos Neuroprotectores/aislamiento & purificación , Estrés Oxidativo , Fenotipo , Convulsiones/tratamiento farmacológico , Convulsiones/etiología , Compuestos de Trimetilestaño/efectos adversos
16.
Epilepsia ; 62(2): 542-556, 2021 02.
Artículo en Inglés | MEDLINE | ID: mdl-33452820

RESUMEN

OBJECTIVE: Many antiseizure drugs (ASDs) act on voltage-dependent sodium channels, and the molecular basis of these effects is well established. In contrast, how ASDs act on the level of neuronal networks is much less understood. METHODS: In the present study, we determined the effects of eslicarbazepine (S-Lic) on different types of inhibitory neurons, as well as inhibitory motifs. Experiments were performed in hippocampal slices from both sham-control and chronically epileptic pilocarpine-treated rats. RESULTS: We found that S-Lic causes an unexpected reduction of feed-forward inhibition in the CA1 region at high concentrations (300 µM), but not at lower concentrations (100 µM). Concurrently, 300 but not 100 µM S-Lic significantly reduced maximal firing rates in putative feed-forward interneurons located in the CA1 stratum radiatum of sham-control and epileptic animals. In contrast, feedback inhibition was not inhibited by S-Lic. Instead, application of S-Lic, in contrast to previous data for other drugs like carbamazepine (CBZ), resulted in a lasting potentiation of feedback inhibitory post-synaptic currents (IPSCs) only in epileptic and not in sham-control animals, which persisted after washout of S-Lic. We hypothesized that this plasticity of inhibition might rely on anti-Hebbian potentiation of excitatory feedback inputs onto oriens-lacunosum moleculare (OLM) interneurons, which is dependent on Ca2+ -permeable α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. Indeed, we show that blocking Ca2+ -permeable AMPA receptors completely prevents upmodulation of feedback inhibition. SIGNIFICANCE: These results suggest that S-Lic affects inhibitory circuits in the CA1 hippocampal region in unexpected ways. In addition, ASD actions may not be sufficiently explained by acute effects on their target channels, rather, it may be necessary to take plasticity of inhibitory circuits into account.


Asunto(s)
Anticonvulsivantes/farmacología , Región CA1 Hipocampal/efectos de los fármacos , Dibenzazepinas/farmacología , Epilepsia/fisiopatología , Interneuronas/efectos de los fármacos , Inhibición Neural/efectos de los fármacos , Células Piramidales/efectos de los fármacos , Adamantano/análogos & derivados , Adamantano/farmacología , Animales , Región CA1 Hipocampal/metabolismo , Región CA1 Hipocampal/fisiopatología , Calcio/metabolismo , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Epilepsia/inducido químicamente , Retroalimentación Fisiológica/efectos de los fármacos , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Hipocampo/fisiopatología , Potenciales Postsinápticos Inhibidores/efectos de los fármacos , Interneuronas/metabolismo , Potenciación a Largo Plazo , Agonistas Muscarínicos/toxicidad , Plasticidad Neuronal , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Pilocarpina/toxicidad , Ratas , Receptores AMPA/antagonistas & inhibidores , Receptores AMPA/metabolismo
17.
Zool Res ; 42(1): 28-42, 2021 Jan 18.
Artículo en Inglés | MEDLINE | ID: mdl-33420763

RESUMEN

Depression is a prevalent mental disorder that is associated with aging and contributes to increased mortality and morbidity. The overall prevalence of geriatric depression with clinically significant symptoms is currently on the rise. Recent studies have demonstrated that altered expressions of long non-coding RNAs (lncRNAs) in the brain affect neurodevelopment and manifest modulating functions during the depression. However, most lncRNAs have not yet been studied. Herein, we analyzed the transcriptome of dysregulated lncRNAs to reveal their expressions in a mouse model exhibiting depressive-like behaviors, as well as their corresponding response following antidepressant fluoxetine treatment. A chronic unpredictable mild stress (CUMS) mouse model was applied. A six-week fluoxetine intervention in CUMS-induced mice attenuated depressive-like behaviors. In addition, differential expression analysis of lncRNAs was performed following RNA-sequencing. A total of 282 lncRNAs (134 up-regulated and 148 down-regulated) were differentially expressed in CUMS-induced mice relative to non-stressed counterparts ( P<0.05). Moreover, 370 differentially expressed lncRNAs were identified in CUMS-induced mice after fluoxetine intervention. Gene Ontology (GO) analyses showed an association between significantly dysregulated lncRNAs and protein binding, oxygen binding, and transport activity, while the Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis indicated that these dysregulated lncRNAs might be involved in inflammatory response pathways. Fluoxetine effectively ameliorated the symptoms of depression in CUMS-induced mice by regulating the expression of lncRNAs in the hippocampus. The findings herein provide valuable insights into the potential mechanism underlying depression in elderly people.


Asunto(s)
Trastorno Depresivo/tratamiento farmacológico , Fluoxetina/uso terapéutico , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , ARN Largo no Codificante/metabolismo , Animales , Antidepresivos de Segunda Generación/uso terapéutico , Masculino , Ratones , Ratones Endogámicos BALB C , ARN Largo no Codificante/genética , Estrés Psicológico
18.
Chem Biol Interact ; 337: 109400, 2021 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-33516661

RESUMEN

The effects of long-term alcohol consumptions on cognitive function remain elusive with contradictory results. Whilst it is widely accepted that long-term intoxication can cause cognitive impairment, moderate drinking can improve cognitive function. In reality, many older people and those with chronic medical conditions are long-term alcohol consumers in Asian countries. Our previous studies have suggested that long-term alcohol consumption can damage blood-brain barrier (BBB) integrity and aggravate cognitive deficit in APPswe/PS1De9 mice, but little is known about the underlying mechanisms, especially whether this consumption can cause cognitive decline via aggravating BBB damage in people who are exposed to the risk factors for cognitive disorders such as aging or inflammation. These questions were addressed in this study. The mouse models of cognitive deficit induced by d-galactose or lipopolysaccharide, the important risk conditions in human on cognitive function, were used to evaluate the effects of long-term alcohol consumption on the BBB integrity. After alcohol administration for 30 days in these models the BBB integrity was significantly destroyed with remarkably increased permeability and down-regulated protein expression of zonula occludens-1, VE-cadherin, occludin, low-density lipoprotein receptor-related protein-1, receptor for advanced glycation end products, major facilitator superfamily domain-containing protein-2a and aquaporin-4, which is the most closely related with the structure and function of BBB integrity. Meanwhile, the level of oxidative stress in d-galactose mice or inflammatory factors in cortex and serum in lipopolysaccharide mice, which might be involved in the cognitive dysfunctions, was significantly amplified. Furthermore, the impaired memory and hippocampal neuron damage induced by d-galactose and lipopolysaccharide were concurrently aggravated. Collectively, our study provided novel and compelling evidence that the structural and functional proteins for BBB integrity may be the primary targets for the detrimental effects of alcohol abuse that lead to cognitive dysfunction and neurological deficits in high risk populations.


Asunto(s)
Barrera Hematoencefálica/efectos de los fármacos , Etanol/toxicidad , Alcoholismo/metabolismo , Alcoholismo/patología , Animales , Barrera Hematoencefálica/metabolismo , Modelos Animales de Enfermedad , Regulación hacia Abajo/efectos de los fármacos , Galactosa/toxicidad , Hipocampo/efectos de los fármacos , Hipocampo/fisiología , Lipopolisacáridos/toxicidad , Proteína 1 Relacionada con Receptor de Lipoproteína de Baja Densidad/metabolismo , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Ratones , Ocludina/metabolismo , Estrés Oxidativo/efectos de los fármacos , Permeabilidad/efectos de los fármacos , Proteína de la Zonula Occludens-1/metabolismo
19.
Psychopharmacology (Berl) ; 238(3): 877-886, 2021 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-33404738

RESUMEN

BACKGROUND: Memory deficit is a common cognitive comorbid in patients with neuropathic pain that need better treatment. Recent research revealed that nanocurcumin has an antinociceptive action and a protective effect against memory disorders, suggesting its possible effectiveness for the treatment of neuropathic pain and its comorbidity. METHODS: Adult male albino Wistar rats (n = 32) were randomly divided into four experimental groups: CCI+ nanocurcumin, CCI + vehicle, sham + nanocurcumin, and sham + vehicle. Neuropathic pain induced by a chronic constriction injury of the sciatic nerve. Nanocurcumin or vehicle was injected intraperitoneally for 10 days. Behavioral assessment achieved to evaluate pain threshold in the von Frey test and radiant heat test, also spatial learning and memory examined by the Morris water maze (MWM) test. To explore the possible relation, IL-1ß, and TNF-α levels of the hippocampus measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: Our data showed that CCI caused neuropathic pain-related behaviors and spatial learning and memory disorders in rats. Chronic treatment with nanocurcumin significantly increased pain threshold (P < 0.001; F = 27.63, F = 20.58), improved spatial memory (P < 0.01; F = 47.37), and decreased the hippocampal levels of IL-1ß (P < 0.001; F = 33.57) and TNF-α (P < 0.01; F = 7.25) in CCI rats. CONCLUSION: Chronic nanocurcumin can ameliorate pain-related behavior, improve spatial learning and memory deficits, and is associated with the reduction of IL-1ß and TNF-α levels in the hippocampus in CCI rats. Nanocurcumin may be potentially providing a therapeutic alternative for the treatment of neuropathic pain and its memory impairment comorbidity.


Asunto(s)
Analgésicos/uso terapéutico , Curcumina/uso terapéutico , Hipocampo/efectos de los fármacos , Interleucina-1beta/metabolismo , Neuralgia/tratamiento farmacológico , Memoria Espacial/efectos de los fármacos , Factor de Necrosis Tumoral alfa/metabolismo , Analgésicos/administración & dosificación , Analgésicos/química , Animales , Conducta Animal/efectos de los fármacos , Constricción , Curcumina/administración & dosificación , Curcumina/química , Modelos Animales de Enfermedad , Hipocampo/metabolismo , Masculino , Trastornos de la Memoria/complicaciones , Trastornos de la Memoria/tratamiento farmacológico , Trastornos de la Memoria/metabolismo , Nanopartículas/administración & dosificación , Nanopartículas/química , Neuralgia/complicaciones , Neuralgia/metabolismo , Umbral del Dolor/efectos de los fármacos , Ratas , Ratas Wistar , Nervio Ciático/efectos de los fármacos , Nervio Ciático/lesiones
20.
Nutrients ; 13(1)2021 Jan 08.
Artículo en Inglés | MEDLINE | ID: mdl-33435613

RESUMEN

Gynura procumbens has been used in Southeast Asia for the treatment of hypertension, hyperglycemia, and skin problems induced by ultraviolet irradiation. Although considerable studies have reported the biological properties of Gynura procumbens root extract (GPE-R), there are no studies on the effects of GPE-R in brain damages, for example following brain ischemia. In the present study, we screened the neuroprotective effects of GPE-R against ischemic damage and neuroinflammation in the hippocampus based on behavioral, morphological, and biological approaches. Gerbils received oral administration of GPE-R (30 and 300 mg/kg) every day for three weeks and 2 h after the last administration, ischemic surgery was done by occlusion of both common carotid arteries for 5 min. Administration of 300 mg/kg GPE-R significantly reduced ischemia-induced locomotor hyperactivity 1 day after ischemia. Significantly more NeuN-positive neurons were observed in the hippocampal CA1 regions of 300 mg/kg GPE-R-treated animals compared to those in the vehicle-treated group 4 days after ischemia. Administration of GPE-R significantly reduced levels of pro-inflammatory cytokines such as interleukin-1ß, -6, and tumor necrosis factor-α 6 h after ischemia/reperfusion. In addition, activated microglia were significantly decreased in the 300 mg/kg GPE-R-treated group four days after ischemia/reperfusion compared to the vehicle-treated group. These results suggest that GPE-R may be one of the possible agents to protect neurons from ischemic damage by reducing inflammatory responses.


Asunto(s)
Isquemia Encefálica/tratamiento farmacológico , Región CA1 Hipocampal/efectos de los fármacos , Inflamación/tratamiento farmacológico , Neuronas/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Extractos Vegetales/farmacología , Raíces de Plantas/química , Animales , Peso Corporal , Isquemia Encefálica/patología , Isquemia Encefálica/cirugía , Región CA1 Hipocampal/patología , Citocinas , Modelos Animales de Enfermedad , Medicamentos Herbarios Chinos/farmacología , Gerbillinae , Hipocampo/efectos de los fármacos , Masculino , Microglía , Daño por Reperfusión/patología
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