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1.
Acta Cir Bras ; 34(12): e201901205, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32049185

RESUMO

PURPOSE: To investigate the effects of huperzine A (HupA) on hippocampal inflammatory response and neurotrophic factors in aged rats after anesthesia. METHODS: Thirty-six Sprague Dawley rats (20-22 months old) were randomly divided into control, isofluran, and isoflurane+HupA groups; 12 rats in each group. The isoflurane+HupA group was intraperitoneally injected with 0.2 mg/kg of HupA. After 30 min, isoflurane inhalation anesthesia was performed in the isoflurane and isoflurane+HupA groups. After 24 h from anesthesia, Morris water maze experiment and open-field test were performed. Hippocampal inflammatory and neurotrophic factors were determined. RESULTS: Compared with isoflurane group, in isofluran+HupA group the escape latency of rats was significantly decreased (P < 0.05), the original platform quadrant residence time and traversing times were significantly increased (P < 0.05), the central area residence time was significantly increased (P < 0.05), the hippocampal tumor necrosis factor α, interleukin 6 and interleukin 1ß levels were significantly decreased (P < 0.05), and the hippocampal nerve growth factor, brain derived neurotrophic factor and neurotrophin-3 levels were significantly increased (P < 0.05). CONCLUSION: HupA may alleviate the cognitive impairment in rats after isoflurane anesthesia by decreasing inflammatory factors and increasing hippocampal neurotrophic factors in hippocampus tissue.


Assuntos
Alcaloides/farmacologia , Anestésicos Inalatórios/efeitos adversos , Hipocampo/efeitos dos fármacos , Isoflurano/efeitos adversos , Fatores de Crescimento Neural/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Sesquiterpenos/farmacologia , Anestesia/efeitos adversos , Animais , Ensaio de Imunoadsorção Enzimática , Hipocampo/metabolismo , Humanos , Interleucina-1beta/análise , Interleucina-6/análise , Masculino , Aprendizagem em Labirinto , Fatores de Crescimento Neural/análise , Distribuição Aleatória , Ratos Sprague-Dawley , Reprodutibilidade dos Testes , Fatores de Tempo , Resultado do Tratamento , Fator de Necrose Tumoral alfa/análise
2.
Cell Physiol Biochem ; 54(2): 180-194, 2020 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-32068980

RESUMO

BACKGROUND/AIMS: Still in 1999 the first hints were published for the pharmacoresistant Cav2.3 calcium channel to be involved in the generation of epileptic seizures, as transcripts of alpha1E (Cav2.3) and alpha1G (Cav3.1) are changed in the brain of genetic absence epilepsy rats from Strasbourg (GAERS). Consecutively, the seizure susceptibility of mice lacking Cav2.3 was analyzed in great detail by using 4-aminopyridine, pentylene-tetrazol, N-methyl-D-aspartate and kainic acid to induce experimentally convulsive seizures. Further, γ-hydroxybutyrolactone was used for the induction of non-convulsive absence seizures. For all substances tested, Cav2.3-competent mice differed from their knockout counterparts in the sense that for convulsive seizures the deletion of the pharmacoresistant channel was beneficial for the outcome during experimentally induced seizures [1]. The antiepileptic drug lamotrigine reduces seizure activity in Cav2.3-competent but increases it in Cav2.3-deficient mice. In vivo, Cav2.3 must be under tight control by endogenous trace metal cations (Zn2+ and Cu2+). The dyshomeostasis of either of them, especially of Cu2+, may alter the regulation of Cav2.3 severely and its activity for Ca2+ conductance, and thus may change hippocampal and neocortical signaling to hypo- or hyperexcitation. METHODS: To investigate by telemetric EEG recordings the mechanism of generating hyperexcitation by kainate, mice were tested for their sensitivity of changes in neuronal (intracerebroventricular) concentrations of the trace metal cation Zn2+. As the blood-brain barrier limits the distribution of bioavailable Zn2+ or Cu2+ into the brain, we administered micromolar Zn2+ ions intracerebroventricularly in the presence of 1 mM histidine as carrier and compared the effects on behavior and EEG activity in both genotypes. RESULTS: Kainate seizures are more severe in Cav2.3-competent mice than in KO mice and histidine lessens seizure severity in competent but not in Cav2.3-deficient mice. Surprisingly, Zn2+ plus histidine resembles the kainate only control with more seizure severity in Cav2.3-competent than in deficient mice. CONCLUSION: Cav2.3 represents one important Zn2+-sensitive target, which is useful for modulating convulsive seizures.


Assuntos
Canais de Cálcio Tipo R/metabolismo , Proteínas de Transporte de Cátions/metabolismo , Convulsões/tratamento farmacológico , Zinco/uso terapêutico , Animais , Canais de Cálcio Tipo R/genética , Proteínas de Transporte de Cátions/genética , Eletroencefalografia , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Histidina/farmacologia , Íons/química , Ácido Caínico/toxicidade , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Convulsões/induzido quimicamente , Convulsões/patologia , Índice de Gravidade de Doença , Zinco/farmacologia , Ácido gama-Aminobutírico/metabolismo
3.
Life Sci ; 248: 117468, 2020 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-32105705

RESUMO

AIMS: Treatment with 5-fluorouracil (5-FU) can cause impairment to adult hippocampal neurogenesis, resulting in cognitive deficits. As melatonin has been shown to enhance memory and hippocampal neurogenesis in animal models, this research investigated the neuroprotective effects of melatonin against spatial memory and hippocampal neurogenesis impairment in 5-fluorouracil (5-FU)-treated rats. MATERIALS AND METHODS: Four-Five weeks old male Spraque-Dawley rats weighing between 180 and 200 g were used. Animals were maintained under standard laboratory conditions with 25 °C and 12 h light/dark cycle. Animal were administered intravenous (i.v.) injections of 5-FU (25 mg/kg) 5 times every 3 days starting on day 9 of the experiment. The rats were divided into preventive, recovery, and throughout groups and co-treated with melatonin (8 mg/kg, i.p.) once daily (at 7.00 pm) for 21 days prior to, after, and throughout 5-FU treatment, respectively. Spatial memory was assessed using a novel object location (NOL) test. Hippocampal neurogenesis was then examined using Ki67, bromodeoxyuridine (BrdU), and doublecortin (DCX) immunohistochemistry staining. KEY FINDINGS: Melatonin administration was able to both protect the subjects from and reverse spatial memory deficits. 5-FU was also found to reduce the generation of hippocampal newborn neurons. However, co-treatment with melatonin ameliorated the reductions in neurogenesis caused by 5-FU. SIGNIFICANCE: These findings suggest that melatonin administration was able to ameliorate the 5-FU-induced spatial memory deficits associated with neurogenesis. The present work will be valuable for patients who suffer memory deficits from 5-FU chemotherapy.


Assuntos
Disfunção Cognitiva/tratamento farmacológico , Fluoruracila/antagonistas & inibidores , Melatonina/farmacologia , Transtornos da Memória/tratamento farmacológico , Neurogênese/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Memória Espacial/efeitos dos fármacos , Animais , Antimetabólitos/efeitos adversos , Biomarcadores/metabolismo , Proliferação de Células/efeitos dos fármacos , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/fisiopatologia , Giro Denteado/efeitos dos fármacos , Giro Denteado/metabolismo , Giro Denteado/patologia , Esquema de Medicação , Fluoruracila/efeitos adversos , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/patologia , Injeções Intravenosas , Antígeno Ki-67/genética , Antígeno Ki-67/metabolismo , Masculino , Transtornos da Memória/metabolismo , Transtornos da Memória/fisiopatologia , Proteínas Associadas aos Microtúbulos/genética , Proteínas Associadas aos Microtúbulos/metabolismo , Neurogênese/genética , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Neuropeptídeos/genética , Neuropeptídeos/metabolismo , Ratos , Ratos Sprague-Dawley , Memória Espacial/fisiologia
4.
J Agric Food Chem ; 68(10): 3099-3111, 2020 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-32067456

RESUMO

Sesamol, a lignan in sesame, possesses several bioactivities, such as antioxidation, anti-inflammation, and neuroprotective capability. In this study, the effects of sesamol on aging-caused cognitive defects are investigated. Twelve-month-old mice were treated with sesamol (0.1%, w/w) as dietary supplementation for 12 weeks. Behavioral tests revealed that sesamol improved aging-associated cognitive impairments. Sesamol decreased aging-induced oxidative stress via suppression of malondialdehyde production and increased antioxidant enzymes. Histological staining showed that sesamol treatment improved aging-induced neuronal damage and synaptic dysfunction in the hippocampus. Furthermore, sesamol significantly reduced aging-induced neuroinflammation by inhibiting the microglial overactivation and inflammatory cytokine expressions. Meanwhile, the accumulation of Aß1-42 was reduced by sesamol treatment. Moreover, sesamol protected the gut barrier integrity and reduced LPS release, which was highly associated with its beneficial effects on behavioral and inflammatory changes. In conclusion, our findings indicated that the use of sesamol is feasible in the treatment of aging-related diseases.


Assuntos
Envelhecimento/efeitos dos fármacos , Benzodioxóis/administração & dosagem , Disfunção Cognitiva/tratamento farmacológico , Fármacos Neuroprotetores/administração & dosagem , Fenóis/administração & dosagem , Envelhecimento/imunologia , Envelhecimento/psicologia , Peptídeos beta-Amiloides/imunologia , Animais , Disfunção Cognitiva/imunologia , Disfunção Cognitiva/psicologia , Hipocampo/efeitos dos fármacos , Hipocampo/imunologia , Humanos , Masculino , Malondialdeído/imunologia , Camundongos , Microglia/efeitos dos fármacos , Microglia/imunologia , Estresse Oxidativo/efeitos dos fármacos
5.
Life Sci ; 245: 117386, 2020 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-32006528

RESUMO

AIMS: Steroid receptor coactivator-1 (SRC-1) is a key coactivator for the efficient transcriptional activity of steroids in the regulation of hippocampal functions. However, the effect of SRC-1 on hippocampal memory processes remains unknown. Our aim was to investigate the roles of hippocampal SRC-1 in the consolidation and reconsolidation of contextual fear memory in mice. MAIN METHODS: Contextual fear conditioning paradigm was constructed in adult male C57BL/6 mice to examine the fear learning and memory processes. Adeno-associated virus (AAV) vector-mediated RNA interference (RNAi) was infused into hippocampus to block hippocampal SRC-1 level. Immunofluorescent staining was used to detect the efficiency of transfection. High plus maze and open field test were used to determine anxiety and locomotor activity. Western blot analyses were used to detect the expression of SRC-1 and synaptic proteins in the hippocampus. KEY FINDINGS: We first showed that the expression of SRC-1 was regulated by fear conditioning training in a time-dependent manner, and knockdown of SRC-1 impaired contextual fear memory consolidation without affecting innate anxiety or locomotor activity. In addition, hippocampal SRC-1 was also regulated by the retrieval of contextual fear memory, and downregulation of SRC-1 disrupted fear memory reconsolidation. Moreover, knockdown of SRC-1 reversed the increased GluR1 and PSD-95 levels induced by contextual fear memory retrieval. SIGNIFICANCE: Our data indicate that hippocampal SRC-1 is required for the consolidation and reconsolidation of contextual fear memory, and SRC-1 may be a potential therapeutic target for mental disorders that are involved in hippocampal memory dysfunction.


Assuntos
Medo/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Memória/efeitos dos fármacos , Coativador 1 de Receptor Nuclear/antagonistas & inibidores , Animais , Western Blotting , Condicionamento Clássico/efeitos dos fármacos , Condicionamento Clássico/fisiologia , Medo/fisiologia , Medo/psicologia , Imunofluorescência , Hipocampo/fisiologia , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Coativador 1 de Receptor Nuclear/fisiologia
6.
Life Sci ; 245: 117388, 2020 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-32007576

RESUMO

AIMS: The higher incidence rate of Alzheimer's disease (AD) among women has led to explorations on the association between estrogen deficiency and AD. Also, usage of antihypertensive drugs has been suggested to reduce the incidence of AD in elderly hypertensive patients. Thus, this study aimed to investigate the effects of telmisartan and/or 17ß-estradiol on a cognitively impaired ovariectomized rat model of AD. MAIN METHODS: 75 female Wistar rats were randomly allocated into five groups. One group was sham operated and the other four groups were subjected to ovariectomy, received D-galactose and either untreated or treated with telmisartan and/or 17ß-estradiol for 6 weeks. KEY FINDINGS: Ovariectomized rats showed cognitive impairment in Morris water maze and novel object recognition tests, increasing inflammatory biomarkers (tumor necrosis factor-α, and interleukin-1ß), increasing AD biomarkers (amyloid beta1-42, and acetylcholine esterase), and over activation of classical arm of renin angiotensin system (RAS) (ACE1/Ang2/AT1) in hippocampi. Also, hippocampi histopathological examination revealed amyloid beta deposition. Whereas, administration of telmisartan and/or 17ß-estradiol improved animals' behavior, alleviated histopathological alterations and reduced the level of inflammatory and AD biomarkers, modulated RAS activity favoring the novel neuroprotective arm (ACE2/Ang(1-7)/MasR). SIGNIFICANCE: Our findings suggest that combined administration of both drugs has synergetic neuroprotective effects; supporting their potential application in AD treatment.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Estradiol/uso terapêutico , Nootrópicos/uso terapêutico , Telmisartan/uso terapêutico , Doença de Alzheimer/patologia , Animais , Western Blotting , Disfunção Cognitiva/tratamento farmacológico , Modelos Animais de Doenças , Sinergismo Farmacológico , Quimioterapia Combinada , Feminino , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/patologia , Aprendizagem em Labirinto , Ovariectomia , Ratos , Ratos Wistar , Sistema Renina-Angiotensina/efeitos dos fármacos
7.
Life Sci ; 245: 117393, 2020 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-32017872

RESUMO

AIMS: Receptor for advanced glycation end products (RAGE) production is induced by diabetes. Microglial cells are activated by RAGE and produce inflammatory cytokines such as tumor necrosis factor-α (TNF-α) and oxidative stress markers. Persistent production of TNF-α can provide a link between diabetes and Alzheimer's disease (AD). The purpose of this study was to investigate the effect of concomitant use of omega-3 polyunsaturated fatty acids (ω-3 PUFAs) with iron supplements on microglial cell activation and inflammatory conditions in the hippocampus of type 2 diabetic rats. MAIN METHODS: Diabetic and normal Wistar rats were divided into six groups. Oxidative stress markers (total oxidant status (TOS), total antioxidant capacity (TAC), and malondialdehyde (MDA)), mRNA expression and protein levels of RAGE and TNF-α were evaluated in the hippocampus of the controls and supplemented with ferrous sulfate and ω-3 PUFAs alone and together rats. Also, the entry of microglia cells into the hippocampus was evaluated by immunohistochemistry technique. KEY FINDINGS: Levels of the microglial activation (2.4 fold, p < 0.0001), MDA (84%, p < 0.0001) and oxidative stress index (OSI) (11%, p = 0.0094), mRNA expression and protein contents of RAGE (1.83 fold and 82% respectively) and TNF-α (2.25 fold and 86% respectively) were strongly influenced by negative effect of iron compared to the group receiving only ω-3 PUFAs which was dramatically improved by vitamin E. SIGNIFICANCE: These observations indicated that the co-supplementation of ferrous sulfate with ω-3 PUFAs decreases the anti-inflammatory ability of ω-3 PUFAs in the hippocampus of diabetic rats via RAGE/TNF-α-induced oxidative stress pathway up-regulation.


Assuntos
Diabetes Mellitus Experimental/metabolismo , Ácidos Graxos Ômega-3/farmacologia , Compostos Ferrosos/farmacologia , Hipocampo/efeitos dos fármacos , Animais , Hipocampo/química , Inflamação/tratamento farmacológico , Malondialdeído/metabolismo , Microglia/efeitos dos fármacos , Microglia/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Wistar , Receptor para Produtos Finais de Glicação Avançada/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
8.
Food Chem Toxicol ; 135: 110906, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31669603

RESUMO

Zinc oxide nanoparticles (ZnONPs) have been widely used in food storage containers and food additives in daily life. However, the impact of oral intake of ZnONPs on nervous system is extremely limited, especially on children and adolescents. In this study, four weeks old mice were treated with either vehicle or ZnONPs suspension solution at 26 mg/kg by intragastric administration for 30 days. Our results demonstrated that oral ZnONPs exposure could induce pathological changes in gut and abnormal excitement of enteric neurons. Interestingly, we found that ZnONPs caused enhancement of 5-hydroxytryptamine (5-HT) in gut by activation of its biosynthesis, transport and receptors, and subsequently resulting in increased level of 5-HT in brain via gut-brain communication by blood. Our data also showed that there were no apparent changes on the expressions of interleukin (Il)-6, Il-1ß, C-C motif chemokine ligand 2 (Ccl2), tumor necrosis factor (Tnf) in gut and zinc chelator Mt2 in gut and cortex. Meanwhile, no significant changes were observed on the expressions of tryptophan hydroxylase type 1, 5-HT receptor 3A (Htr3a) and Htr4 in hippocampus and cortex. Our study indicate that oral ZnONPs exposure causes hyperfunction of 5-HT in gut in young mice which may further spread to brain via gut-brain communication.


Assuntos
Sistema Nervoso Entérico/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Nanopartículas Metálicas/química , Serotonina/metabolismo , Óxido de Zinco/farmacologia , Administração Oral , Animais , Sistema Nervoso Entérico/metabolismo , Hipocampo/metabolismo , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Masculino , Nanopartículas Metálicas/administração & dosagem , Camundongos Endogâmicos C57BL , Serotonina/sangue , Junções Íntimas/efeitos dos fármacos , Óxido de Zinco/administração & dosagem
9.
Toxicol Lett ; 319: 66-73, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31726083

RESUMO

Thallium ion (Tl+) and its neurotoxic products are widely known to cause severe neurological complications. However, the exact mechanism of action remains unknown, with limited therapeutic options available. This study aims to examine the toxic effects of Thallium (I) Nitrate (TlNO3) on primary hippocampal neurons of E17-E18 Wistar rat embryos, and the potential neuroprotective role of Nrf2- Keap1 signaling pathway against thallium-induced oxidative stress and mitochondrial dysfunction. TlNO3 induces a significant increase in reactive oxygen species levels and mitochondrial dysfunction in primary hippocampal neurons. Furthermore, the Nrf2-Keap1 signaling pathway played a protective role against TlNO3-induced hippocampal neuronal cytotoxicity. Moreover, mitochondrial fusion protein Mitofusin 2 (Mfn2) levels significantly decreased in hippocampal neurons when exposed to TlNO3, indicating that Mfn2 protein levels are linked to TlNO3-induced neurotoxicity. t-BHQ, a Nrf2 and phase II detoxification enzyme inducer, counteracted the oxidative damage in hippocampal neurons by activating the Nrf2-Keap1 signaling pathway after TlNO3 exposure; the activated Nrf2-Keap1 pathway could then maintain Mfn2 function by regulating Mfn2 protein expression. Thus, Nrf2-Keap1 pathway activation plays a protective role in Tl+-induced brain damage, and specific agonists have been identified to have great potential for treating thallium poisoning.


Assuntos
Hipocampo/efeitos dos fármacos , Proteína 1 Associada a ECH Semelhante a Kelch/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Tálio/toxicidade , Animais , Encefalopatias/induzido quimicamente , Encefalopatias/patologia , Encefalopatias/prevenção & controle , Feminino , Hipocampo/citologia , Proteínas de Membrana/efeitos dos fármacos , Proteínas de Membrana/metabolismo , Proteínas Mitocondriais/efeitos dos fármacos , Proteínas Mitocondriais/metabolismo , Cultura Primária de Células , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo
10.
Chem Biol Interact ; 315: 108895, 2020 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-31715133

RESUMO

Lithium and cannabinoids can disrupt learning and memory performance. The goal of the present study is to investigate the additive or synergistic effect of lithium and cannabinoid combination doses on spatial learning and memory in rats by isobolographic analyses. Although several studies have suggested synergistic effects of cannabinoids or lithium in response to other compounds, in most of them isobolographic analyses were not used; Thus, there is a need for more detailed studies using isobolographic analyses. In this study, spatial memory was evaluated in the Morris Water Maze (MWM) apparatus by eight trials in the training day and one trial in the test day. Lithium was injected intraperitoneal and ACPA (cannabinoid type 1 receptor agonist) was injected into the dorsal hippocampal region (intra-CA1). For the isobolographic analyses, the ED50 of lithium (2.5 mg/kg) and ACPA (0.5 µg/rat) was measured by linear regression analysis, considering the doses were tested in our previous research. The results showed that, combinations of low, medium and high doses of lithium (0.312 mg/kg, 0.625 mg/kg and 1.25 mg/kg, respectively) and ACPA (0.0625 µg/rat, 0.125 µg/rat and 0.25 µg/rat, respectively) had synergistic but not additive effect on spatial learning and spatial memory. In conclusion, we suggest that combination doses of lithium and ACPA have synergistic but not additive effect on spatial learning and memory in the rat's dorsal hippocampal region.


Assuntos
Ácidos Araquidônicos/farmacologia , Hipocampo/efeitos dos fármacos , Lítio/farmacologia , Aprendizagem em Labirinto/efeitos dos fármacos , Receptores de Canabinoides/metabolismo , Aprendizagem Espacial/efeitos dos fármacos , Memória Espacial/efeitos dos fármacos , Animais , Agonistas de Receptores de Canabinoides/farmacologia , Canabinoides/metabolismo , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Sinergismo Farmacológico , Hipocampo/metabolismo , Masculino , Ratos , Ratos Wistar , Lobo Temporal/efeitos dos fármacos , Lobo Temporal/metabolismo
11.
J Biochem Mol Toxicol ; 34(2): e22425, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31729815

RESUMO

The effect of combined administration of calcium (Ca), iron (Fe), zinc (Zn), chrysanthemum flavonoids, and meso-2,3-dimercaptosuccinic acid (DMSA) on the treatment of lead (Pb) intoxication in mice was studied. One hundred ninety female mice (SPF level, aged 18-22 days) were randomly divided into two groups as experimental animals. Mice in group I (10 mice) served as normal control animals, and were administered deionized water containing 12.5 µL/L acetate acid for 6 weeks, whereas mice in group II (180 mice) were exposed to 0.1% (wt/vol) of lead acetate in deionized water for 6 weeks and served as experimental animals. After 6 weeks of successful modeling, 180 mice from group II (lead-exposed) were divided into 18 groups of 10 mice each, 16 of which were treated by the combined administration of Ca, Fe, Zn, chrysanthemum flavonoids, and DMSA by L16 (215 ) orthogonal design. The remaining two groups were given treatment with low and high doses of DMSA, respectively. After three weeks of intervention (ig), the optimal treatment group was identified according to its blood lead level, as well as some antioxidant indices in the blood, liver, and hippocampus. The results indicated that the combined administration of Fe, Zn, chrysanthemum flavonoids, and DMSA with low dosage had the most significant effect on increasing the activities of blood delta-aminolevulinic acid dehydratase and superoxide dismutase (SOD), hepatic SOD and hippocampus nitric oxide synthase while decreasing the blood lead level, the content of hepatic malondialdehyde and hippocampus nitric oxide; this was considered the optimal treatment group. There was no difference in the level of blood hemoglobin between the optimal treatment group and the model control group (the first group of the orthogonal experiment). The activities of blood glutathione (GSH), hepatic GSH and glutathione peroxidase of the optimal treatment group were the same as other groups', and the recovery of the related indexes in the optimal effect group closely resembled the high dosage DMSA group. It can be concluded that the coadministration of Fe, Zn, and chrysanthemum flavonoids along with a low-dose DMSA effectively reduces Pb poisoning and lead-induced oxidative damage in lead-exposed mice; the result may provide a theoretical reference for the treatment of Pb poisoning.


Assuntos
Cálcio/farmacologia , Chrysanthemum/química , Flavonoides/farmacologia , Ferro/farmacologia , Intoxicação por Chumbo/tratamento farmacológico , Extratos Vegetais/farmacologia , Succímero/farmacologia , Zinco/farmacologia , Animais , Cálcio/administração & dosagem , Modelos Animais de Doenças , Quimioterapia Combinada , Feminino , Flavonoides/administração & dosagem , Glutationa/sangue , Glutationa Peroxidase/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Ferro/administração & dosagem , Chumbo/efeitos adversos , Chumbo/sangue , Fígado/efeitos dos fármacos , Fígado/metabolismo , Malondialdeído/metabolismo , Camundongos , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/administração & dosagem , Sintase do Porfobilinogênio/sangue , Succímero/administração & dosagem , Superóxido Dismutase/sangue , Resultado do Tratamento , Zinco/administração & dosagem
12.
Life Sci ; 241: 117160, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31837331

RESUMO

AIMS: Theanine, as a naturally occurring component in tea, has been shown to deliver benefits against various diseases. However, the exact molecular mechanisms underlying theanine's protective actions against cerebral ischemia/reperfusion (IR) injury still remains largely unknown. MAIN METHODS: In this study, rat cerebral IR injury model was established and were randomly divided into the following five groups: Sham (SH), IR, IR + Theanine (TH), IR + TH+ heme oxygenase-1 (HO-1) inducer cobalt protoporphyrin (Copp), and IR + Copp groups. KEY FINDINGS: We found that theanine significantly inhibited neuron damage and apoptosis in the hippocampus during the 48 h detection period, as detected by hematoxylin and eosin (HE) and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining. Meanwhile, reduced levels of malondialdehyde (MDA) and elevated activities of superoxide dismutase (SOD), glutathione (GSH), and glutathione peroxidase (GSH-PX) were observed in the theanine-treated group. Enzyme-linked immunosorbent (ELISA) assay also revealed that theanine markedly decreased the levels of inflammatory cytokines, such as IL-6, IL-1ß, and TNF-α, in IR rats. The anti-apoptotic effect of theanine on IR injury was further verified by flow cytometry assay. Besides, theanine dramatically inhibited HO-1 expression and activity but increased extracellular signal-regulated kinase 1/2 (ERK1/2) activity in hippocampal tissue from rats with cerebral IR injury. However, co-treatment with Copp remarkably abolished the protective effects of theanine on cerebral IR injury. SIGNIFICANCE: These findings demonstrated that the neuroprotective role of theanine was associated with its anti-oxidative, anti-inflammatory, and anti-apoptotic properties, which might be through regulation of HO-1 activation in rats with cerebral IR injury.


Assuntos
Isquemia Encefálica/prevenção & controle , Regulação da Expressão Gênica/efeitos dos fármacos , Glutamatos/farmacologia , Heme Oxigenase (Desciclizante)/antagonistas & inibidores , Hipocampo/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Traumatismo por Reperfusão/prevenção & controle , Animais , Apoptose/efeitos dos fármacos , Isquemia Encefálica/etiologia , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patologia , Hipocampo/metabolismo , Hipocampo/patologia , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Inflamação/patologia , Masculino , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Traumatismo por Reperfusão/etiologia , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia
13.
Int J Vitam Nutr Res ; 90(1-2): 156-168, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31017555

RESUMO

Protective effects of vitamin E (Vit E) on long term potentiation (LTP) impairment, neuronal apoptosis and increase of nitric oxide (NO) metabolites in the hippocampus of juvenile rats were examined. The rats were grouped (n=13) as: (1) control; (2) hypothyroid (Hypo) and (3) Hypo-Vit E. Propylthiouracil (PTU) was given in drinking water (0.05%) during 6 weeks. Vit E (20 mg/ kg) was daily injected (IP). To evaluate synaptic plasticity, LTP from the CA1 area of the hippocampus followed by high frequency stimulation to the ipsilateral Schafer collateral pathway was carried out. The cortical and hippocampal tissues were then removed to measure NO metabolites. The brains of 5 animals in each group were removed for apoptosis study. The hypothyroidism status decreased the slope, 10-90% slope and amplitude of field excitatory post synaptic potential (fEPSP) compared to the control group (P<0.01-P<0.001). Injection of Vit E increased the slope, 10-90% slope and amplitude of the fEPSP in the Hypo-Vit E group in comparison to the Hypo group (P<0.05-P<0.01). TUNEL positive neurons and NO metabolites were higher in the hippocampus of the Hypo rats, as compared to those in the hippocampus of the control ones (P<0.001). Treatment of the Hypo rats by Vit E decreased apoptotic neurons (P<0.01-P<0.001) and NO metabolites (P<0.001) in the hippocampus compared to the Hypo rats. The results of the present study showed that Vit E prevented the LTP impairment and neuronal apoptosis in the hippocampus of juvenile hypothyroid rats.


Assuntos
Hipocampo/efeitos dos fármacos , Hipotireoidismo , Potenciação de Longa Duração , Vitamina E/farmacologia , Animais , Hipotireoidismo/tratamento farmacológico , Ratos , Ratos Wistar , Vitamina E/química
14.
Life Sci ; 242: 117151, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31843526

RESUMO

AIMS: Anaesthesia-related neurotoxicity in the developing brain is a controversial issue that has recently attracted much attention. Hemin plays a protective role in hypoxic and ischemic brain damage; however, its effects on sevoflurane-induced neurotoxicity remain unclear. Our aim was to investigate the mechanisms of sevoflurane neurotoxicity and potential neuroprotective roles of hemin upon sevoflurane exposure. MAIN METHODS: Hippocampi were harvested 18 h after sevoflurane exposure. Haem oxygenase 1 (HMOX1), superoxide dismutase 2 (SOD2), discs large MAGUK scaffold protein 4 (DLG4), phosphorylated Akt, Akt, cleaved caspase 3, and neuroglobin were detected by western blotting. A water maze test was used to assess learning and memory ability in P30 rats. KEY FINDINGS: Sevoflurane inhalation increased cleaved caspase 3 levels. Hemin treatment enhanced the antioxidant defence response, protecting rats from oxidative stress injury. Hemin plays its neuroprotective role via phosphoinositide 3-kinase (PI3K)/Akt signalling. A single inhalation of sevoflurane did not affect DLG4 expression, while hemin treatment did. Platform crossing increased in rats treated with hemin as well, which may be related to increased DLG4. Neuroglobin expression was not affected, suggesting that it may act upstream of PI3K/Akt signalling. SIGNIFICANCE: Our study demonstrates that hemin plays a protective role in anaesthesia-induced neurotoxicity by both inhibiting apoptosis via the PI3K/Akt pathway and increasing the expression of antioxidant enzymes, reducing oxidative damage. The results provide mechanistic insight into the effects of sevoflurane anaesthesia on the developing brain and suggest that hemin could help avoid these effects.


Assuntos
Anestésicos Inalatórios/toxicidade , Encéfalo/efeitos dos fármacos , Hemina/farmacologia , Fármacos Neuroprotetores/farmacologia , Fosfatidilinositol 3-Quinase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Sevoflurano/toxicidade , Transdução de Sinais/efeitos dos fármacos , Administração por Inalação , Animais , Animais Recém-Nascidos , Western Blotting , Caspase 3/metabolismo , Proteína 4 Homóloga a Disks-Large/metabolismo , Heme Oxigenase (Desciclizante)/metabolismo , Hipocampo/química , Hipocampo/efeitos dos fármacos , Hipocampo/enzimologia , Aprendizagem em Labirinto/efeitos dos fármacos , Neuroglobina/metabolismo , Ratos , Ratos Sprague-Dawley , Sevoflurano/antagonistas & inibidores , Superóxido Dismutase/metabolismo
15.
J Enzyme Inhib Med Chem ; 35(1): 31-41, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31645149

RESUMO

The present study describes the synthesis of a novel series of thiazolidin-4-one and thiazinan-4-one using 1-(2-aminoethyl)pyrrolidine as amine precursor. All compounds were synthesised by one-pot three component cyclocondensation reaction from the amine, a substituted benzaldehyde and a mercaptocarboxylic acid. The compounds were obtained in moderate to good yields and were identified and characterised by 1H, 13 C, 2 D NMR and GC/MS techniques. The compounds also were screened for their in vitro acetylcholinesterase (AChE) activity in hippocampus and cerebral cortex on Wistar rats. The six most potent compounds have been investigated for their cytotoxicity by cell viability assay of astrocyte primary culture, an important cell of central nervous system. We highlighted two compounds (6a and 6k) that had the lowest IC50 in hippocampus (5.20 and 4.46 µM) and cerebral cortex (7.40 and 6.83 µM). These preliminary and important results could be considered a starting point for the development of new AChE inhibitory agents.


Assuntos
Acetilcolinesterase/metabolismo , Inibidores da Colinesterase/farmacologia , Tiazinas/farmacologia , Tiazolidinas/farmacologia , Animais , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/enzimologia , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Relação Dose-Resposta a Droga , Hipocampo/efeitos dos fármacos , Hipocampo/enzimologia , Estrutura Molecular , Ratos , Ratos Wistar , Relação Estrutura-Atividade , Tiazinas/síntese química , Tiazinas/química , Tiazolidinas/síntese química , Tiazolidinas/química
16.
Life Sci ; 242: 117210, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31874166

RESUMO

OBJECTIVES: Exposure of healthy subjects to ambient airborne dusty particulate matter (PM) causes brain dysfunction. This study aimed to investigate the effect of sub-chronic inhalation of ambient PM in a designed special chamber to create factual dust storm (DS) conditions on spatial cognition, hippocampal long-term potentiation (LTP), inflammatory cytokines, and oxidative stress in the brain tissue. METHODS: Adult male Wistar rats (250-300 g) were randomly divided into four groups: Sham (clean air, the concentration of dusty PM was <150 µg/m3), DS1 (200-500 µg/m3), DS2 (500-2000 µg/m3) and DS3 (2000-8000 µg/m3). Experimental rats were exposed to clean air or different sizes and concentrations of dust PM storm for four consecutive weeks (exposure was during 1-4, 8-11, 15-16 and 20-23 days, 30 min, twice daily) in a real-ambient dust exposure chamber. Subsequently, cognitive performance, hippocampal LTP, blood-brain barrier (BBB) permeability and brain edema of the animals evaluated. As well as, inflammatory cytokines and oxidative stress indexes in the brain tissue measured using ELISA assays. RESULTS: Exposing to dust PM impaired spatial memory (p < 0.001), hippocampal LTP (p < 0.001). These disturbances were in line with the severe damage to respiratory system followed by disruption of BBB integrity (p < 0.001), increased brain edema (p < 0.001), inflammatory cytokines (p < 0.001) excretion and oxidative stress (p < 0.001) in brain tissue. CONCLUSIONS: Our study showed that exposure to ambient dust PM increased brain edema and BBB permeability, induced memory impairment and hippocampal LTP deficiency by increasing the inflammatory responses and oxidative stress in the brain of the rats.


Assuntos
Edema Encefálico/induzido quimicamente , Encéfalo/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Potenciação de Longa Duração/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Material Particulado/efeitos adversos , Memória Espacial/efeitos dos fármacos , Animais , Barreira Hematoencefálica/efeitos dos fármacos , Citocinas/metabolismo , Relação Dose-Resposta a Droga , Exposição por Inalação/efeitos adversos , Masculino , Tamanho da Partícula , Ratos , Ratos Wistar
17.
Sheng Li Xue Bao ; 71(6): 839-845, 2019 Dec 25.
Artigo em Chinês | MEDLINE | ID: mdl-31879739

RESUMO

The purpose of this study was to explore the effects of calcitonin gene-related peptide (CGRP) on the long-term depression (LTD) of hippocampus in mice. Sixty C57BL/6J mice (30 days old) were randomly divided into control group, three CGRP (50, 100, and 200 nmol/L) groups, CGRP + CGRP8-37 group and CGRP + APV group (10 mice for each group). The effects of exogenous application of different concentrations of CGRP on synaptic plasticity and LTD in hippocampus of mice were detected by in vitro recording of local field potential. The results showed that higher doses (100 and 200 nmol/L) of CGRP significantly enhanced the induction of LTD in the hippocampus. Moreover, CGRP increased the magnitude of N-methyl-D-aspartate (NMDA) receptor-mediated excitatory postsynaptic currents. The above-mentioned effects of CGRP were blocked by either CGRP selective antagonist CGRP8-37 or NMDA receptor antagonist APV. These results suggest that CGRP can dose-dependently enhance the induction of LTD in hippocampus of mice, and the underlying mechanism involves the mediation of NMDA receptor function.


Assuntos
Peptídeo Relacionado com Gene de Calcitonina , Hipocampo , Animais , Peptídeo Relacionado com Gene de Calcitonina/farmacologia , Hipocampo/efeitos dos fármacos , Depressão Sináptica de Longo Prazo/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Distribuição Aleatória
18.
J Agric Food Chem ; 67(49): 13767-13774, 2019 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-31722531

RESUMO

Recent studies indicated that neuroinflammation contributes to the exacerbation of Alzheimer's disease (AD) and plays an important role in AD. The NOD-like receptor protein 3 (NLRP3) inflammasome, which is an important component of innate immune system, is associated with a wide range of human central nervous system disorders, including AD. Most of the studies focus on the protective effects of docosahexaenoic acid (DHA) in AD, but eicosapentaenoic acid (EPA) has rarely been involved. Here, we investigate the effects of EPA in the forms of phosphatidylcholine (EPA-PC) and ethyl esters (EPA-EE) in improving Aß1-42-induced neurotoxicity. The spatial memory ability and the biochemical changes in the hippocampus were measured, including glial cell activation, tumor necrosis factor α production, NLRP3 inflammasome activation, and autophagic flux. The present results showed that the AD rats were significantly protected from spatial memory loss by the supplementation (EPA + DHA = 60 mg/kg, i.g., 20 days) of EPA-PC, while EPA-EE showed no significant benefit. Further mechanism studies suggested that EPA-PC could inhibit Aß-induced neurotoxicity by alleviating NLRP3 inflammasome activation and enhancing autophagy. These findings indicate that EPA could improve cognitive deficiency in Aß1-42-induced AD rats via autophagic inflammasomal pathway and the bioactivity differs in its molecular form.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/toxicidade , Autofagia/efeitos dos fármacos , Ácido Eicosapentaenoico/administração & dosagem , Inflamassomos/efeitos dos fármacos , Fosfatidilcolinas/administração & dosagem , Doença de Alzheimer/metabolismo , Doença de Alzheimer/fisiopatologia , Doença de Alzheimer/psicologia , Peptídeos beta-Amiloides/metabolismo , Animais , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Humanos , Inflamassomos/genética , Inflamassomos/metabolismo , Masculino , Memória/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley
19.
Sichuan Da Xue Xue Bao Yi Xue Ban ; 50(5): 689-694, 2019 Sep.
Artigo em Chinês | MEDLINE | ID: mdl-31762239

RESUMO

OBJECTIVE: To assess changes in the cognitive function and hippocampal ultrastructure of elderly rats exposed to sevoflurane. METHODS: Ault male Sprague-Dawley rats were given subcutaneous injection of D-galactose on the neck for 40 d to establish elderly models, after 9-day behavioral training. The model rats were divided into 3 groups randomly: control group with natural air, A/O group with 6 h exposure to carrier gas (2 L/min Air+2 L/min O2), and Sev group with 6 h exposure to 3.2% sevoflurane through carrier gas. Morris Water Maze and balance beam experiment were conducted on 6 rats in each group 2 h, 1 week and 4 weeks after treatments, respectively. The hippocampal tissues of the rats were rapidly dissected and prepared by glutaraldehyde fixation, ethanol dehydration, infiltration, embedding polymerization, semimembrane section localization and staining for examinations under transmission electron microscopy. The hippocampal ultrastructure such as nucleus, cytoplasm, mitochondria, endoplasmic reticulum, medullary nerve fiber, synapse and apoptotic corpuscle were observed. RESULTS: Ethology: compared with the control and A/O groups, significant reductions in the probe trial capability were found in the rats after 2 h exposure to sevoflurane, which recovered at 1 week and 4 weeks. Sevoflurane also increased the working memory escape latency 2 h and 1 week after exposure. The balance beam experiment showed that sevoflurane prolonged the staring time of rats after 2 h exposure, which recovered at 1 week and 4 weeks. Prolonged length for going through the balance beam was found consistently in the rats exposed to sevoflurane. Transmission electron microscopy: rats in the control group were found to have clear hippocampal ultrastructure, intact nuclear membrane, no edema fluid in the cytoplasm, intact mitochondria and endoplasmic reticulum, normal medullary nerve fibers, intact synaptic structure, and no apoptotic bodies in the cells. But a small amount of edema were observed in the cytoplasm of hippocampal cells in the rats exposed to sevoflurane and A/O at 2 h, which increased at 1 week. The cytoplasmic morphology of rats in the A/O group returned to normal at 4 weeks. But further increase of edema was observed in the rats 4 weeks after exposure to sevoflurane. No abnormal morphological structures or apoptotic bodies in other organelles were found. CONCLUSIONS: Sevoflurane can induce early neurocognitive impairments in elderly rats, which may be related with changes in the hippocampus ultrastructure.


Assuntos
Envelhecimento , Cognição , Hipocampo/ultraestrutura , Sevoflurano/farmacologia , Animais , Hipocampo/efeitos dos fármacos , Masculino , Aprendizagem em Labirinto , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley
20.
Life Sci ; 238: 116898, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31610193

RESUMO

AIMS: Learning and memory impairment is a common symptom in the early stages of various types of dementia. It is likely to reduce the incidence of dementia with correct intervention. α-Asarone is the main bioactive substance isolated from Acorus tatarinowii Schott and has been proven to improve memory dysfunction; however, at present, the specific underlying mechanism is poorly understood. The aim of the present study was to investigate the effect of α-asarone on ethanol-impaired cognitive ability and explore the underlying mechanism in mice. MAIN METHODS: A mouse model of impaired learning and memory was created by ethanol (2.0 g/kg, i.g.). α-Asarone (7.5, 15 or 30 mg/kg, i.p.) was delivered 10 min prior to ethanol administration. The behavioral effect of α-asarone was evaluated using the novel object recognition test. Glutamate (Glu) and γ-aminobutyric acid (GABA) levels in the hippocampus were determined by ELISA, and the protein expression levels of hippocampal GluR2, NMDAR2B, SYNΙ, GLT-1 and CaMKⅡ were detected by western blotting. KEY FINDINGS: Pretreatment with α-asarone significantly improved the behavioral performance, regulated the imbalance of Glu and GABA in the hippocampus and the abnormal expression of related proteins. A possible underlying mechanism is regulation of the calcium signaling cascade to correct functioning of related proteins, and thus, maintain the level of Glu. SIGNIFICANCE: Our results show that the improvement in learning and memory elicited by α-asarone may providing a possible novel candidate for the prevention of learning and memory impairment in the early stages of dementia.


Assuntos
Anisóis/farmacologia , Depressores do Sistema Nervoso Central/toxicidade , Etanol/toxicidade , Fibrinolíticos/farmacologia , Hipocampo/efeitos dos fármacos , Aprendizagem/efeitos dos fármacos , Transtornos da Memória/tratamento farmacológico , Animais , Modelos Animais de Doenças , Ácido Glutâmico/metabolismo , Hipocampo/metabolismo , Masculino , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/metabolismo , Transtornos da Memória/patologia , Camundongos , Camundongos Endogâmicos C57BL , Neurotransmissores/metabolismo
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