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1.
Behav Neurosci ; 138(2): 125-141, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38661671

RESUMO

Selenium is an essential trace element that is delivered to the brain by the selenium transport protein selenoprotein P (SEPP1), primarily by binding to its receptor low-density lipoprotein receptor-related protein 8 (LRP8), also known as apolipoprotein E receptor 2 (ApoER2), at the blood-brain barrier. Selenium transport is required for several important brain functions, with transgenic deletion of either Sepp1 or Lrp8 resulting in severe neurological dysfunction and death in mice fed a selenium-deficient diet. Previous studies have reported that although feeding a standard chow diet can prevent these severe deficits, some motor coordination and cognitive dysfunction remain. Importantly, no single study has directly compared the motor and cognitive performance of the Sepp1 and Lrp8 knockout (KO) lines. Here, we report the results of a comprehensive parallel analysis of the motor and spatial learning and memory function of Sepp1 and Lrp8 knockout mice fed a standard mouse chow diet. Our results revealed that Sepp1 knockout mice raised on a selenium-replete diet displayed motor and cognitive function that was indistinguishable from their wild-type littermates. In contrast, we found that although Lrp8-knockout mice fed a selenium-replete diet had normal motor function, their spatial learning and memory showed subtle deficits. We also found that the deficit in baseline adult hippocampal neurogenesis exhibited by Lrp8-deficit mice could not be rescued by dietary selenium supplementation. Taken together, these findings further highlight the importance of selenium transport in maintaining healthy brain function. (PsycInfo Database Record (c) 2024 APA, all rights reserved).


Assuntos
Proteínas Relacionadas a Receptor de LDL , Camundongos Knockout , Selênio , Aprendizagem Espacial , Animais , Camundongos , Dieta , Hipocampo/metabolismo , Proteínas Relacionadas a Receptor de LDL/genética , Proteínas Relacionadas a Receptor de LDL/metabolismo , Aprendizagem em Labirinto/fisiologia , Aprendizagem em Labirinto/efeitos dos fármacos , Memória/fisiologia , Memória/efeitos dos fármacos , Selênio/administração & dosagem , Selênio/deficiência , Selênio/farmacologia , Selenoproteína P/genética , Selenoproteína P/metabolismo , Aprendizagem Espacial/fisiologia , Aprendizagem Espacial/efeitos dos fármacos , Memória Espacial/fisiologia , Memória Espacial/efeitos dos fármacos
2.
Exp Gerontol ; 191: 112442, 2024 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-38663491

RESUMO

In this study we investigated the potential synergistic effects of moderate interval training (MIT) and lithium on spatial learning and memory. Forty-two male Wistar males were classified into six groups including I: Control, II: 10 mg/kg/day IP lithium (Li10), III: MIT, IV: Li10 + MIT, V: 40 mg/kg/day IP lithium (Li40), and VI: Li40 + MIT. Then, the rats underwent Morris Water Maze (MWM) test to assess their spatial memory and learning ability. Brain-derived neurotrophic factor (BDNF) density was measured by enzyme-linked immunosorbent assay (ELISA), and the expression of PGC1 and SIRT3 were assessed via qRT-PCR. The results show that MIT improves both memory and spatial learning; but lithium alone, does not cause this. Additionally, those exposed to a combination of exercise and lithium also had improved spatial learning and memory. Finally, we observed a positive role of BDNF protein, and PGC1 gene on the effects of exercise and lithium.


Assuntos
Fator Neurotrófico Derivado do Encéfalo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo , Condicionamento Físico Animal , Ratos Wistar , Sirtuína 3 , Memória Espacial , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Masculino , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Sirtuína 3/metabolismo , Sirtuína 3/genética , Condicionamento Físico Animal/fisiologia , Ratos , Memória Espacial/efeitos dos fármacos , Aprendizagem Espacial/efeitos dos fármacos , Aprendizagem em Labirinto/efeitos dos fármacos , Lítio/farmacologia , Sirtuínas
3.
Brain Res ; 1822: 148636, 2024 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-37865139

RESUMO

Macamides, amides of fatty acids first isolated from maca (Lepidium meyenii) are potentially responsible for the reduction of ischemic injury in the stroke animal model followed by maca extract administration. This deduction comes from its ability to inhibit the fatty acid amide hydrolase activity, an enzyme related to the endocannabinoid anandamide hydrolysis. However, no study about the effects of isolated macamides on in-vivo models has been published yet. Our objective was to evaluate the effect of a 10-day 30 mg/kg i.p. MCH1 administration, the macamide with the higher FAAH inhibition capability, on the neurological recovery and brain infarction area of Sprague-Dawley rats exposed to the transient middle cerebral artery occlusion (MCAO) model. Our results showed that the group receiving MCH1 for 10 days did not improve Garcia's neurological score compared to receiving the vehicle only. Likewise, the MCH1 group did not improve their sensorimotor dysfunction as indicated by the latency to detect and remove the tape from the contralateral forepaw in the adhesive removal test, and a similar number of errors with the contralateral forepaw in the foot fault test compared to the vehicle group at the 10th day. Evaluation of the spatial memory and learning using the Barnes test showed longer latency to reach the escape box in the Vehicle and MCH1 groups compared to the control group (no MCAO) only in the retrieval test, while no effect of MCAO procedure or MCH1 administration was observed in the reversal learning test. Despite the lack of behavioral effect of MCH1, analysis of the infarcted areas in the brain using the 2, 3, 5-Triphenyltetrazolium chloride (TTC) staining method in the seven consecutive coronal sections revealed that the infarcted area in the first (bregma + 4.2 mm) and fifth (bregma -3.8 mm) coronal sections of the MCAO + MCH1 group remained similar to the Control group. These results provide evidence that MCH1 can limit damage from ischemic stroke, although it is not reflected in neurological or sensorimotor behavior and spatial learning and memory.


Assuntos
Infarto da Artéria Cerebral Média , Córtex Motor , Acidente Vascular Cerebral , Animais , Ratos , Modelos Animais de Doenças , Infarto da Artéria Cerebral Média/tratamento farmacológico , Córtex Motor/efeitos dos fármacos , Ratos Sprague-Dawley , Aprendizagem Espacial/efeitos dos fármacos , Amidoidrolases/antagonistas & inibidores
4.
Brain Res ; 1815: 148443, 2023 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-37290608

RESUMO

BACKGROUND: Autism spectrum disorder (ASD) is categorized as a neurodevelopmental disorder, presenting with a variety of aetiological and phenotypical features. Ibudilast is known to produce beneficial effects in several neurological disorders including neuropathic pain, multiple sclerosis, etc. by displaying its neuroprotective and anti-inflammatory properties. Here, in our study, the pharmacological outcome of ibudilast administration was investigated in the prenatal valproic acid (VPA)-model of ASD in Wistar rats. METHODS: Autistic-like symptoms were induced in Wistar male pups of dams administered with Valproic acid (VPA) on embryonic day 12.5. VPA-exposed male pups were administered with two doses of ibudilast (5 and10 mg/kg) and all the groups were evaluated for behavioral parameters like social interaction, spatial memory/learning, anxiety, locomotor activity, and nociceptive threshold. Further, the possible neuroprotective effect of ibudilast was evaluated by assessing oxidative stress, neuroinflammation (IL-1ß, TNF-α, IL-6, IL-10) in the hippocampus, % area of Glial fibrillary acidic protein (GFAP)-positive cells and neuronal damage in the cerebellum. KEY FINDINGS: Treatment with ibudilast significantly attenuated prenatal VPA exposure associated social interaction and spatial learning/memory deficits, anxiety, hyperactivity, and increased nociceptive threshold, and it decreased oxidative stress markers, pro-inflammatory markers (IL-1ß, TNF-α, IL-6), and % area of GFAP-positive cells and restored neuronal damage. CONCLUSIONS: Ibudilast treatment has restored crucial ASD-related behavioural abnormalities, potentially through neuroprotection. Therefore, benefits of ibudilast administration in animal models of ASD suggest that ibudilast may have therapeutic potential in the treatment of ASD.


Assuntos
Transtorno do Espectro Autista , Inibidores de Fosfodiesterase , Efeitos Tardios da Exposição Pré-Natal , Ácido Valproico , Animais , Feminino , Gravidez , Ratos , Ansiedade/tratamento farmacológico , Transtorno do Espectro Autista/induzido quimicamente , Transtorno do Espectro Autista/tratamento farmacológico , Transtorno do Espectro Autista/fisiopatologia , Transtorno do Espectro Autista/psicologia , Modelos Animais de Doenças , Mediadores da Inflamação/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Limiar da Dor/efeitos dos fármacos , Inibidores de Fosfodiesterase/farmacologia , Inibidores de Fosfodiesterase/uso terapêutico , Efeitos Tardios da Exposição Pré-Natal/tratamento farmacológico , Agitação Psicomotora/tratamento farmacológico , Ratos Wistar , Comportamento Social , Aprendizagem Espacial/efeitos dos fármacos , Ácido Valproico/administração & dosagem , Ácido Valproico/efeitos adversos , Masculino
5.
PLoS One ; 17(2): e0257932, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35157725

RESUMO

BACKGROUND: The burdens of psychostimulant use disorders are becoming a worldwide problem. One of the psychostimulants widely consumed in Ethiopia and East African countries is Catha edulis Forsk (khat). However, no studies have been conducted on the cognitive effects of khat and its correlation with serum electrolytes. The present study was aimed to evaluate the effects of khat on spatial learning and memory and their correlation with serum electrolytes. MATERIALS AND METHODS: Diethyl ether and chloroform (3:1v/v ratio) were solvents used to obtain the crude khat extract in this study. T80W was used to prepare the khat juice, fresh khat leave extract. The rats were received crude khat extract subchronically (KESC) (100 mg/kg, 200 mg/kg and 300 mg/kg b.w), khat juice (KHJ 2.5 mL/kg), 2% tween 80 in distilled water (T80W- v/v, vehicle) and khat extract subacutely (KESA) (300 mg/kg). For subchronic treatment, each rat was administered for twelve weeks before Morris water maze experiment has been started, while it was administered for a week for acute treatment. Spatial learning and memory were measured using the Morris water maze model and serum sodium, calcium, potassium, and chloride were evaluated using Cobas 6000. RESULTS: Spatial learning was improved with trials across the groups, while average escape latency (s) of rats received KESC 200 mg/kg (p<0.001), KESC 300 mg/kg (p<0.01) and KHJ 2.5 mL/kg (p<0.05) was significantly greater than rats that received vehicle. There was no significant difference in the latency between rats that received KESA 300mg/kg and vehicle (p>0.05). Thigmotaxis was significantly higher in rats that received all doses of khat extract (p<0.001). The time spent in the target quadrant in rats that received KESC 300 mg/kg was significantly reduced (p<0.05). Serum calcium level was inversely correlated with the escape latency (R = -0.417, p<0.05) in rats that received khat. CONCLUSIONS: Khat extract and juice administered subchronically, but not subacutely, impaired learning and memory and was associated with serum calcium reduction. The neuronal basis for such alteration should be investigated.


Assuntos
Catha/química , Eletrólitos/sangue , Extratos Vegetais/farmacologia , Aprendizagem Espacial/efeitos dos fármacos , Animais , Catha/metabolismo , Relação Dose-Resposta a Droga , Masculino , Extratos Vegetais/química , Ratos , Natação/fisiologia
6.
Gene ; 822: 146348, 2022 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-35183682

RESUMO

Aging is referred to progressive dysfunction of body organs, including the brain. This study aims to explore the anti-aging effect of combing nicotinamide mononucleotide (NMN) and lycopene (Lyco) (NMN + Lyco) on aging rats and senescent PC12 cells. Both in vivo and in vitro aging models were established using D-galactose (D-gal). The combination showed a trend to superiority over monotherapy in preventing aging in vivo and in vitro. Morris water maze test showed that NMN + Lyco effectively improved the ability of spatial location learning and memory of aging model rats. NMN + Lyco mitigated the oxidative stress of rat brains, livers, and PC12 cells by elevating the levels of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px), GSH, as well as total antioxidant capacity (T-AOC), and reducing malondialdehyde (MDA) content. CCK-8 assay, senescence-associated ß-galactosidase staining, and flow cytometer confirmed the cellular senescence of PC12 cells after exposing D-gal, and indicated the anti-senescence effect of NMN + Lyco in vitro. Moreover, NMN + Lyco effectively down-regulated the expressions of p53, p21, and p16 (senescence-related genes), and activated Keap1-Nrf2 signaling in both in vivo and in vitro aging models. In total, NMN + Lyco protected rats and PC12 cells from cognitive impairment and cellular senescence induced by D-gal, of which effects might be linked to the reduction of oxidative stress and the activation of Keap1-Nrf2 signaling.


Assuntos
Envelhecimento/psicologia , Disfunção Cognitiva/prevenção & controle , Galactose/efeitos adversos , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Licopeno/administração & dosagem , Fator 2 Relacionado a NF-E2/metabolismo , Mononucleotídeo de Nicotinamida/administração & dosagem , Envelhecimento/efeitos dos fármacos , Animais , Disfunção Cognitiva/etiologia , Quimioterapia Combinada , Regulação da Expressão Gênica/efeitos dos fármacos , Licopeno/farmacologia , Masculino , Teste do Labirinto Aquático de Morris , Mononucleotídeo de Nicotinamida/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Células PC12 , Ratos , Transdução de Sinais/efeitos dos fármacos , Aprendizagem Espacial/efeitos dos fármacos , Resultado do Tratamento
7.
Food Chem Toxicol ; 161: 112831, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-35090998

RESUMO

Lanthanum is one of REEs documented to have neurotoxicity that led to learning and memory ability impairments. However, the mechanisms underlying La-induced neurotoxicity remain largely unexplored. Autophagy is a self-balancing and self-renewal process that degrades damaged organelles and macromolecules through lysosomal pathway. Importantly, appropriate autophagy levels have protective effects against harmful stress, while excessive autophagy has been demonstrated to be implicated in neurological diseases. ER is close to mitochondria at specific sites with a reported distance of 10-30 nm. The functional domains between the two organelles, called MAM, have been associated with autophagosome synthesis. In this study, the pregnant Wistar rats were randomly divided into four groups and given distilled water solution containing 0%, 0.125%, 0.25%, and 0.5% LaCl3 for drinking during gestation and lactation. The pups were exposed to LaCl3 via the maternal placenta and three-week lactation. Experimental results showed that LaCl3 decreased spatial learning and memory ability of offspring rats, decreased tethering protein complexes expression of MAM, damaged MAM structure, up-regulated NOX4 expression which led to active ROS-AMPK-mTOR signaling pathway. Our findings suggest that decreased spatial learning and memory ability induced by LaCl3 may be related to the abnormally autophagy regulated by tethering protein complexes of MAM.


Assuntos
Autofagia/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Lantânio/toxicidade , Membranas Mitocondriais/efeitos dos fármacos , Animais , Relação Dose-Resposta a Droga , Feminino , Hipocampo/metabolismo , Lactação , Masculino , Mitocôndrias , Membranas Mitocondriais/metabolismo , Gravidez , Efeitos Tardios da Exposição Pré-Natal , Distribuição Aleatória , Ratos , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos , Aprendizagem Espacial/efeitos dos fármacos
8.
Toxicol Lett ; 354: 24-32, 2022 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-34757177

RESUMO

The infant and fetus may be exposed to cyanuric acid (CA) via several different routes into the diet or milk product as well as deliberate contamination. Previous findings indicated chronic CA treatment caused neurotransmission and synaptic impairment in the early developing hippocampus. This study was designed to characterize the effects of different doses (10 mg/kg, 20 mg/kg and 40 mg/kg) of CA exposure on the developing fetus. Pregnant rats were intraperitoneally exposed to CA during the entire period of gestation and male offspring were selected for water maze task, neural recording and N-methyl-d-aspartate (NMDA) receptor detection around the eighth postnatal week. We found that CA exposure impaired the learning and memory function in a dose-dependent manner. The paired-pulse ratio (PPR) and GluN2A-dependent long-term potentiation (LTP) at the Schaffer collateral-CA1 pathway were affected in CA-exposed rats. Remarkably, hippocampal levels of NMDA-GluN2A, but not NMDA-GluN2B, were significantly decreased. Meanwhile, the spine density of hippocampal CA1 neurons was not altered by the CA exposure. Our findings are consistent with the hypothesis that CA treatment during the prenatal period produces deficits in spatial cognition by disrupting hippocampal synaptic function.


Assuntos
Cognição/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Memória/efeitos dos fármacos , Plasticidade Neuronal/efeitos dos fármacos , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Aprendizagem Espacial/efeitos dos fármacos , Triazinas/toxicidade , Animais , Animais Recém-Nascidos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Feminino , Feto/efeitos dos fármacos , Gravidez , Ratos
9.
Eur J Pharmacol ; 914: 174691, 2022 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-34896111

RESUMO

Hydroxy-α-sanshool (HAS) is an unsaturated fatty acid amide from Zanthoxylum bungeanum Maxim. with hypolipidemic, hypoglycemic, anti-inflammatory, and neurotrophic effects, etc. In this study, results indicated that HAS effectively ameliorated spontaneous locomotion deficit of mice induced by D-galactose (D-gal) and AlCl3 treatment in open field test. Results of Morris water maze test (MWM) showed that HAS significantly improved the spatial learning and memory ability of aging mice. Histopathological evaluations revealed that HAS markedly alleviated morphological changes and increased number of Nissl neurons in hippocampus of D-gal/AlCl3-induced Alzheimer's disease (AD)-like mice. HAS markedly reduced malondialdehyde (MDA) production, and increased the activity of antioxidative enzymes including superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and catalase (CAT), showing an inhibitory effect on oxidative stress. Furthermore, HAS treatment obviously reversed the inhibitory expressions of mRNA and protein of HO-1 and Nrf2 in the hippocampus of AD mice, suggesting that neuroprotective effects of HAS against oxidative stress might be mediated by the Nrf2/HO-1 pathway. Meanwhile, HAS significantly inhibited neuronal apoptosis by decreasing mRNA and protein expressions of Cyt-c, Bax and Caspase 3, and increasing Bcl-2 expression in the hippocampus of AD mice. These results suggest that HAS have the potential to be developed as antioxidant drug for the prevention and early therapy of AD.


Assuntos
Doença de Alzheimer , Ácidos Graxos Insaturados/farmacologia , Heme Oxigenase-1/metabolismo , Proteínas de Membrana/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Corpos de Nissl , Estresse Oxidativo/efeitos dos fármacos , Alcamidas Poli-Insaturadas/farmacologia , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Animais , Antioxidantes/farmacologia , Modelos Animais de Doenças , Hipocampo/patologia , Malondialdeído/metabolismo , Camundongos , Fármacos Neuroprotetores/farmacologia , Corpos de Nissl/efeitos dos fármacos , Corpos de Nissl/metabolismo , Transdução de Sinais/efeitos dos fármacos , Aprendizagem Espacial/efeitos dos fármacos , Zanthoxylum
10.
Bioengineered ; 13(1): 531-543, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34968163

RESUMO

In this study, we aimed to investigate the effect of Magnolol on Alzheimer's disease (AD). After the model of streptozotocin-induced AD mice with brain insulin resistance was established, the mice were treated with Magnolol or miR-200c antagomiR. The abilities of ambulations, rearings, discrimination, spatial learning, and memory were evaluated by open-field test (OFT), novel object recognition (NOR), and morris water maze (MWM) tests. The levels of malondialdehyde (MDA), glutathione (GSH), superoxide dismutase (SOD), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), C-reactive protein (CRP), and miR-200c in the mice hippocampus were evaluated by enzyme-linked immunosorbent assay, Western blot, or Quantitative real-time Polymerase Chain Reaction. In AD mice model, streptozotocin induced the locomotor impairment and cognitive deficit, up-regulated levels of MDA, TNF-α, IL-6, and CRP, while down-regulated levels of GSH, SOD, and miR-200c. Magnolol increased the rearings numbers and discrimination index of AD mice in OFT and NOR tests. Magnolol increased the number of entries in the target quadrant and time spent in the target quadrant and decreased the escape latency of AD mice in the MWM test. Magnolol also down-regulated the levels of MDA, TNF-α, IL-6, and CRP, and up-regulated the levels of GSH, SOD, and miR-200c in the hippocampus tissues of AD mice. However, miR-200c antagomiR did the opposite and further offset the effects of the Magnolol on AD mice. Magnolol attenuated the locomotor impairment, cognitive deficit, and neuroinflammatory in AD mice with brain insulin resistance via up-regulating miR-200c.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Antagomirs/administração & dosagem , Compostos de Bifenilo/administração & dosagem , Resistência à Insulina , Lignanas/administração & dosagem , Estreptozocina/efeitos adversos , Doença de Alzheimer/induzido quimicamente , Doença de Alzheimer/genética , Doença de Alzheimer/psicologia , Animais , Antagomirs/farmacologia , Compostos de Bifenilo/farmacologia , Encéfalo , Modelos Animais de Doenças , Lignanas/farmacologia , Locomoção/efeitos dos fármacos , Masculino , Malondialdeído/metabolismo , Camundongos , Teste do Labirinto Aquático de Morris/efeitos dos fármacos , Aprendizagem Espacial/efeitos dos fármacos
11.
Brain Res Bull ; 178: 120-130, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34838642

RESUMO

In addition to motor dysfunction, cognitive impairments have been reported to occur in patients with early-stage Parkinson's disease (PD). In this study, we examined a PD mouse model induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). This treatment led to the degeneration of nigrostriatal dopaminergic neurons in mice, a phenomenon that is consistent with previous studies. Besides, spatial memory and object recognition of MPTP-treated mice were impaired, as denoted by the Morris water maze (MWM) and novel object recognition (NOR) tests, respectively. Moreover, hippocampal synaptic plasticity (long-term potentiation and depotentiation) and the levels of synaptic proteins in hippocampus were decreased after MPTP treatment. We also found that MPTP resulted in the microglial activation and an inflammatory response in the striatum and hippocampus. Mammalian asparagine endopeptidase (AEP), a cysteine lysosomal protease, is involved in the cleavage and activation of Toll-like receptors (TLRs). The deletion of AEP can inhibit TLR4 in a mouse model of Alzheimer's disease, and TLR4 is upregulated in PD, inducing microglial activation and inflammation. We found that AEP deletion provided greater resistance to the toxic effects of MPTP. AEP knockout ameliorated the cognition and the synaptic plasticity defects in the hippocampus. Furthermore, AEP deletion decreased the expression of TLR4 and reduced microglial activation and the levels of several proinflammatory cytokines. Thus, we suggest that AEP plays a role in the inflammation induced by MPTP, and TLR4 might also involve in this process. AEP deletion could be a possible treatment strategy for the cognitive deficits of PD.


Assuntos
1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina/farmacologia , Disfunção Cognitiva/induzido quimicamente , Cisteína Endopeptidases/metabolismo , Dopaminérgicos/farmacologia , Neurônios Dopaminérgicos/efeitos dos fármacos , Intoxicação por MPTP , Doenças Neuroinflamatórias/induzido quimicamente , Plasticidade Neuronal/efeitos dos fármacos , Receptor 4 Toll-Like/efeitos dos fármacos , Animais , Comportamento Animal/efeitos dos fármacos , Modelos Animais de Doenças , Intoxicação por MPTP/metabolismo , Intoxicação por MPTP/fisiopatologia , Camundongos , Camundongos Knockout , Reconhecimento Psicológico/efeitos dos fármacos , Aprendizagem Espacial/efeitos dos fármacos , Memória Espacial/efeitos dos fármacos
12.
Brain Res Bull ; 178: 155-163, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34800583

RESUMO

Some studies suggest that the effect of cannabis on behavior performance depends on the presence of ovarian hormones and the age of use initiation. Estradiol is the main ovarian hormone that can interact with cannabinoids. It has been suggested that cannabinoids exert some of their effects directly through estrogen receptors (ERs). A novel G-protein-coupled receptor (GPR30) was described as mediating estrogen signaling in various cell lines. Since there are few studies on the interaction of cannabis and ovarian hormones on cognitive behaviors, so, this study evaluated the role of GPR30 in the effects of marijuana (M) and estrogen, alone and in combination, on spatial learning and memory of young (non-ovarian(OVX)) and old female rats. Young (5-7 months) and old (22-24 months) female rats received an intraperitoneal injection (i.p) of 17ß-estradiol (E2), G1 (GPR30 agonist), and G15 (GPR30 antagonist) every four days, and M (every day), either alone or in combination, for 28 days. One hour after the last injection, the Morris water maze (MWM) test was conducted to evaluate of spatial learning and memory. Moreover, hippocampal BDNF level was assessed by the ELISA method. The results showed a positive effect of M on spatial learning in both young and old rats, however, E2 showed beneficial effects on the memory of young, but not old rats. Our results showed that GPR30 does not have any role in the interaction effects of M and E2 in young rats. Although both E2 and M alone showed positive effects on spatial learning and memory in old rats, however, our results showed a negative interaction between marijuana and E2 combined effects on spatial learning and memory in old female rats which is mediated by GPR30. Our results showed that the effects of GPR30 on spatial learning and memory is age dependent. Furthermore, this study showed that hippocampal BDNF does not have any role in the interaction effects of M and E2 on spatial learning and memory in young and old rats.


Assuntos
Agonistas de Receptores de Canabinoides/farmacologia , Estradiol/farmacologia , Receptores Acoplados a Proteínas G/metabolismo , Aprendizagem Espacial/efeitos dos fármacos , Fatores Etários , Animais , Comportamento Animal/efeitos dos fármacos , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Agonistas de Receptores de Canabinoides/administração & dosagem , Interações Medicamentosas , Estradiol/administração & dosagem , Hipocampo/metabolismo , Ratos , Receptores Acoplados a Proteínas G/agonistas , Receptores Acoplados a Proteínas G/antagonistas & inibidores
13.
Bioengineered ; 12(2): 10982-10993, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34851228

RESUMO

To investigate the protective effects of metformin on the diabetic mice with cognitive impairment induced by the combination of streptozotocin (STZ) and isoflurane anesthesia. The isoflurane-anesthetized cognitive impairment model mice were established and then observed via behavioral tests and histopathological examination. Then these model mice were randomly assigned to three groups, which received the PBS, low and high doses of metformin, respectively. The body weight, food and water consumption of model mice were measured every other day. The mechanisms of metformin on ameliorating the cognitive dysfunction were further investigated by histomorphological, biochemical and Western blot analysis. After 14-days treatment of metformin, the diabetic symptoms in STZ-induced diabetic mice were significantly alleviated. Metformin could restore the isoflurane- and STZ-induced hippocampal tissue damage, cognitive and memory impairment in exposed space via improving the oxidative stress, upregulating the contents of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) in the hippocampus tissues of diabetic mice. Furthermore, chronic treatment of metformin significantly down-regulated the expression of AGEs, RAGE, pNF-κB, iNOS, and COX-2. In conclusion, metformin can improve the isoflurane- and STZ-induced cognitive impairment in diabetic mice via improving oxidative stress and inhibiting the AGEs/RAGE/NF-κB signaling pathway.


Assuntos
Anestesia/efeitos adversos , Disfunção Cognitiva/induzido quimicamente , Disfunção Cognitiva/tratamento farmacológico , Diabetes Mellitus Experimental/tratamento farmacológico , Metformina/uso terapêutico , Animais , Disfunção Cognitiva/complicações , Disfunção Cognitiva/fisiopatologia , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/fisiopatologia , Modelos Animais de Doenças , Hipocampo/patologia , Isoflurano , Masculino , Memória/efeitos dos fármacos , Metformina/farmacologia , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Receptor para Produtos Finais de Glicação Avançada/metabolismo , Transdução de Sinais/efeitos dos fármacos , Aprendizagem Espacial/efeitos dos fármacos , Estreptozocina
14.
Biochem Biophys Res Commun ; 584: 46-52, 2021 12 20.
Artigo em Inglês | MEDLINE | ID: mdl-34768081

RESUMO

Efavirenz (EFV) is a non-nucleoside reverse transcriptase inhibitor (NNRTI), which is widely used for anti-HIV-1. Evidences revealed that several central nervous system side effects could be observed in mice and patients with administration of EFV. However, the detailed mechanisms are still unknown. In this study, we investigated the effects of long-term EFV treatment on cognitive functions and the potential underlying mechanisms in mice. We maintained C57BL/6 mice aged 2 months with treatment containing 40 or 80 mg/kg/day EFV for 5 months, while control group treated with saline. The cognitive functions were evaluated by novel object recognition test, Barnes maze test and Morris water maze. The results showed significant short-term memory impairment in 40 and 80 mg/kg groups, and notable spatial learning and memory impairments in 80 mg/kg group, without any spontaneous activity alteration. Moreover, EFV induced impairments in dendritic integrity and synaptic plasticity in hippocampus. Furthermore, Significant increases were observed in the expression levels of pro-IL-1ß, a similar tendency of TNF-α and phosphorylation of p65 of the 80 mg/kg group compared with control group. These results imply that long-term EFV treatment causes synaptic dysfunction resulting in cognitive deficits, which might be induced by the enhanced pro-inflammatory cytokines IL-1ß and TNF-α via activating NF-κB pathway.


Assuntos
Alcinos/toxicidade , Benzoxazinas/toxicidade , Cognição/efeitos dos fármacos , Disfunção Cognitiva/fisiopatologia , Ciclopropanos/toxicidade , Transtornos da Memória/fisiopatologia , Doenças Neuroinflamatórias/fisiopatologia , Animais , Cognição/fisiologia , Disfunção Cognitiva/induzido quimicamente , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Humanos , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Transtornos da Memória/induzido quimicamente , Camundongos Endogâmicos C57BL , Doenças Neuroinflamatórias/induzido quimicamente , Inibidores da Transcriptase Reversa/toxicidade , Aprendizagem Espacial/efeitos dos fármacos , Aprendizagem Espacial/fisiologia , Sinapsinas/metabolismo , Sinaptofisina/metabolismo , Sinaptotagmina I/metabolismo , Fatores de Tempo
15.
Inflammopharmacology ; 29(6): 1807-1818, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34780009

RESUMO

3,4-Methylenedioxymethamphetamine (MDMA) or "Ecstasy", which has been used for recreational purposes, is shown to impair memory and brain functions. Statins, beyond their efficient cholesterol-lowering impact through inhibition of HMG-COA reductase enzyme, possess multiple actions referred to as pleiotropic effects. In this regard, we aimed to investigate the neuroprotective effects of atorvastatin and rosuvastatin on MDMA-induced neurotoxicity. Adult male Wistar rats received atorvastatin (5, 10, and 20 mg/kg; orally) and rosuvastatin (5, 10, 20 mg/kg; orally) for 21 consecutive days. Then, spatial memory and learning were evaluated by Morris water maze (MWM) test. Rats were intraperitoneally injected with MDMA (2.5, 5, and 10 mg/kg) 30 min before the first training session in 4 training days of MWM task. Afterward, rats were euthanized and their hippocampuses were dissected to evaluate reactive oxygen species (ROS) production, lipid peroxidation (LPO), and caspase-3 and -9 activities. Our findings showed that MDMA (5 and 10 mg/kg) significantly impaired spatial memory functions and dramatically increased ROS production, LPO, and caspase-3 and -9 activities compared to control. Also, atorvastatin (5, 10, and 20 mg/kg) and rosuvastatin (20 mg/kg) significantly improved memory performances and inhibited the elevation of ROS, LPO, and caspase-3 and -9 activities induced by MDMA. In conclusion, the results indicated that MDMA-induced cognitive impairment is followed by oxidative stress and activation of apoptotic pathways in the hippocampus. However, atorvastatin and rosuvastatin suppressed these deleterious consequences of MDMA and revealed protective effects against activation of pathways leading to cell damage.


Assuntos
Atorvastatina/farmacologia , N-Metil-3,4-Metilenodioxianfetamina/toxicidade , Fármacos Neuroprotetores/farmacologia , Rosuvastatina Cálcica/farmacologia , Animais , Apoptose/efeitos dos fármacos , Atorvastatina/administração & dosagem , Disfunção Cognitiva/induzido quimicamente , Disfunção Cognitiva/prevenção & controle , Relação Dose-Resposta a Droga , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , N-Metil-3,4-Metilenodioxianfetamina/administração & dosagem , Fármacos Neuroprotetores/administração & dosagem , Síndromes Neurotóxicas/etiologia , Síndromes Neurotóxicas/prevenção & controle , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Rosuvastatina Cálcica/administração & dosagem , Aprendizagem Espacial/efeitos dos fármacos , Memória Espacial/efeitos dos fármacos
16.
Sci Rep ; 11(1): 20558, 2021 10 18.
Artigo em Inglês | MEDLINE | ID: mdl-34663844

RESUMO

Aronia melanocarpa is a natural medicinal plant that has a variety of biological activities, its fruit is often used for food and medicine. Aronia melanocarpa polysaccharide (AMP) is the main component of the Aronia melanocarpa fruit. This research evaluated the delay and protection of AMP obtained from Aronia melanocarpa fruit on aging mice by D-Galactose (D-Gal) induction and explored the effect of supplementing AMP on the metabolism of the intestinal flora of aging mice. The aging model was established by intraperitoneal injection of D-Gal (200 mg/kg to 1000 mg/kg) once per 3 days for 12 weeks. AMP (100 and 200 mg/kg) was given daily by oral gavage after 6 weeks of D-Gal-induced. The results showed that AMP treatment significantly improved the spatial learning and memory impairment of aging mice determined by the eight-arm maze test. H&E staining showed that AMP significantly reversed brain tissue pathological damage and structural disorders. AMP alleviated inflammation and oxidative stress injury in aging brain tissue by regulating the AMPK/SIRT1/NF-κB and Nrf2/HO-1 signaling pathways. Particularly, AMP reduced brain cell apoptosis and neurological deficits by activating the PI3K/AKT/mTOR signaling pathway and its downstream apoptotic protein family. Importantly, 16S rDNA analysis indicated the AMP treatment significantly retarded the aging process by improving the composition of intestinal flora and abundance of beneficial bacteria. In summary, this study found that AMP delayed brain aging in mice by inhibiting inflammation and regulating intestinal microbes, which providing the possibility for the amelioration and treatment of aging and related metabolic diseases.


Assuntos
Envelhecimento/efeitos dos fármacos , Inflamação/tratamento farmacológico , Extratos Vegetais/farmacologia , Proteínas Quinases Ativadas por AMP/metabolismo , Adenilato Quinase/metabolismo , Envelhecimento/metabolismo , Animais , Microbioma Gastrointestinal/efeitos dos fármacos , Inflamação/metabolismo , Masculino , Memória/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos ICR , NF-kappa B/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Photinia/metabolismo , Polissacarídeos/farmacologia , Transdução de Sinais/efeitos dos fármacos , Sirtuína 1/metabolismo , Aprendizagem Espacial/efeitos dos fármacos
17.
JCI Insight ; 6(19)2021 10 08.
Artigo em Inglês | MEDLINE | ID: mdl-34622797

RESUMO

Mucopolysaccharidosis type II (MPS II) is a lysosomal storage disorder caused by deficiency of the iduronate-2-sulfatase (IDS) enzyme, resulting in cellular accumulation of glycosaminoglycans (GAGs) throughout the body. Treatment of MPS II remains a considerable challenge as current enzyme replacement therapies do not adequately control many aspects of the disease, including skeletal and neurological manifestations. We developed an IDS transport vehicle (ETV:IDS) that is engineered to bind to the transferrin receptor; this design facilitates receptor-mediated transcytosis of IDS across the blood-brain barrier and improves its distribution into the brain while maintaining distribution to peripheral tissues. Here we show that chronic systemic administration of ETV:IDS in a mouse model of MPS II reduced levels of peripheral and central nervous system GAGs, microgliosis, and neurofilament light chain, a biomarker of neuronal injury. Additionally, ETV:IDS rescued auricular and skeletal abnormalities when introduced in adult MPS II mice. These effects were accompanied by improvements in several neurobehavioral domains, including motor skills, sensorimotor gating, and learning and memory. Together, these results highlight the therapeutic potential of ETV:IDS for treating peripheral and central abnormalities in MPS II. DNL310, an investigational ETV:IDS molecule, is currently in clinical trials as a potential treatment for patients with MPS II.


Assuntos
Barreira Hematoencefálica/metabolismo , Terapia de Reposição de Enzimas/métodos , Iduronato Sulfatase/administração & dosagem , Mucopolissacaridose II/tratamento farmacológico , Receptores da Transferrina/metabolismo , Vesículas Transportadoras/metabolismo , Animais , Comportamento Animal/efeitos dos fármacos , Modelos Animais de Doenças , Glicosaminoglicanos/metabolismo , Iduronato Sulfatase/genética , Memória/efeitos dos fármacos , Camundongos , Camundongos Knockout , Destreza Motora/efeitos dos fármacos , Mucopolissacaridose II/genética , Mucopolissacaridose II/metabolismo , Mucopolissacaridose II/fisiopatologia , Fenótipo , Filtro Sensorial/efeitos dos fármacos , Esqueleto/efeitos dos fármacos , Aprendizagem Espacial/efeitos dos fármacos , Transcitose
18.
Brain Res ; 1771: 147660, 2021 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-34529964

RESUMO

Since we found that inhibition of cyclooxygenase-2 (COX-2) with concomitant application of a metabotropic glutamate receptor subtype 5 (mGluR5) antagonist (MTEP) down-regulates mGluR7 in the hippocampus (HC) and changes behavior of mice, our team decided to investigate the mechanism responsible for the observed changes. The amino acid glutamate (Glu) is a major excitatory neurotransmitter in the brain. Glu uptake is regulated by excitatory amino acid transporters (EAAT). There are five transporters with documented expression in neurons and glia in the central nervous system (CNS). EAATs, maintain the correct transmission of the Glu signal and prevent its toxic accumulation by removing Glu from the synapse. It has been documented that the toxic level of Glu is one of the main causes of mental and cognitive abnormalities. Given the above mechanisms involved in the functioning of the Glu synapse, we hypothesized modification of Glu uptake, involving EAATs as the cause of the observed changes. This study investigated the level of selected EAATs in the HC after chronic treatment with mGluR5 antagonist MTEP, NS398, and their combination using Western blot. Concomitant MTEP treatment with NS398 or a single administration of the above causes changes in LTP and modulation of EAAT levels in mouse HC. As EAATs are cellular markers of oxidative stress mechanisms, the E. coli lipopolysaccharide (LPS) challenge was performed. The modified Barnes maze test (MBM) revealed alterations in the mouse spatial learning abilities. This study reports an interaction between the mGluR5 and COX-2 in the HC, with EAAT1 and EAAT3 involvement.


Assuntos
Ciclo-Oxigenase 2/fisiologia , Transportador 1 de Aminoácido Excitatório/biossíntese , Transportador 3 de Aminoácido Excitatório/biossíntese , Hipocampo/metabolismo , Estresse Oxidativo , Receptores de Ácido Caínico/fisiologia , Animais , Inibidores de Ciclo-Oxigenase 2/farmacologia , Transportador 1 de Aminoácido Excitatório/genética , Transportador 3 de Aminoácido Excitatório/genética , Lipopolissacarídeos/farmacologia , Potenciação de Longa Duração/efeitos dos fármacos , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Receptores de Ácido Caínico/antagonistas & inibidores , Aprendizagem Espacial/efeitos dos fármacos
19.
Mol Neurobiol ; 58(11): 5756-5771, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34403042

RESUMO

Aging is an irreversible biological process that involves oxidative stress, neuroinflammation, and apoptosis, and eventually leads to cognitive dysfunction. However, the underlying mechanisms are not fully understood. In this study, we investigated the role and potential mechanisms of Synaptotagmin-7, a calcium membrane transporter in cognitive impairment in aging mice. Our results indicated that Synaptotagmin-7 expression significantly decreased in the hippocampus of D-galactose-induced or naturally aging mice when compared with healthy controls, as detected by western blot and quantitative reverse transcriptase-polymerase chain reaction analysis. Synaptotagmin-7 overexpression in the dorsal CA1 of the hippocampus reversed long-term potentiation and improved hippocampus-dependent spatial learning in D-galactose-induced aging mice. Synaptotagmin-7 overexpression also led to fully preserved learning and memory in 6-month-old mice. Mechanistically, we demonstrated that Synaptotagmin-7 improved learning and memory by elevating the level of fEPSP and downregulating the expression of aging-related genes such as p53 and p16. The results of our study provide new insights into the role of Synaptotagmin-7 in improving neuronal function and overcoming memory impairment caused by aging, suggesting that Synaptotagmin-7 overexpression may be an innovative therapeutic strategy for treating cognitive impairment.


Assuntos
Envelhecimento/psicologia , Região CA1 Hipocampal/fisiopatologia , Transtornos Cognitivos/fisiopatologia , Proteínas do Tecido Nervoso/fisiologia , Sinaptotagminas/fisiologia , Envelhecimento/metabolismo , Animais , Transtornos Cognitivos/terapia , Condicionamento Clássico , Dependovirus/genética , Eletrochoque , Medo/fisiologia , Galactose/toxicidade , Regulação da Expressão Gênica , Genes Reporter , Genes p16 , Genes p53 , Vetores Genéticos/administração & dosagem , Potenciação de Longa Duração , Masculino , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/fisiopatologia , Transtornos da Memória/terapia , Camundongos , Camundongos Endogâmicos C57BL , Teste do Labirinto Aquático de Morris , Distribuição Aleatória , Reconhecimento Psicológico , Proteínas Recombinantes/metabolismo , Aprendizagem Espacial/efeitos dos fármacos , Organismos Livres de Patógenos Específicos , Sinaptotagminas/genética
20.
Biomolecules ; 11(7)2021 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-34356631

RESUMO

Chronic sensitization to serotonin 1A and 7 receptors agonist 8-OH-DPAT induces compulsive checking and perseverative behavior. As such, it has been used to model obsessive-compulsive disorder (OCD)-like behavior in mice and rats. In this study, we tested spatial learning in the 8-OH-DPAT model of OCD and the effect of co-administration of memantine and riluzole-glutamate-modulating agents that have been shown to be effective in several clinical trials. Rats were tested in the active place avoidance task in the Carousel maze, where they learned to avoid the visually imperceptible shock sector. All rats were subcutaneously injected with 8-OH-DPAT (0.25 mg/kg) or saline (control group) during habituation. During acquisition, they were pretreated with riluzole (1 mg/kg), memantine (1 mg/kg), or saline solution 30 min before each session and injected with 8-OH-DPAT ("OH" groups) or saline ("saline" groups) right before the experiment. We found that repeated application of 8-OH-DPAT during both habituation and acquisition significantly increased locomotion, but it impaired the ability to avoid the shock sector. However, the application of 8-OH-DPAT in habituation had no impact on the learning process if discontinued in acquisition. Similarly, memantine and riluzole did not affect the measured parameters in the "saline" groups, but in the "OH" groups, they significantly increased locomotion. In addition, riluzole increased the number of entrances and decreased the maximum time avoided of the shock sector. We conclude that monotherapy with glutamate-modulating agents does not reduce but exacerbates cognitive symptoms in the animal model of OCD.


Assuntos
8-Hidroxi-2-(di-n-propilamino)tetralina/efeitos adversos , Comportamento Animal/efeitos dos fármacos , Memantina/farmacologia , Transtorno Obsessivo-Compulsivo , Riluzol/farmacologia , Aprendizagem Espacial/efeitos dos fármacos , 8-Hidroxi-2-(di-n-propilamino)tetralina/farmacologia , Animais , Modelos Animais de Doenças , Masculino , Memória/efeitos dos fármacos , Transtorno Obsessivo-Compulsivo/induzido quimicamente , Transtorno Obsessivo-Compulsivo/tratamento farmacológico , Transtorno Obsessivo-Compulsivo/fisiopatologia , Ratos , Ratos Long-Evans
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