RESUMEN
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.
Asunto(s)
Cloruro de Aluminio , Enfermedad de Alzheimer , Modelos Animales de Enfermedad , Células Madre Mesenquimatosas , Nestina , Ratas Wistar , Factores de Transcripción SOXB1 , Animales , Cloruro de Aluminio/farmacología , Ratas , Masculino , Enfermedad de Alzheimer/terapia , Nestina/genética , Trasplante de Células Madre Mesenquimatosas/métodos , Compuestos de Aluminio/farmacología , Aprendizaje Espacial/efectos de los fármacos , Aprendizaje Espacial/fisiología , Cloruros , Aprendizaje por Laberinto/efectos de los fármacos , Aprendizaje por Laberinto/fisiologíaRESUMEN
Consumption of saturated fat-enriched diets during adolescence has been closely associated with the reduction of hippocampal synaptic plasticity and the impairment of cognitive function. Nevertheless, the effect of long-term intake of these foods has not yet been studied. In the present study, we have investigated the effect of a treatment, lasting for 40 weeks, with a diet enriched in saturated fat (SOLF) on i) spatial learning and memory, ii) hippocampal synaptic transmission and plasticity, and iii) hippocampal gene expression levels in aged male and female mice. Our findings reveal that SOLF has a detrimental impact on spatial memory and synaptic plasticity mechanisms, such as long-term potentiation (LTP), and downregulates Gria1 expression specifically in males. In females, SOLF downregulates the gene expression of Gria1/2/3 and Grin1/2A/2B glutamate receptor subunits as well as some proinflammatory interleukins. These findings highlight the importance of considering sex-specific factors when assessing the long-term effects of high-fat diets on cognition and brain plasticity.
Asunto(s)
Dieta Alta en Grasa , Hipocampo , Caracteres Sexuales , Animales , Masculino , Femenino , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Dieta Alta en Grasa/efectos adversos , Ratones , Ratones Endogámicos C57BL , Plasticidad Neuronal/efectos de los fármacos , Plasticidad Neuronal/fisiología , Aprendizaje Espacial/efectos de los fármacos , Aprendizaje Espacial/fisiología , Receptores AMPA/metabolismo , Memoria Espacial/efectos de los fármacos , Memoria Espacial/fisiología , Memoria/efectos de los fármacos , Memoria/fisiología , Potenciación a Largo Plazo/efectos de los fármacos , Potenciación a Largo Plazo/fisiología , Receptores de N-Metil-D-Aspartato/metabolismo , Transmisión Sináptica/efectos de los fármacos , Transmisión Sináptica/fisiología , Grasas de la Dieta/farmacologíaRESUMEN
Alcohol exposure in adolescence is considered a major cause of cognitive impairments later in life including spatial learning and memory. Integrated stress response (ISR), a program of conservative translation and transcription, is crucial in synaptic plasticity and memory. Although previous studies have elucidated ISR in different brain areas involved in learning and memory disorders, the impact of ISR on learning and memory following adolescent alcohol exposure remains unclear. Here, we demonstrated that adolescent intermittent ethanol (AIE) exposure caused spatial learning and memory impairment, combined with neuronal damage in the medial prefrontal cortex (mPFC), nucleus accumbens (NAc) and hippocampus (HIP) in adult rats. Moreover, integrated stress response inhibitor (ISRIB) administration not only improved spatial learning and memory impairment and neuronal damage but also inhibited the endoplasmic reticulum stress (ER) and reversed changes in synaptic proteins. These findings suggested that ISRIB ameliorates AIE exposure-induced spatial learning and memory deficits by improving neural morphology and synaptic function through inhibiting ER stress signaling pathway in the mPFC, NAc and HIP in adulthood. Our findings may enhance comprehension of cognitive function and neuronal effects of adolescent ethanol exposure and ISRIB treatment may be an underlying potential option for addressing alcohol-induced learning and memory deficits.
Asunto(s)
Etanol , Trastornos de la Memoria , Ratas Sprague-Dawley , Aprendizaje Espacial , Animales , Masculino , Etanol/toxicidad , Etanol/administración & dosificación , Ratas , Trastornos de la Memoria/inducido químicamente , Trastornos de la Memoria/tratamiento farmacológico , Trastornos de la Memoria/metabolismo , Aprendizaje Espacial/efectos de los fármacos , Corteza Prefrontal/efectos de los fármacos , Corteza Prefrontal/metabolismo , Estrés del Retículo Endoplásmico/efectos de los fármacos , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Aprendizaje por Laberinto/efectos de los fármacos , Aprendizaje por Laberinto/fisiologíaRESUMEN
BACKGROUND/AIM: In a previous report, our group showed that oral administration of lipopolysaccharides (LPS) from Pantoea agglomerans can prevent the progression of streptozotocin (STZ)-induced diabetes-related cognitive dysfunction (DRCD) in mice without causing significant side-effects. However, the treatment effects of oral administration of LPS to DRCD remain unknown. MATERIALS AND METHODS: We modified our previous animal experimental model to investigate whether oral administration of LPS can recover cognitive function after DRCD onset. RESULTS: The Morris water maze (MWM) revealed a significant decrease in learning and memory abilities at 13 days after intracerebroventricular administration of STZ, thereby providing evidence of the occurrence of DRCD in the animal model. Oral administration of LPS (1 mg/kg per day) started after cognitive impairment was observed. After 28 days of treatment, mice receiving LPS via the oral route showed significant recovery of spatial learning ability, a symptom of early dementia, while only a trend toward recovery was seen for spatial memory compared to the untreated group. CONCLUSION: These results, limited to MWM, suggest that oral administration of LPS is a promising therapeutic strategy for restoring decreased spatial learning ability.
Asunto(s)
Disfunción Cognitiva , Diabetes Mellitus Experimental , Modelos Animales de Enfermedad , Lipopolisacáridos , Aprendizaje por Laberinto , Aprendizaje Espacial , Animales , Lipopolisacáridos/efectos adversos , Lipopolisacáridos/administración & dosificación , Ratones , Administración Oral , Disfunción Cognitiva/etiología , Disfunción Cognitiva/tratamiento farmacológico , Masculino , Diabetes Mellitus Experimental/complicaciones , Aprendizaje Espacial/efectos de los fármacos , Aprendizaje por Laberinto/efectos de los fármacos , Estreptozocina/administración & dosificaciónRESUMEN
Estrogens have inconsistent effects on learning and memory in both the clinical and preclinical literature. Preclinical literature has the advantage of investigating an array of potentially important factors contributing to the varied effects of estrogens on learning and memory, with stringently controlled studies. This study set out to identify specific factors in the animal literature that influence the effects of estrogens on cognition, for possible translation back to clinical practice. The literature was screened and studies meeting strict inclusion criteria were included in the analysis. Eligible studies included female ovariectomized rodents with an adequate vehicle for the estrogen treatment, with an outcome of spatial learning and memory in the Morris water maze. Training days of the Morris water maze were used to assess acquisition of spatial learning, and the probe trial was used to evaluate spatial memory recall. Continuous outcomes were pooled using a random effects inverse variance method and reported as standardized mean differences with 95 % confidence intervals. Subgroup analyses were developed a priori to assess important factors. The overall analysis favoured treatment for the later stages of training and for the probe trial. Factors including the type of estrogen, route, schedule of administration, age of animals, timing relative to ovariectomy, and duration of treatment were all found to be important. The subgroup analyses showed that chronic treatment with 17ß-estradiol, either cyclically or continuously, to young animals improved spatial recall. These results, observed in animals, can inform and guide further clinical research on hormone replacement therapy for cognitive benefits.
Asunto(s)
Estrógenos , Aprendizaje Espacial , Memoria Espacial , Animales , Femenino , Estradiol/farmacología , Estradiol/administración & dosificación , Estrógenos/farmacología , Estrógenos/administración & dosificación , Aprendizaje por Laberinto/efectos de los fármacos , Aprendizaje por Laberinto/fisiología , Memoria/efectos de los fármacos , Memoria/fisiología , Ovariectomía , Roedores/fisiología , Aprendizaje Espacial/efectos de los fármacos , Aprendizaje Espacial/fisiología , Memoria Espacial/efectos de los fármacos , Memoria Espacial/fisiologíaRESUMEN
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.
Asunto(s)
Ansiedad , Factor Neurotrófico Derivado del Encéfalo , Hipocampo , Hipotiroidismo , Condicionamiento Físico Animal , Tiroxina , Animales , Hipotiroidismo/tratamiento farmacológico , Hipotiroidismo/metabolismo , Hipotiroidismo/terapia , Hipotiroidismo/fisiopatología , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Masculino , Tiroxina/farmacología , Tiroxina/administración & dosificación , Ratas , Ansiedad/terapia , Ansiedad/etiología , Ansiedad/tratamiento farmacológico , Hipocampo/metabolismo , Hipocampo/efectos de los fármacos , Femenino , Condicionamiento Físico Animal/fisiología , Embarazo , Ratas Wistar , Efectos Tardíos de la Exposición Prenatal/terapia , Efectos Tardíos de la Exposición Prenatal/metabolismo , Aprendizaje Espacial/efectos de los fármacos , Aprendizaje Espacial/fisiología , Terapia Combinada , Propiltiouracilo/farmacología , Propiltiouracilo/administración & dosificaciónRESUMEN
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.
Asunto(s)
Enfermedad de Alzheimer , Modelos Animales de Enfermedad , Transportador de Glucosa de Tipo 4 , Hipotálamo , Factor I del Crecimiento Similar a la Insulina , Insulina , Condicionamiento Físico Animal , Ratas Wistar , Transducción de Señal , Animales , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/terapia , Factor I del Crecimiento Similar a la Insulina/metabolismo , Masculino , Insulina/metabolismo , Ratas , Hipotálamo/metabolismo , Transducción de Señal/efectos de los fármacos , Transportador de Glucosa de Tipo 4/metabolismo , Transportador de Glucosa de Tipo 4/genética , Péptidos beta-Amiloides/metabolismo , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Factor Neurotrófico Derivado del Encéfalo/genética , Hipocampo/metabolismo , Hipocampo/efectos de los fármacos , Administración Intranasal , Fragmentos de Péptidos , Memoria Espacial/efectos de los fármacos , Aprendizaje Espacial/efectos de los fármacosRESUMEN
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.
Asunto(s)
Derivados de Alilbenceno , Anisoles , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina , Proteína de Unión a Elemento de Respuesta al AMP Cíclico , Fatiga , Hipocampo , Trastornos de la Memoria , Condicionamiento Físico Animal , Ratas Sprague-Dawley , Receptores de N-Metil-D-Aspartato , Animales , Masculino , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/metabolismo , Ratas , Fatiga/tratamiento farmacológico , Fatiga/metabolismo , Derivados de Alilbenceno/farmacología , Condicionamiento Físico Animal/fisiología , Receptores de N-Metil-D-Aspartato/metabolismo , Anisoles/farmacología , Trastornos de la Memoria/tratamiento farmacológico , Aprendizaje Espacial/efectos de los fármacos , Aprendizaje Espacial/fisiología , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiología , Homólogo 4 de la Proteína Discs Large/metabolismo , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Sistema de Señalización de MAP Quinasas/fisiología , Aprendizaje por Laberinto/efectos de los fármacos , Aprendizaje por Laberinto/fisiologíaRESUMEN
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.
Asunto(s)
Enfermedad de Alzheimer , Astrocitos , Proliferación Celular , Modelos Animales de Enfermedad , Metalotioneína 3 , Ratones Transgénicos , Proteínas tau , Animales , Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/metabolismo , Astrocitos/metabolismo , Astrocitos/patología , Ratones , Proliferación Celular/efectos de los fármacos , Proteínas tau/metabolismo , Hipocampo/patología , Hipocampo/metabolismo , Péptidos beta-Amiloides/metabolismo , Masculino , Humanos , Aprendizaje por Laberinto/efectos de los fármacos , Aprendizaje Espacial/efectos de los fármacos , Proteína Ácida Fibrilar de la Glía/metabolismoRESUMEN
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.
Asunto(s)
Enfermedad de Alzheimer , Péptidos beta-Amiloides , Carotenoides , Disfunción Cognitiva , Hipocampo , Enfermedades Neuroinflamatorias , Fármacos Neuroprotectores , Fosfatidilinositol 3-Quinasas , Proteínas Proto-Oncogénicas c-akt , Transducción de Señal , Animales , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Carotenoides/farmacología , Carotenoides/administración & dosificación , Ratones , Disfunción Cognitiva/tratamiento farmacológico , Disfunción Cognitiva/etiología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Transducción de Señal/efectos de los fármacos , Masculino , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/administración & dosificación , Péptidos beta-Amiloides/metabolismo , Enfermedades Neuroinflamatorias/tratamiento farmacológico , Modelos Animales de Enfermedad , Fragmentos de Péptidos/farmacología , Aprendizaje por Laberinto/efectos de los fármacos , Aprendizaje Espacial/efectos de los fármacos , Neuronas/efectos de los fármacos , Neuronas/metabolismoRESUMEN
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.
Asunto(s)
Enfermedad de Alzheimer , Trastornos de la Memoria , Aprendizaje Espacial , Animales , Masculino , Ratones , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Modelos Animales de Enfermedad , Hipocampo/metabolismo , Hipocampo/efectos de los fármacos , Aprendizaje por Laberinto/efectos de los fármacos , Aprendizaje por Laberinto/fisiología , Trastornos de la Memoria/tratamiento farmacológico , Trastornos de la Memoria/metabolismo , Ratones Transgénicos , Microtúbulos/metabolismo , Microtúbulos/efectos de los fármacos , Aprendizaje Espacial/efectos de los fármacos , Proteínas tau/metabolismo , Dinamina I/metabolismoRESUMEN
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).
Asunto(s)
Proteínas Relacionadas con Receptor de LDL , Ratones Noqueados , Selenio , Aprendizaje Espacial , Animales , Ratones , Dieta , Hipocampo/metabolismo , Proteínas Relacionadas con Receptor de LDL/genética , Proteínas Relacionadas con Receptor de LDL/metabolismo , Aprendizaje por Laberinto/fisiología , Aprendizaje por Laberinto/efectos de los fármacos , Memoria/fisiología , Memoria/efectos de los fármacos , Selenio/administración & dosificación , Selenio/deficiencia , Selenio/farmacología , Selenoproteína P/genética , Selenoproteína P/metabolismo , Aprendizaje Espacial/fisiología , Aprendizaje Espacial/efectos de los fármacos , Memoria Espacial/fisiología , Memoria Espacial/efectos de los fármacosRESUMEN
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.
Asunto(s)
Factor Neurotrófico Derivado del Encéfalo , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma , Condicionamiento Físico Animal , Sirtuina 3 , Memoria Espacial , Animales , Masculino , Ratas , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Litio/farmacología , Aprendizaje por Laberinto/efectos de los fármacos , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/metabolismo , Condicionamiento Físico Animal/fisiología , Ratas Wistar , Sirtuina 3/metabolismo , Sirtuina 3/genética , Sirtuinas , Aprendizaje Espacial/efectos de los fármacos , Memoria Espacial/efectos de los fármacosRESUMEN
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.
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Infarto de la Arteria Cerebral Media , Corteza Motora , Accidente Cerebrovascular , Animales , Ratas , Modelos Animales de Enfermedad , Infarto de la Arteria Cerebral Media/tratamiento farmacológico , Corteza Motora/efectos de los fármacos , Ratas Sprague-Dawley , Aprendizaje Espacial/efectos de los fármacos , Amidohidrolasas/antagonistas & inhibidoresRESUMEN
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.
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Trastorno del Espectro Autista , Inhibidores de Fosfodiesterasa , Efectos Tardíos de la Exposición Prenatal , Ácido Valproico , Animales , Femenino , Embarazo , Ratas , Ansiedad/tratamiento farmacológico , Trastorno del Espectro Autista/inducido químicamente , Trastorno del Espectro Autista/tratamiento farmacológico , Trastorno del Espectro Autista/fisiopatología , Trastorno del Espectro Autista/psicología , Modelos Animales de Enfermedad , Mediadores de Inflamación/metabolismo , Estrés Oxidativo/efectos de los fármacos , Umbral del Dolor/efectos de los fármacos , Inhibidores de Fosfodiesterasa/farmacología , Inhibidores de Fosfodiesterasa/uso terapéutico , Efectos Tardíos de la Exposición Prenatal/tratamiento farmacológico , Agitación Psicomotora/tratamiento farmacológico , Ratas Wistar , Conducta Social , Aprendizaje Espacial/efectos de los fármacos , Ácido Valproico/administración & dosificación , Ácido Valproico/efectos adversos , MasculinoRESUMEN
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.
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Envejecimiento/psicología , Disfunción Cognitiva/prevención & control , Galactosa/efectos adversos , Proteína 1 Asociada A ECH Tipo Kelch/metabolismo , Licopeno/administración & dosificación , Factor 2 Relacionado con NF-E2/metabolismo , Mononucleótido de Nicotinamida/administración & dosificación , Envejecimiento/efectos de los fármacos , Animales , Disfunción Cognitiva/etiología , Quimioterapia Combinada , Regulación de la Expresión Génica/efectos de los fármacos , Licopeno/farmacología , Masculino , Prueba del Laberinto Acuático de Morris , Mononucleótido de Nicotinamida/farmacología , Estrés Oxidativo/efectos de los fármacos , Células PC12 , Ratas , Transducción de Señal/efectos de los fármacos , Aprendizaje Espacial/efectos de los fármacos , Resultado del TratamientoRESUMEN
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.
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Catha/química , Electrólitos/sangre , Extractos Vegetales/farmacología , Aprendizaje Espacial/efectos de los fármacos , Animales , Catha/metabolismo , Relación Dosis-Respuesta a Droga , Masculino , Extractos Vegetales/química , Ratas , Natación/fisiologíaRESUMEN
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.
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Autofagia/efectos de los fármacos , Regulación de la Expresión Génica/efectos de los fármacos , Hipocampo/efectos de los fármacos , Lantano/toxicidad , Membranas Mitocondriales/efectos de los fármacos , Animales , Relación Dosis-Respuesta a Droga , Femenino , Hipocampo/metabolismo , Lactancia , Masculino , Mitocondrias , Membranas Mitocondriales/metabolismo , Embarazo , Efectos Tardíos de la Exposición Prenatal , Distribución Aleatoria , Ratas , Ratas Wistar , Transducción de Señal/efectos de los fármacos , Aprendizaje Espacial/efectos de los fármacosRESUMEN
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.
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Enfermedad de Alzheimer , Ácidos Grasos Insaturados/farmacología , Hemo-Oxigenasa 1/metabolismo , Proteínas de la Membrana/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Cuerpos de Nissl , Estrés Oxidativo/efectos de los fármacos , Alcamidas Poliinsaturadas/farmacología , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Animales , Antioxidantes/farmacología , Modelos Animales de Enfermedad , Hipocampo/patología , Malondialdehído/metabolismo , Ratones , Fármacos Neuroprotectores/farmacología , Cuerpos de Nissl/efectos de los fármacos , Cuerpos de Nissl/metabolismo , Transducción de Señal/efectos de los fármacos , Aprendizaje Espacial/efectos de los fármacos , ZanthoxylumRESUMEN
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.