RESUMO
Background: Alzheimer's disease (AD) is a neurodegenerative condition characterized by gradual cognitive impairment, including loss of synapses and nerve cells involved in learning, memory, and habit formation processes. Bone Marrow Mesenchymal Stem Cells (BM-MSCs) are multipotent cells. Because of their self-renewable, differentiation, and immunomodulatory capabilities, they are commonly used to treat many disorders. Hence, the current study intends to examine the effect of BM-MSCs transplantation on Aluminum chloride (AlCl3)-induced cognitive problems, an experimental model resembling AD's hallmarks in rats. Methods: The study was conducted in 2022 at The Biomedical Laboratory Faculty of Medicine, Andalas University, Indonesia. Adult male Wistar rats (three groups: negative control; no intervention+treatment with PBS; positive control: AlCl3+treatment with aqua dest; AlCl3+BM-MSCs: AlCl3+treatment with BM-MSCs, n=5 each) were treated daily with AlCl3 orally for five days. Stem cells were intraperitoneally injected into rats at a dose of 1x106 cells/rat. The same quantity of phosphate-buffered saline was given to the control group. One month after stem cell injection, the rat brain tissue was removed and placed in the film bottles that had been created. The expression of neural progenitor cell markers, including nestin and sex-determining Y-box 2 (SOX-2), was analyzed using real-time polymerase chain reaction (RT-PCR). Rats' cognitive and functional memory were examined using Y-maze. Data were analyzed using SPSS software (version 26.0) with a one-way analysis of variance (ANOVA) test. Results: The gene expression of nestin (29.74±0.42), SOX-2 (31.44±0.67), and percent alternation of Y-maze (67.04±2.28) increased in the AlCl3+BM-MSCs group compared to that in the positive control group. RT-PCR analysis indicated that nestin (P<0.001) and SOX-2 (P<0.001) were significantly enhanced in the AlCl3+BM-MSCs group compared to the positive control group. This group also indicated an increased percent alternation of Y-maze (P<0.001) in the AlCl3+BM-MSCs group compared to the positive control group. Conclusion: Due to its potential effects on cell therapy, BM-MSCs were found effective in a rat model of AD on the impairment of the rats' behavior and increased expression of neural progenitor cell markers.
Assuntos
Cloreto de Alumínio , Doença de Alzheimer , Modelos Animais de Doenças , Células-Tronco Mesenquimais , Nestina , Ratos Wistar , Fatores de Transcrição SOXB1 , Animais , Cloreto de Alumínio/farmacologia , Ratos , Masculino , Doença de Alzheimer/terapia , Nestina/genética , Transplante de Células-Tronco Mesenquimais/métodos , Compostos de Alumínio/farmacologia , Aprendizagem Espacial/efeitos dos fármacos , Aprendizagem Espacial/fisiologia , Cloretos , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologiaRESUMO
PURPOSE: Levothyroxine (LEV) monotherapy cannot completely improve cognitive and behavioral impairments induced by hypothyroidism, whereas a combination therapy of exercise and LEV may ameliorate these deficits. This study aimed to determine the effects of mild-intensity forced exercise and LEV treatment on the anxiety profile and cognitive functions in male offspring of hypothyroid dams. METHOD: Twenty-four female rats (mothers) were randomly divided into sham (healthy) and hypothyroidism groups and then placed with male rats to mate. The presence of vaginal plaque confirmed pregnancy (gestational day, GD 0). 6-propyl-2-thiouracil (PTU, 100 ppm) was added to the drinking water of the hypothyroidism group from GD 6 to the 21st postnatal day (PND). The sham group received tap water. On PND 21, serum T4 levels of mothers, and 10 pups were measured to confirm hypothyroidism. Sixty-four male pups were left undisturbed for 30 days and then were divided into eight groups that received saline or LEV (50 µg/kg, i.p.) with or without forced mild-intensity exercise. After 14 days of interventions, anxiety-like behaviors, spatial learning and memory, and hippocampal brain-derived neurotrophic factor (BDNF) levels were evaluated. FINDING: A pre and postnatal PTU-induced model of hypothyroidism increased anxiety-like behaviors, impaired spatial learning and memory, and decreased hippocampal BDNF levels in male offspring rats. LEV alone increased BDNF levels and improved spatial learning. Exercise alone increased BDNF levels, improved spatial learning and memory, and decreased anxiety-like behaviors. Exercise plus LEV more effectively improved anxiety-like behaviors and spatial learning than exercise or LEV alone. CONCLUSION: Practically, these pre-clinical findings highlight the importance of the combination of exercise and LEV regimen in treating patients with hyperthyroidism.
Assuntos
Ansiedade , Fator Neurotrófico Derivado do Encéfalo , Hipocampo , Hipotireoidismo , Condicionamento Físico Animal , Tiroxina , Animais , Hipotireoidismo/tratamento farmacológico , Hipotireoidismo/metabolismo , Hipotireoidismo/terapia , Hipotireoidismo/fisiopatologia , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Masculino , Tiroxina/farmacologia , Tiroxina/administração & dosagem , Ratos , Ansiedade/terapia , Ansiedade/etiologia , Ansiedade/tratamento farmacológico , Hipocampo/metabolismo , Hipocampo/efeitos dos fármacos , Feminino , Condicionamento Físico Animal/fisiologia , Gravidez , Ratos Wistar , Efeitos Tardios da Exposição Pré-Natal/terapia , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Aprendizagem Espacial/efeitos dos fármacos , Aprendizagem Espacial/fisiologia , Terapia Combinada , Propiltiouracila/farmacologia , Propiltiouracila/administração & dosagemRESUMO
Alzheimer's disease (AD) is a neurological condition that is connected with a decline in a person's memory as well as their cognitive ability. One of the key topics of AD research has been the exploration of metabolic causes. We investigated the effects of treadmill exercise and intranasal insulin on learning and memory impairment and the expression of IGF1, BDNF, and GLUT4 in hypothalamus. The animals were put into 9 groups at random. In this study, we examined the impact of insulin on spatial memory in male Wistar rats and analyzed the effects of a 4-week pretreatment of moderate treadmill exercise and insulin on the mechanisms of improved hypothalamic glucose metabolism through changes in gene and protein expression of IGF1, BDNF, and GLUT4. We discovered that rat given Aß25-35 had impaired spatial learning and memory, which was accompanied by higher levels of Aß plaque burden in the hippocampus and lower levels of IGF1, BDNF, and GLUT4 mRNA and protein expression in the hypothalamus. Additionally, the administration of exercise training and intranasal insulin results in the enhancement of spatial learning and memory impairments, the reduction of plaque burden in the hippocampus, and the enhancement of the expression of IGF1, BDNF, and GLUT4 in the hypothalamus of rats that were treated with Aß25-35. Our results show that the improvement of learning and spatial memory due to the improvement of metabolism and upregulation of the IGF1, BDNF, and GLUT4 pathways can be affected by pretreatment exercise and intranasal insulin.
Assuntos
Doença de Alzheimer , Modelos Animais de Doenças , Transportador de Glucose Tipo 4 , Hipotálamo , Fator de Crescimento Insulin-Like I , Insulina , Condicionamento Físico Animal , Ratos Wistar , Transdução de Sinais , Animais , Doença de Alzheimer/metabolismo , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/terapia , Fator de Crescimento Insulin-Like I/metabolismo , Masculino , Insulina/metabolismo , Ratos , Hipotálamo/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transportador de Glucose Tipo 4/metabolismo , Transportador de Glucose Tipo 4/genética , Peptídeos beta-Amiloides/metabolismo , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Fator Neurotrófico Derivado do Encéfalo/genética , Hipocampo/metabolismo , Hipocampo/efeitos dos fármacos , Administração Intranasal , Fragmentos de Peptídeos , Memória Espacial/efeitos dos fármacos , Aprendizagem Espacial/efeitos dos fármacosRESUMO
OBJECTIVE: It is to investigate the effects of ß-asarone on learning and memory, hippocampal morphology, synaptophysin (SYP) and postsynaptic density 95(PSD95) protein expression, N-methyl-D-aspartic acid receptor 2B (NR2B)- Ca2+/calmodulin (CaM)-dependent protein kinase II (CaMKII) - Extracellular signal-regulated kinase (ERK) / Cyclic-AMP response element binding protein (CREB) signal in hippocampus of rats with exhaustive exercise-induced fatigue. METHODS: Fifty Sprague-Dawley male rats were randomly divided into five groups: normal group, exercise group, exercise and ß-asarone (2.5, 10, 40â¯mg/kg)-treated groups. The learning and memory in rats were tested by Morris water maze experiment. We measured the hippocampal morphology by Nissl staining. The levels of SYP, PSD95, NR2B, CaMKII, ERK1/2, CREB, p-NR2B, p-CaMKII, p-ERK1/2 and p-CREB expression were measured by western blot analysis. RESULTS: The results demonstrated that ß-asarone (10, 40â¯mg/kg) treatment significantly decreased the latency to find the platform, increased the time spent in the target quadrant and the number of crossing the platform of rats with exhaustive exercise-induced fatigue. ß-asarone (10, 40â¯mg/kg) treatment increased the cell density in the hippocampus CA1 region, significantly up-regulated NR2B-CaMKII-ERK/CREB signal and improved the protein expression levels of SYP and PSD95 in hippocampus of rats with exhaustive exercise-induced fatigue. CONCLUSIONS: It suggests that ß-asarone could improve learning and memory of rats with exhaustive exercise-induced fatigue. The mechanism might be related to ß-asarone protecting the morphology of hippocampus, increasing the protein expression levels of SYP and PSD95 and up-regulating NR2B-CaMKII-ERK/CREB signal in hippocampus of rats with exhaustive exercise-induced fatigue.
Assuntos
Derivados de Alilbenzenos , Anisóis , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico , Fadiga , Hipocampo , Transtornos da Memória , Condicionamento Físico Animal , Ratos Sprague-Dawley , Receptores de N-Metil-D-Aspartato , Animais , Masculino , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Ratos , Fadiga/tratamento farmacológico , Fadiga/metabolismo , Derivados de Alilbenzenos/farmacologia , Condicionamento Físico Animal/fisiologia , Receptores de N-Metil-D-Aspartato/metabolismo , Anisóis/farmacologia , Transtornos da Memória/tratamento farmacológico , Aprendizagem Espacial/efeitos dos fármacos , Aprendizagem Espacial/fisiologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Proteína 4 Homóloga a Disks-Large/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/fisiologia , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologiaRESUMO
BACKGROUND: Alzheimer's disease (AD) affects the brain and causes difficulties with cognition and emotions. At present, there are no viable therapies to halt or slow down the advancement of AD. Metallothionein III (MT-III) exhibits antioxidant and anti-inflammatory characteristics, indicating possible therapeutic benefits. This study aimed to explore the influence of MT-III on AD pathological alterations and cognitive abilities. METHODS: In this research, we employed the universally accepted AD mouse models (3xTg-AD) as test subjects and administrated vehicle or MT-III. The mice were subjected to the Morris water maze test to assess their spatial learning and memory capabilities. Moreover, to evaluate the consequent effects on neuronal groups in the hippocampus, the Nissl staining and neuronal nuclear antigen (NeuN) immunohistochemistry were used to identify the cellular morphology changes and density. Immunohistochemistry was also used to detect ß-amyloid (Aß) and glial fibrillary acidic protein (GFAP) to measure Aß accumulation and astrocyte growth. Western blot was also used to measure Tau pathology-related PHD finger protein 1 (PHF-1), phosphorylated Tau (AT-8), and total Tau protein. RESULTS: The administration of MT-III notably enhanced spatial learning and memory function in 3xTg-AD mice, as evidenced by the Morris water maze test (p < 0.01). According to immunohistochemistry and the obtained findings, it was observed that brain tissues of mice treated with MT-III showed a notable increase of Nissl bodies and NeuN intensity (p < 0.01) while a remarkable decrease in Aß accumulation and GFAP (p < 0.01). Additionally, MT-III largely decreased levels of Tau phosphorylation-related PHF-1 and AT-8 (p < 0.01) and slightly reduced the level of Tau 5 (p < 0.05). CONCLUSION: In summary, our research indicates that MT-III has the capacity to ameliorate pathological alterations in AD mouse models and safeguard their cognitive and emotional abilities. By decreasing ß-amyloid accumulation and reducing the intensity of Tau pathology, MT-III protected hippocampal subfield neurons against pathological harm. Furthermore, MT-III reduced inflammation by inhibiting abnormal proliferation of astrocytes. Of utmost importance, MT-III greatly enhanced the cognitive abilities related to spatial learning and memory in mice, suggesting its promising therapeutic properties for AD.
Assuntos
Doença de Alzheimer , Astrócitos , Proliferação de Células , Modelos Animais de Doenças , Metalotioneína 3 , Camundongos Transgênicos , Proteínas tau , Animais , Doença de Alzheimer/patologia , Doença de Alzheimer/metabolismo , Astrócitos/metabolismo , Astrócitos/patologia , Camundongos , Proliferação de Células/efeitos dos fármacos , Proteínas tau/metabolismo , Hipocampo/patologia , Hipocampo/metabolismo , Peptídeos beta-Amiloides/metabolismo , Masculino , Humanos , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem Espacial/efeitos dos fármacos , Proteína Glial Fibrilar Ácida/metabolismoRESUMO
BACKGROUND: Crocin has a good prospect in the treatment of Alzheimer's disease (AD), but the mechanisms underlying its neuroprotective effects remain elusive. This study aimed to investigate the neuroprotective effects of Crocin and its underlying mechanisms in AD. METHODS: AD mice were set up by injecting Aß25-35 solution into the hippocampus. Then, the AD mice were injected intraperitoneally with 40 mg/kg/day of Crocin for 14 days. Following the completion of Crocin treatment, an open-field test, Y-maze test and Morris water maze test were conducted to evaluate the impact of Crocin on spatial learning and memory deficiency in mice. The effects of Crocin on hippocampal neuron injury, proinflammatory cytokine expressions (IL-1ß, IL-6, and TNF-α), and PI3K/AKT signaling-related protein expressions were measured using hematoxylin and eosin staining, Western blot, and quantitative real-time polymerase chain reaction (qRT-PCR) experiments, respectively. RESULTS: Crocin attenuated Aß25-35-induced spatial learning and memory deficiency and hippocampal neuron injury. Furthermore, the Western blot and qRT-PCR results showed that Crocin effectively suppressed inflammation and activated the PI3K/AKT pathway in Aß25-35-induced mice. CONCLUSION: Crocin restrained neuroinflammation via the activation of the PI3K/AKT pathway, thereby ameliorating the cognitive dysfunction of AD mice.
Assuntos
Doença de Alzheimer , Peptídeos beta-Amiloides , Carotenoides , Disfunção Cognitiva , Hipocampo , Doenças Neuroinflamatórias , Fármacos Neuroprotetores , Fosfatidilinositol 3-Quinases , Proteínas Proto-Oncogênicas c-akt , Transdução de Sinais , Animais , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Carotenoides/farmacologia , Carotenoides/administração & dosagem , Camundongos , Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/etiologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Transdução de Sinais/efeitos dos fármacos , Masculino , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/administração & dosagem , Peptídeos beta-Amiloides/metabolismo , Doenças Neuroinflamatórias/tratamento farmacológico , Modelos Animais de Doenças , Fragmentos de Peptídeos/farmacologia , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem Espacial/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/metabolismoRESUMO
Dynamin is a microtubule (MT) binding protein playing a key role in vesicle endocytosis. In a brain slice model, tau loaded in presynaptic terminals assembles MTs, thereby impairing vesicle endocytosis via depletion of cytosolic dynamin. The peptide PHDP5, derived from the pleckstrin homology domain of dynamin 1, inhibits dynamin-MT interaction and rescues endocytosis and synaptic transmission impaired by tau when co-loaded in presynaptic terminals. We tested whether in vivo administration of PHDP5 could rescue the learning/memory deficits observed in Alzheimer's disease (AD) model mice. A modified PHDP5 incorporating a cell-penetrating peptide (CPP) and a FITC fluorescent marker was delivered intranasally to Tau609 transgenic (Tg) and 3xTg-AD mice. FITC-positive puncta were observed in the hippocampus of mice infused with PHDP5 or scrambled (SPHDP5) peptide, but not in saline-infused controls. In the Morris water maze (MWM) test for spatial learning/memory, AD model mice treated with FITC-PHDP5-CPP showed prominent improvements in learning and memory, performing close to the level of saline-infused WT mice control. In contrast, mice treated with a scrambled construct (FITC-SPHDP5-CPP) showed no significant improvement. We conclude that PHDP5 can be a candidate for human AD therapy.
Assuntos
Doença de Alzheimer , Transtornos da Memória , Aprendizagem Espacial , Animais , Masculino , Camundongos , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Modelos Animais de Doenças , Hipocampo/metabolismo , Hipocampo/efeitos dos fármacos , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Transtornos da Memória/tratamento farmacológico , Transtornos da Memória/metabolismo , Camundongos Transgênicos , Microtúbulos/metabolismo , Microtúbulos/efeitos dos fármacos , Aprendizagem Espacial/efeitos dos fármacos , Proteínas tau/metabolismo , Dinamina I/metabolismoRESUMO
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 fármacosRESUMO
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 , Sirtuína 3 , Memória Espacial , Animais , Masculino , Ratos , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Lítio/farmacologia , Aprendizagem em Labirinto/efeitos dos fármacos , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Condicionamento Físico Animal/fisiologia , Ratos Wistar , Sirtuína 3/metabolismo , Sirtuína 3/genética , Sirtuínas , Aprendizagem Espacial/efeitos dos fármacos , Memória Espacial/efeitos dos fármacosRESUMO
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 & inibidoresRESUMO
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 , MasculinoRESUMO
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/fisiologiaRESUMO
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 TratamentoRESUMO
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 fármacosRESUMO
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 , ZanthoxylumRESUMO
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 & inibidoresRESUMO
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 fármacosRESUMO
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 fármacosRESUMO
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 , RatosRESUMO
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.