RESUMEN
Previously, we found that dCA1 A1-like polarization of astrocytes contributes a lot to the spatial memory deficit in methamphetamine abstinence mice. However, the underlying mechanism remains unclear, resulting in a lack of promising therapeutic targets. Here, we found that methamphetamine abstinence mice exhibited an increased M1-like microglia and A1-like astrocytes, together with elevated levels of interleukin 1α and tumor necrosis factor α in dCA1. In vitro, the M1-like BV2 microglia cell medium, containing high levels of Interleukin 1α and tumor necrosis factor α, elevated A1-like polarization of astrocytes, which weakened their capacity for glutamate clearance. Locally suppressing dCA1 M1-like microglia activation with minocycline administration attenuated A1-like polarization of astrocytes, ameliorated dCA1 neurotoxicity, and, most importantly, rescued spatial memory in methamphetamine abstinence mice. The effective time window of minocycline treatment on spatial memory is the methamphetamine exposure period, rather than the long-term methamphetamine abstinence.
Asunto(s)
Astrocitos , Trastornos de la Memoria , Metanfetamina , Microglía , Minociclina , Memoria Espacial , Animales , Metanfetamina/toxicidad , Microglía/efectos de los fármacos , Microglía/metabolismo , Ratones , Trastornos de la Memoria/inducido químicamente , Astrocitos/metabolismo , Astrocitos/efectos de los fármacos , Astrocitos/patología , Memoria Espacial/fisiología , Memoria Espacial/efectos de los fármacos , Masculino , Minociclina/farmacología , Ratones Endogámicos C57BL , Síndrome de Abstinencia a Sustancias/metabolismo , Síndrome de Abstinencia a Sustancias/patología , Estimulantes del Sistema Nervioso Central/toxicidadRESUMEN
Both hypertension and aging are known to increase the vulnerability of the brain to neurovascular damage, resulting in cognitive impairment. The present study investigated the efficacy of the antihypertensive drug losartan on age- and hypertension-associated cognitive decline and the possible mechanism underlying its effect in spontaneously hypertensive rats (SHRs). Losartan was administered (10 mg/kg, i.p. for 19 days) to 3- and 14-month-old SHRs. Age-matched Wistar rats were used as controls. Working memory, short-term object recognition, and spatial memory were assessed using the Y-maze, object recognition test (ORT) and radial arm maze (RAM) test. The expression of markers associated with aging, oxidative stress, and memory-related signaling was assessed in the frontal cortex (FC) and hippocampus. Motor activity measured over 24 h was not different between groups. Middle-aged vehicle-treated SHRs showed poorer performance in spontaneous alternation behavior (SAB) and activity in the first Y-maze test than their younger counterparts, suggesting age-related reduced "decision making" and reactivity in a novel environment. Losartan improved the age- and hypertension-induced decline in short-term recognition and spatial memory measured in the ORT and the second Y-maze test, particularly in the middle-aged rats, but was ineffective in the young adult rats. Changes in memory and age-related markers such as cAMP response element-binding protein (CREB) and amyloid-ß1-42 (Aß1-42) and increased oxidative stress were observed in the hippocampus but not in the FC between young adult and middle-aged vehicle-treated SHRs. Losartan increased CREB expression while reducing Aß1-42 levels and concomitant oxidative stress in middle-aged SHRs compared with vehicle-treated SHRs. In conclusion, our study highlights the complex interplay between hypertension, aging, and cognitive impairment. It suggests that there is a critical time window for therapeutic intervention with angiotensin II type 1 receptor blockers.
Asunto(s)
Envejecimiento , Bloqueadores del Receptor Tipo 1 de Angiotensina II , Disfunción Cognitiva , Hipertensión , Losartán , Aprendizaje por Laberinto , Estrés Oxidativo , Ratas Endogámicas SHR , Animales , Losartán/farmacología , Losartán/uso terapéutico , Ratas , Disfunción Cognitiva/tratamiento farmacológico , Disfunción Cognitiva/etiología , Disfunción Cognitiva/metabolismo , Masculino , Envejecimiento/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Hipertensión/tratamiento farmacológico , Hipertensión/metabolismo , Aprendizaje por Laberinto/efectos de los fármacos , Bloqueadores del Receptor Tipo 1 de Angiotensina II/farmacología , Bloqueadores del Receptor Tipo 1 de Angiotensina II/uso terapéutico , Ratas Wistar , Hipocampo/metabolismo , Hipocampo/efectos de los fármacos , Memoria Espacial/efectos de los fármacos , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Antihipertensivos/farmacología , Antihipertensivos/uso terapéuticoRESUMEN
BACKGROUND: The study investigated the effect of co-administration of curcumin and donepezil on several markers of cognitive function (such as spatial memory, astrocyte activation, cholinesterase expressions) in the brain cortex and hippocampus of scopolamine-treated rats. METHOD AND RESULTS: For seven consecutive days, a pre-treatment of curcumin (50 mg/kg) and/or donepezil (2.5 mg/kg) was administered. On the seventh day, scopolamine (1 mg/kg) was administered to elicit cognitive impairment, 30 min before memory test was conducted. This was followed by evaluating changes in spatial memory, cholinesterase, and adenosine deaminase (ADA) activities, as well as nitric oxide (NO) level were determined. Additionally, RT-qPCR for glial fibrillary acidic protein (GFAP) and cholinesterase gene expressions was performed in the brain cortex and hippocampus. Also, GFAP immunohistochemistry of the brain tissues for neuronal injury were performed in the brain cortex and hippocampus. In comparison to the control group, rats given scopolamine had impaired memory, higher levels of acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and ADA activities, as well as elevated markers of oxidative stress. In addition to enhanced GFAP immunoreactivity, there was also overexpression of the GFAP and BChE genes in the brain tissues. The combination of curcumin and donepezil was, however, observed to better ameliorate these impairments in comparison to the donepezil-administered rat group. CONCLUSION: Hence, this evidence provides more mechanisms to support the hypothesis that the concurrent administration of curcumin and donepezil mitigates markers of cognitive dysfunction in scopolamine-treated rat model.
Asunto(s)
Acetilcolinesterasa , Astrocitos , Curcumina , Donepezilo , Proteína Ácida Fibrilar de la Glía , Hipocampo , Escopolamina , Memoria Espacial , Animales , Donepezilo/farmacología , Curcumina/farmacología , Curcumina/administración & dosificación , Escopolamina/farmacología , Astrocitos/efectos de los fármacos , Astrocitos/metabolismo , Ratas , Masculino , Memoria Espacial/efectos de los fármacos , Acetilcolinesterasa/metabolismo , Acetilcolinesterasa/genética , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Proteína Ácida Fibrilar de la Glía/metabolismo , Proteína Ácida Fibrilar de la Glía/genética , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Ratas Wistar , Estrés Oxidativo/efectos de los fármacos , Colinesterasas/metabolismo , Adenosina Desaminasa/metabolismo , Adenosina Desaminasa/genética , Butirilcolinesterasa/metabolismo , Butirilcolinesterasa/genética , Óxido Nítrico/metabolismo , Inhibidores de la Colinesterasa/farmacología , Inhibidores de la Colinesterasa/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
BACKGROUND: The mutually beneficial coevolutionary relationships between rodents and plant seeds have been a theme of research in plant-animal relationships. Seed tannins are important secondary metabolites of plants that regulate the food-hoarding behavior of rodents; however, the underlying molecular mechanisms are not yet clear. In this study, we investigated whether and how seed tannins improve spatial memory and regulate the hoarding behavior of Tamias sibiricus by altering their gut microbiota. RESULTS: We showed that acorn tannins not only improved spatial memory but also enhanced scatter-hoarding in T. sibiricus. Changes in the composition and function of the gut microbiota in response to tannins from acorns are closely related to these improvements. Metabonomic analyses revealed the role of gut isovaleric acid and isobutyric acid as well as serum L-tryptophan in mediating the spatial memory of T. sibiricus via the gut microbiota. The hippocampal proteome provides further evidence that the microbiota-gut-brain axis regulates spatial memory and scatter-hoarding in animals. Our study is likely the first to report that plant secondary metabolites improve hippocampal function and spatial memory and ultimately modulate food-hoarding behavior via the microbiota-gut-brain axis. CONCLUSION: Our findings may have resolved the long-standing puzzle about the hidden role of plant secondary metabolites in manipulating food-hoarding behavior in rodents via the microbiota-gut-brain axis. Our study is important for better understanding the mutualistic coevolution between plants and animals. Video Abstract.
Asunto(s)
Eje Cerebro-Intestino , Microbioma Gastrointestinal , Hipocampo , Memoria Espacial , Taninos , Animales , Microbioma Gastrointestinal/efectos de los fármacos , Memoria Espacial/efectos de los fármacos , Taninos/farmacología , Hipocampo/metabolismo , Eje Cerebro-Intestino/fisiología , Semillas , Masculino , Triptófano/metabolismo , Conducta Animal/efectos de los fármacosRESUMEN
Neuroinflammation has been implicated in cognitive deficits of neurological and neurodegenerative diseases. There is abundant evidence that the application of ghrelin, an orexigenic hormone regulating appetite and energy balance, abrogates neuroinflammation and rescues associated memory impairment. However, the underlying mechanism is uncertain. In this study, we find that both intraperitoneal (i.p.) and intracerebroventricular (i.c.v.) administration of lipopolysaccharide (LPS) impairs spatial memory in mice. LPS treatment causes neuroinflammation and microglial activation in the hippocampus. Ghsr1a deletion suppresses LPS-induced microglial activation and neuroinflammation, and rescued LPS-induced memory impairment. Our findings thus suggest that GHS-R1a signaling may promote microglial immunoactivation and contribute to LPS-induced neuroinflammation. GHS-R1a may be a new therapeutic target for cognitive dysfunction associated with inflammatory conditions.
Asunto(s)
Lipopolisacáridos , Trastornos de la Memoria , Ratones Endogámicos C57BL , Microglía , Receptores de Ghrelina , Memoria Espacial , Animales , Memoria Espacial/efectos de los fármacos , Receptores de Ghrelina/deficiencia , Receptores de Ghrelina/genética , Receptores de Ghrelina/metabolismo , Trastornos de la Memoria/genética , Trastornos de la Memoria/inducido químicamente , Trastornos de la Memoria/metabolismo , Ratones , Masculino , Microglía/metabolismo , Microglía/efectos de los fármacos , Microglía/patología , Hipocampo/metabolismo , Hipocampo/efectos de los fármacos , Hipocampo/patología , Ratones Noqueados , Enfermedades Neuroinflamatorias/metabolismo , Enfermedades Neuroinflamatorias/patologíaRESUMEN
Clothianidin (CLO), a neonicotinoid that is widely used in forests and agricultural areas, was recently reported to cause toxicity in mammals. Although sensitivity to chemicals varies between sexes and developmental stages, studies that comprehensively evaluate both males and females are limited. Therefore, in this study we utilized murine models to compare the sex-specific differences in behavioral effects following CLO exposure at different developmental stages. We orally administered CLO to male and female mice as a single high-dose solution (80 mg/kg) during the postnatal period (2-week-old), adolescence (6-week-old), or maturity (10-week-old), and subsequently evaluated higher brain function. The behavioral battery test consisted of open field, light/dark transition, and contextual/cued fear conditioning tests conducted at three and seven months of age. After the behavioral test, the brains were dissected and prepared for immunohistochemical staining. We observed behavioral abnormalities in anxiety, spatial memory, and cued memory only in female mice. Moreover, the immunohistochemical analysis showed a reduction in astrocytes within the hippocampus of female mice with behavioral abnormalities. The behavioral abnormalities observed in female CLO-treated mice were consistent with the typical behavioral abnormalities associated with hippocampal astrocyte dysfunction. It is therefore possible that the CLO-induced behavioral abnormalities are at least in part related to a reduction in astrocyte numbers. The results of this study highlight the differences in behavioral effects following CLO exposure between sexes and developmental stages.
Asunto(s)
Conducta Animal , Guanidinas , Hipocampo , Neonicotinoides , Tiazoles , Animales , Femenino , Neonicotinoides/toxicidad , Guanidinas/toxicidad , Guanidinas/administración & dosificación , Masculino , Conducta Animal/efectos de los fármacos , Tiazoles/toxicidad , Tiazoles/administración & dosificación , Hipocampo/efectos de los fármacos , Caracteres Sexuales , Miedo/efectos de los fármacos , Astrocitos/efectos de los fármacos , Ansiedad/inducido químicamente , Ratones , Factores Sexuales , Memoria Espacial/efectos de los fármacos , Administración Oral , Insecticidas/toxicidadRESUMEN
Acetaminophen (APAP) is a leading cause of acute liver failure. The effect of APAP metabolite's effects in the periphery are well characterized; however, associated consequences in the brain remain poorly understood. Animal studies on this subject are few and reveal that frequent APAP intake can trigger cerebral abnormalities that vary depending on the subject's age. Alarmingly, experimental efforts have yet to examine associated consequences in elderly hosts, who correspond to the highest risk of medication overload, impaired drug clearance, and cognitive deficits. Here, we interrogated the cerebral and peripheral pathology of elderly mice submitted to monthly episodes of APAP intoxication since a young adult age. We found that weeks after the final episode of recurrent APAP exposure, mice exhibited worsened non-spatial memory deficit whereas spatial memory performance was unaltered. Interestingly, one month after the period of APAP intoxication, these mice showed increased glial burden without associated drivers, namely, blood-brain barrier disruption, cholesterol accumulation, and elevation of inflammatory molecules in the brain and/or periphery. Our experimental study reveals how recurrent APAP exposure affects the cognitive performance and cellular events in elderly brains. These data suggest that APAP-containing pharmacological interventions may foreshadow the elevated risk of neuropsychiatric disorders that afflict elderly populations.
Asunto(s)
Acetaminofén , Astrocitos , Disfunción Cognitiva , Microglía , Animales , Acetaminofén/toxicidad , Acetaminofén/efectos adversos , Disfunción Cognitiva/inducido químicamente , Disfunción Cognitiva/patología , Disfunción Cognitiva/metabolismo , Ratones , Astrocitos/metabolismo , Astrocitos/efectos de los fármacos , Astrocitos/patología , Microglía/metabolismo , Microglía/efectos de los fármacos , Microglía/patología , Masculino , Encéfalo/metabolismo , Encéfalo/efectos de los fármacos , Encéfalo/patología , Ratones Endogámicos C57BL , Barrera Hematoencefálica/metabolismo , Barrera Hematoencefálica/efectos de los fármacos , Envejecimiento , Modelos Animales de Enfermedad , Memoria Espacial/efectos de los fármacosRESUMEN
BACKGROUND: Alzheimer's disease (AD) is a complex and common neurodegenerative disorder. The present study aimed to investigate the potential effects of selegiline (SEL) on various aspects of memory performance, anxiety, and oxidative stress in an AD rat model induced by intracerebroventricular injection of amyloid beta1-42 (Aß1-42). METHODS: Oral administration of SEL at a dose of 0.5 mg/kg/day was performed for 30 consecutive days. Following the 30 days, several tests, including the open-field, elevated plus-maze, novel object recognition, Morris water maze, and passive avoidance learning were conducted to assess locomotor activity, anxiety-like behavior, recognition memory, spatial memory, and passive avoidance memory, respectively. RESULTS: The results indicate that the induction of AD in rats led to recognition memory, spatial memory, and passive avoidance memory impairments, as well as increased anxiety. Additionally, the AD rats exhibited a decrease in total antioxidant capacity and an increase in total oxidant status levels, suggesting an imbalance in oxidative-antioxidant status. However, the administration of SEL improved memory performance, reduced anxiety, and modulated oxidative-antioxidant status in AD rats. CONCLUSIONS: These findings provide evidence that SEL may alleviate anxiety-like behavior and cognitive deficits induced by Aß through modulation of oxidative-antioxidant status.
Asunto(s)
Enfermedad de Alzheimer , Péptidos beta-Amiloides , Ansiedad , Trastornos de la Memoria , Estrés Oxidativo , Selegilina , Animales , Péptidos beta-Amiloides/metabolismo , Ansiedad/tratamiento farmacológico , Ansiedad/inducido químicamente , Ratas , Masculino , Selegilina/farmacología , Selegilina/administración & dosificación , Trastornos de la Memoria/tratamiento farmacológico , Trastornos de la Memoria/inducido químicamente , Estrés Oxidativo/efectos de los fármacos , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/inducido químicamente , Modelos Animales de Enfermedad , Reacción de Prevención/efectos de los fármacos , Fragmentos de Péptidos , Memoria Espacial/efectos de los fármacos , Aprendizaje por Laberinto/efectos de los fármacos , Ratas Wistar , Reconocimiento en Psicología/efectos de los fármacos , Conducta Animal/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/administración & dosificación , Antioxidantes/farmacología , Antioxidantes/administración & dosificaciónRESUMEN
Drug addiction may result in sleep problems. Importantly, sleep deprivation (SD) is known as an important risk factor for relapse to drug abuse as SD mimics the effects of psychostimulants on dopamine system of the brain. Moreover, aging may affect sleep and drug addiction. This study, therefore, set out to assess the effects of methamphetamine (METH) and REM sleep deprivation (RSD) on locomotor activity, anxiety-like behavior and spatial memory in adult and adolescent rats. Adult and adolescent male Wistar rats received a neurotoxic METH regimen; four subcutaneous injections of 6 mg/kg, at 2 h intervals. Five days later, the animals underwent a 48-h RSD episode using the multiple platforms method. They were then examined using the open field (OF), elevated plus maze (EPM) and Y-maze tasks. We found that the METH and RSD paradigms showed synergistic effects to increase locomotion and risk-taking behavior in both adult and adolescent animals, while only adolescent rats revealed RSD-induced anxiety-like behavior. Moreover, adolescent animals revealed greater sensitization for vertical activity following METH plus RSD episode. In addition, METH and RSD paradigms revealed synergistic effects to impair spatial working memory, but neither METH nor RSD alone affected performance of animals in the Y-maze task. Our findings may indicate that there are important relationships between METH and RSD to induce hyperlocomotion, risk-taking behavior and spatial memory impairment, particularly in adolescent animals. Moreover, it seems that adolescent rats may be more susceptible to anxiety-like behavior and hyperlocomotion than adults.
Asunto(s)
Ansiedad , Estimulantes del Sistema Nervioso Central , Aprendizaje por Laberinto , Metanfetamina , Ratas Wistar , Privación de Sueño , Animales , Metanfetamina/farmacología , Masculino , Estimulantes del Sistema Nervioso Central/farmacología , Aprendizaje por Laberinto/efectos de los fármacos , Ratas , Memoria Espacial/efectos de los fármacos , Memoria Espacial/fisiología , Locomoción/efectos de los fármacos , Locomoción/fisiología , Sueño REM/efectos de los fármacos , Sueño REM/fisiología , Actividad Motora/efectos de los fármacos , Conducta Animal/efectos de los fármacos , Envejecimiento/fisiología , Envejecimiento/efectos de los fármacosRESUMEN
The effects of intra-hippocampal manipulation of glycine receptors on the reconsolidation of recent and late long-term spatial memory were evaluated and assessed in the Morris water maze. The results obtained from the intra-hippocampal infusion of glycine and taurine demonstrated that taurine at a 100 nmol/side dose impaired the reconsolidation of recent and late long-term spatial memory. In comparison, at a dose of 10 nmol/side, it only affected the reconsolidation of late long-term spatial memory, reinforcing that there are differences between molecular mechanisms underlying recent and late long-term memory reconsolidation. On the other hand, glycine impaired the reconsolidation of early and late spatial memory when infused at a dose of 10 nmol/side, but not at a dose of 100 nmol/side, unless it is co-infused with an allosteric site antagonist of the NMDA receptor. Altogether these results show that glycine acting in situ in the hippocampal CA1 region exerts a pharmacological effect on U-curve, which can be explained by its concomitant action on its ionotropic receptor GlyR and on its NMDA receptor co-agonist site.
Asunto(s)
Glicina , Memoria a Largo Plazo , Ratas Wistar , Receptores de Glicina , Memoria Espacial , Taurina , Animales , Receptores de Glicina/metabolismo , Receptores de Glicina/efectos de los fármacos , Masculino , Glicina/farmacología , Ratas , Memoria Espacial/efectos de los fármacos , Memoria Espacial/fisiología , Memoria a Largo Plazo/efectos de los fármacos , Memoria a Largo Plazo/fisiología , Taurina/farmacología , Taurina/administración & dosificación , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Consolidación de la Memoria/efectos de los fármacos , Consolidación de la Memoria/fisiología , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Receptores de N-Metil-D-Aspartato/metabolismo , Receptores de N-Metil-D-Aspartato/efectos de los fármacos , Región CA1 Hipocampal/efectos de los fármacos , Región CA1 Hipocampal/metabolismo , Región CA1 Hipocampal/fisiología , Aprendizaje por Laberinto/efectos de los fármacos , Aprendizaje por Laberinto/fisiologíaRESUMEN
The 5xFAD mouse model shows age-related weight loss as well as cognitive and motor deficits. Metabolic dysregulation, especially impaired insulin signaling, is also present in AD. This study examined whether intranasal delivery of insulin (INI) at low (0.875 U) or high (1.750 U) doses would ameliorate these deficits compared to saline in 10-month-old female 5xFAD and B6SJL wildtype (WT) mice. INI increased forelimb grip strength in the wire hang test in 5xFAD mice in a dose-dependent manner but did not improve the performance of 5xFAD mice on the balance beam. High INI doses reduced frailty scores in 5xFAD mice and improved spatial memory in both acquisition and reversal probe trials in the Morris water maze. INI increased swim speed in 5xFAD mice but had no effect on object recognition memory or working memory in the spontaneous alternation task, nor did it improve memory in the contextual or cued fear memory tasks. High doses of insulin increased the liver, spleen, and kidney weights and reduced brown adipose tissue weights. P-Akt signaling in the hippocampus was increased by insulin in a dose-dependent manner. Altogether, INI increased strength, reduced frailty scores, and improved visual spatial memory. Hypoglycemia was not present after INI, however alterations in tissue and organ weights were present. These results are novel and important as they indicate that intra-nasal insulin can reverse cognitive, motor and frailty deficits found in this mouse model of AD.
Asunto(s)
Administración Intranasal , Modelos Animales de Enfermedad , Fragilidad , Insulina , Ratones Transgénicos , Fuerza Muscular , Memoria Espacial , Animales , Insulina/administración & dosificación , Insulina/farmacología , Fuerza Muscular/efectos de los fármacos , Memoria Espacial/efectos de los fármacos , Femenino , Fragilidad/tratamiento farmacológico , Ratones , Hipoglucemiantes/administración & dosificación , Hipoglucemiantes/farmacología , Enfermedad de Alzheimer/tratamiento farmacológico , Aprendizaje por Laberinto/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Trastornos de la Memoria/tratamiento farmacológico , Precursor de Proteína beta-Amiloide/genética , Fuerza de la Mano/fisiología , Miedo/efectos de los fármacos , Hipocampo/efectos de los fármacos , Hipocampo/metabolismoRESUMEN
BACKGROUND AND AIM: Vascular dementia (VD) is a common type of dementia. This study aimed to evaluate the effects of low and high doses of lutein administration in bilateral-carotid vessel occlusion (2VO) rats. EXPERIMENTAL PROCEDURE: The rats were divided into the following groups: the control, sham-, vehicle (2VO+V) groups, and two groups after 2VO were treated with lutein 0.5 (2VO+LUT-o.5) and 5mg/kg (2VO+LUT-5). The passive-avoidance and Morris water maze were performed to examine fear and spatial memory. The field-potential recording was used to investigate the properties of basal synaptic transmission (BST), paired-pulse ratio (PPR), as an index for measurement of neurotransmitter release, and long-term potentiation (LTP). The hippocampus was removed to evaluate hippocampal cells, volume, and MDA level. RESULT: Treatment with low and high doses improves spatial memory and LTP impairment in VD rats, but only the high dose restores the fear memory, hippocampal cell loss, and volume and MDA level. Interestingly, low-dose, but not high-dose, increased PPR. However, BST recovered only in the high-dose treated group. CONCLUSIONS: Treatment with a low dose might affect neurotransmitter release probability, but a high dose affects postsynaptic processes. It seems likely that low and high doses improve memory and LTP through different mechanisms.
Asunto(s)
Demencia Vascular , Modelos Animales de Enfermedad , Hipocampo , Potenciación a Largo Plazo , Luteína , Plasticidad Neuronal , Animales , Demencia Vascular/tratamiento farmacológico , Demencia Vascular/fisiopatología , Ratas , Masculino , Plasticidad Neuronal/efectos de los fármacos , Potenciación a Largo Plazo/efectos de los fármacos , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Luteína/farmacología , Luteína/administración & dosificación , Luteína/uso terapéutico , Memoria/efectos de los fármacos , Ratas Wistar , Memoria Espacial/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Aprendizaje por Laberinto/efectos de los fármacos , Transmisión Sináptica/efectos de los fármacosRESUMEN
Ketamine is a rapid-acting antidepressant associated with various cognitive side effects. To mitigate these side effects while enhancing efficacy, it can be co-administered with other antidepressants. In our study, we adopted a similar strategy by combining ketamine with environmental enrichment, a potent sensory-motor paradigm, in adult male Wistar rats. We divided the animals into four groups based on a combination of housing conditions and ketamine versus vehicle injections. The groups included those housed in standard cages or an enriched environment for 50 days, which encompassed a 13-day-long behavioral testing period. Each group received either two doses of ketamine (20 mg/kg, IP) or saline as a vehicle. We tested the animals in the novel object recognition test (NORT), forced swim test (FST), open field test (OFT), elevated plus maze (EPM), and Morris water maze (MWM), which was followed by ex vivo c-Fos immunohistochemistry. We observed that combining environmental enrichment with ketamine led to a synergistic antidepressant effect. Environmental enrichment also ameliorated the spatial memory deficits caused by ketamine in the MWM. There was enhanced neuronal activity in the habenula of the enrichment only group following the probe trial of the MWM. In contrast, no differential activity was observed in enriched animals that received ketamine injections. The present study showed how environmental enrichment can enhance the antidepressant properties of ketamine while reducing some of its side effects, highlighting the potential of combining pharmacological and sensory-motor manipulations in the treatment of mood disorders.
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Antidepresivos , Ketamina , Trastornos de la Memoria , Ratas Wistar , Memoria Espacial , Animales , Ketamina/farmacología , Ketamina/administración & dosificación , Masculino , Ratas , Antidepresivos/farmacología , Antidepresivos/administración & dosificación , Trastornos de la Memoria/tratamiento farmacológico , Trastornos de la Memoria/inducido químicamente , Memoria Espacial/efectos de los fármacos , Ambiente , Prueba de Campo Abierto/efectos de los fármacos , Aprendizaje por Laberinto/efectos de los fármacos , Conducta Animal/efectos de los fármacosRESUMEN
The neuropeptide relaxin-3 and its cognate receptor, relaxin family peptide-3 receptors (RXFP3), have been implicated in modulating learning and memory processes, but their specific roles remain unclear. This study utilized behavioral and molecular approaches to investigate the effects of putatively reversible blockade of RXFP3 in the ventral dentate gyrus (vDG) of the hippocampus on spatial and fear memory formation in rats. Male Wistar rats received bilateral vDG cannula implantation and injections of the RXFP3 antagonist, R3(BΔ23-27)R/I5 (400â¯ng/0.5⯵L per side), or vehicle at specific time points before acquisition, consolidation, or retrieval phases of the Morris water maze and passive avoidance learning tasks. RXFP3 inhibition impaired acquisition in the passive avoidance task but not the spatial learning task. However, both memory consolidation and retrieval were disrupted in both tasks following RXFP3 antagonism. Ventral hippocampal levels of the consolidation-related kinase p70-S6 kinase (p70S6K) were reduced RXFP3 blockade. These findings highlight a key role for ventral hippocampal RXFP3 signaling in the acquisition, consolidation, and retrieval of spatial and emotional memories, extending previous work implicating this neuropeptide system in hippocampal memory processing.
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Giro Dentado , Miedo , Ratas Wistar , Receptores Acoplados a Proteínas G , Animales , Giro Dentado/metabolismo , Ratas , Receptores Acoplados a Proteínas G/metabolismo , Masculino , Miedo/fisiología , Reacción de Prevención/fisiología , Reacción de Prevención/efectos de los fármacos , Memoria/fisiología , Relaxina/metabolismo , Memoria Espacial/fisiología , Memoria Espacial/efectos de los fármacos , Aprendizaje por Laberinto/fisiología , Aprendizaje por Laberinto/efectos de los fármacos , Hipocampo/metabolismo , Hipocampo/efectos de los fármacos , Receptores de Péptidos/metabolismoRESUMEN
We aimed to investigate ampicillin (AMP) mechanisms in microbiota-gut-brain axis. We evaluated its effect on two gut and brain regions and behavioral performances. We administred AMP (1 g/l) to BALB/c mice for 21 days. Then, we analyzed body weigth change, stool consistency scoring, gut length, intestinal microbiota composition, nitric oxide synthase 2 (NOS2) expression and tissue integrity. We subsequently evaluated NOS2, GFAP, CD68 and NFL cerebral expression and spatial memory.Interestingly, our data showed gut microbiota disruption, NOS2 upregulation and tissue damage, associated to cerebral NOS2, GFAP, CD68 and NFL over-expression and behavioral alteration. Antiobiotic therapy should be prescribed with great caution.
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Ampicilina , Eje Cerebro-Intestino , Disbiosis , Microbioma Gastrointestinal , Ratones Endogámicos BALB C , Óxido Nítrico Sintasa de Tipo II , Animales , Ratones , Ampicilina/farmacología , Microbioma Gastrointestinal/efectos de los fármacos , Microbioma Gastrointestinal/fisiología , Disbiosis/inducido químicamente , Óxido Nítrico Sintasa de Tipo II/metabolismo , Masculino , Eje Cerebro-Intestino/fisiología , Eje Cerebro-Intestino/efectos de los fármacos , Enfermedades Neuroinflamatorias/metabolismo , Antibacterianos/farmacología , Memoria Espacial/efectos de los fármacos , Memoria Espacial/fisiología , Modelos Animales de Enfermedad , Enfermedades Neurodegenerativas/inducido químicamenteRESUMEN
The escalating focus on ageing-associated disease has generated substantial interest in the phenomenon of cognitive impairment linked to diabetes. Hyperglycemia exacerbates oxidative stress, contributes to ß-amyloid accumulation, disrupts mitochondrial function, and impairs cognitive function. Existing therapies have certain limitations, and apigenin (AG), a natural plant flavonoid, has piqued interest due to its antioxidant, anti-inflammatory, and anti-hyperglycemic properties. So, we anticipate that AG might be a preventive medicine for hyperglycemia-associated amnesia. To test our hypothesis, naïve zebrafish were trained to acquire memory and pretreated with AG. Streptozotocin (STZ) was administered to mimic hyperglycemia-induced memory dysfunction. Spatial memory was assessed by T-maze and object recognition through visual stimuli. Acetylcholinesterase (AChE) activity, antioxidant enzyme status, and neuroinflammatory genes were measured, and histopathology was performed in the brain to elucidate the neuroprotective mechanism. AG exhibits a prophylactic effect and improves spatial learning and discriminative memory of STZ-induced amnesia in zebrafish under hyperglycemic conditions. AG also reduces blood glucose levels, brain oxidative stress, and AChE activity, enhancing cholinergic neurotransmission. AG prevented neuronal damage by regulating brain antioxidant response elements (ARE), collectively contributing to neuroprotective properties. AG demonstrates a promising effect in alleviating memory dysfunction and mitigating pathological changes via activation of the Nrf2/ARE mechanism. These findings underscore the therapeutic potential of AG in addressing memory dysfunction and neurodegenerative changes associated with hyperglycemia.
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Amnesia , Apigenina , Hiperglucemia , Factor 2 Relacionado con NF-E2 , Fármacos Neuroprotectores , Estrés Oxidativo , Pez Cebra , Animales , Factor 2 Relacionado con NF-E2/metabolismo , Hiperglucemia/complicaciones , Hiperglucemia/tratamiento farmacológico , Hiperglucemia/metabolismo , Amnesia/tratamiento farmacológico , Amnesia/metabolismo , Estrés Oxidativo/efectos de los fármacos , Apigenina/farmacología , Apigenina/uso terapéutico , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Acetilcolinesterasa/metabolismo , Transducción de Señal/efectos de los fármacos , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Encéfalo/patología , Antioxidantes/farmacología , Antioxidantes/uso terapéutico , Proteínas de Pez Cebra/metabolismo , Glucemia/metabolismo , Glucemia/efectos de los fármacos , Masculino , Estreptozocina , Aprendizaje por Laberinto/efectos de los fármacos , Memoria Espacial/efectos de los fármacos , Modelos Animales de EnfermedadRESUMEN
Chronic unpredictable mild stress (CUMS) method has been introduced as a rodent model of depression. On the other hand, olanzapine, as an antipsychotic, can induce antidepressant and antipsychotic effects. Also, olanzapine may improve cognitive functions. Both CUMS and olanzapine can also affect the expression level of brain-derived neurotrophic factor (BDNF) and synaptophysin, the molecular factors involved in synaptic function, and learning and memory. In this study, we investigated the effect of olanzapine on locomotor activity (using open field test), pain threshold (using hot plate), depressive-like behavior (using forced swim test), spatial learning and memory (using Morris water maze), and BDNF and synaptophysin hippocampal expression (using real-time PCR) in both male and female CUMS rats. CUMS was performed for three consecutive weeks. Olanzapine was also injected intraperitoneally at the dose of 5â¯mg/kg. Our data showed that olanzapine can reverse the effects of CUMS on behavioral functions and BDNF and synaptophysin expression levels in the hippocampus of both males and females. It was also shown that olanzapine effects on spatial memory, pain perception, and BDNF and synaptophysin level were stronger in females than males. In conclusion, we suggested that the therapeutic effects of olanzapine in CUMS rats may be closely related to the function of BDNF and synaptophysin. Also, the therapeutic effects of olanzapine may be stronger in females. Therefore, and for the first time, we showed that there may be a sex difference in the effects of olanzapine on behavioral and molecular changes following CUMS.
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Factor Neurotrófico Derivado del Encéfalo , Depresión , Modelos Animales de Enfermedad , Hipocampo , Olanzapina , Percepción del Dolor , Memoria Espacial , Estrés Psicológico , Sinaptofisina , Animales , Femenino , Masculino , Ratas , Antipsicóticos/farmacología , Conducta Animal/efectos de los fármacos , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Factor Neurotrófico Derivado del Encéfalo/efectos de los fármacos , Depresión/tratamiento farmacológico , Depresión/metabolismo , Hipocampo/metabolismo , Hipocampo/efectos de los fármacos , Trastornos de la Memoria/tratamiento farmacológico , Trastornos de la Memoria/metabolismo , Olanzapina/farmacología , Percepción del Dolor/efectos de los fármacos , Percepción del Dolor/fisiología , Memoria Espacial/efectos de los fármacos , Estrés Psicológico/metabolismo , Estrés Psicológico/tratamiento farmacológico , Sinaptofisina/metabolismo , Ratas WistarRESUMEN
INTRODUCTION: Research has unveiled the neurotoxicity of Bisphenol A (BPA) linked to neuropathological traits of Alzheimer's disease (AD) through varied mechanisms. This study aims to investigate the neuroprotective properties of cyanidin, an anthocyanin, in an in vivo model of BPA-induced Alzheimer's-like neuropathology. METHODS: Three-week-old Sprague-Dawley rats were randomly assigned to four groups: vehicle control, negative control (BPA exposure), low-dose cyanidin treatment (BPA + cyanidin 5 mg/kg), and high-dose cyanidin treatment (BPA + cyanidin 10 mg/kg). Spatial memory was assessed through behavioral tests, including the Y-maze, novel object recognition, and Morris water maze. After behavioral tests, animals were euthanized, and brain regions were examined for acetylcholinesterase inhibition, p-tau, Wnt3, GSK3ß, and ß-catenin levels, antioxidant activities, and histopathological changes. RESULTS: BPA-exposed groups displayed memory impairments, while cyanidin-treated groups showed significant memory improvement (p < 0.0001). Cyanidin down regulated p-tau and glycogen synthase kinase-3ß (GSK3ß) and restored Wnt3 and ß-catenin levels (p < 0.0001). Moreover, cyanidin exhibited antioxidant properties, elevating catalase and superoxide dismutase levels. The intervention significantly reduced the concentrations of acetylcholinesterase in the cortex and hippocampus in comparison to the groups treated with BPA (p < 0.0001). Significant gender-based disparities were not observed. CONCLUSION: Cyanidin demonstrated potent neuroprotection against BPA-induced Alzheimer's-like neuropathology by enhancing antioxidant defenses, modulating tau phosphorylation by restoring the Wnt/ß-catenin pathway, and ameliorating spatial memory deficits. This study highlights the therapeutic potential of cyanidin in countering neurotoxicity linked to BPA exposure.
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Enfermedad de Alzheimer , Antocianinas , Compuestos de Bencidrilo , Cognición , Fármacos Neuroprotectores , Fenoles , Ratas Sprague-Dawley , Memoria Espacial , Vía de Señalización Wnt , Animales , Fenoles/farmacología , Fenoles/toxicidad , Compuestos de Bencidrilo/toxicidad , Compuestos de Bencidrilo/farmacología , Antocianinas/farmacología , Antocianinas/uso terapéutico , Enfermedad de Alzheimer/inducido químicamente , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/patología , Memoria Espacial/efectos de los fármacos , Masculino , Ratas , Vía de Señalización Wnt/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Cognición/efectos de los fármacos , Modelos Animales de Enfermedad , Aprendizaje por Laberinto/efectos de los fármacos , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Encéfalo/patologíaRESUMEN
BACKGROUND: Methamphetamine (METH) is a psychostimulant substance with highly addictive and neurotoxic effects, but no ideal treatment option exists to improve METH-induced neurocognitive deficits. Recently, mesenchymal stem cells (MSCs)-derived exosomes have raised many hopes for treating neurodegenerative sequela of brain disorders. This study aimed to determine the therapeutic potential of MSCs-derived exosomes on cognitive function and neurogenesis of METH-addicted rodents. METHODS: Male BALB/c mice were subjected to chronic METH addiction, followed by intravenous administration of bone marrow MSCs-derived exosomes. Then, the spatial memory and recognition memory of animals were assessed by the Barnes maze and the novel object recognition test (NORT). The neurogenesis-related factors, including NeuN and DCX, and the expression of Iba-1, a microglial activation marker, were assessed in the hippocampus by immunofluorescence staining. Also, the expression of inflammatory cytokines, including TNF-α and NF-κB, were evaluated by western blotting. RESULTS: The results showed that BMSCs-exosomes improved the time spent in the target quadrant and correct-to-wrong relative time in the Barnes maze. Also, NORT's discrimination index (DI) and recognition index (RI) were improved following exosome therapy. Additionally, exosome therapy significantly increased the expression of NeuN and DCX in the hippocampus while decreasing the expression of inflammatory cytokines, including TNF-α and NF-κB. Besides, BMSC-exosomes down-regulated the expression of Iba-1. CONCLUSION: Our findings indicate that BMSC-exosomes mitigated METH-caused cognitive dysfunction by improving neurogenesis and inhibiting neuroinflammation in the hippocampus.