RESUMEN
Transient global cerebral ischemia (tGCI)-induced neuronal damage is variable according to its duration and degree. There are many studies on the damage or death of pyramidal cells of the hippocampus proper (CA1-3) in rodent models of tGCI. However, studies on the death of granule cells in the hippocampal dentate gyrus (DG) following tGCI have not yet been addressed. In this study, we examined the damage/death of granule cells in the gerbil DG at 5 days after various durations (5, 10, and 15 min) of single tGCI and repeated tGCI (two 5-min tGCI with 1-h interval) using cresyl violet staining, NeuN immunohistochemistry and Fluoro-Jade B (F-J B) histofluorescence staining. Neuronal death was observed only in the polymorphic layer in all single tGCI-operated groups. However, in the repeated tGCI-operated group, massive neuronal death was observed in the granule cell layer as well as in the polymorphic layer by using F-J B histofluorescence staining. In addition, microgliosis in the DG was significantly increased in the repeated tGCI-operated group compared to the 15-min tGCI-operated group. Taken together, these findings indicate that repeated brief tGCI causes granule cell death in the DG which could not occur by a longer duration of single tGCI.
Asunto(s)
Fluoresceínas/metabolismo , Hipocampo/metabolismo , Ataque Isquémico Transitorio/metabolismo , Neuronas/metabolismo , Animales , Región CA1 Hipocampal/metabolismo , Muerte Celular/fisiología , Giro Dentado/metabolismo , Gliosis/metabolismo , Ataque Isquémico Transitorio/patología , Masculino , Células Piramidales/metabolismoRESUMEN
The degree of transient ischemic damage in the cerebral hemisphere is different according to duration of transient ischemia and cerebral regions. Mongolian gerbils show various lesions in the hemisphere after transient unilateral occlusion of the common carotid artery (UOCCA) because they have different types of patterns of anterior and posterior communicating arteries. We examined differential regional damage in the ipsilateral hemisphere of the gerbil after 30 min of UOCCA by using 2,3,5-triphenyltetrazolium chloride (TTC) staining, cresyl violet (CV) Nissl staining, Fluoro-Jade B (F-J B) fluorescence staining, and NeuN immunohistochemistry 5 days after UOCCA. In addition, regional differences in reactions of astrocytes and microglia were examined using GFAP and Iba-1 immunohistochemistry. After right UOCCA, neurological signs were assessed to define ischemic symptomatic animals. Moderate symptomatic gerbils showed several infarcts, while mild symptomatic gerbils showed selective neuronal death/loss in the primary motor and sensory cortex, striatum, thalamus, and hippocampus 5 days after UOCCA. In the areas, morphologically changed GFAP immunoreactive astrocytes and Iba-1 immunoreactive microglia were found, and their numbers were increased or decreased according to the damaged areas. In brief, our results demonstrate that 30 min of UOCCA in gerbils produced infarcts or selective neuronal death depending on ischemic severity in the ipsilateral cerebral cortex, striatum, thalamus and hippocampus, showing that astrocytes and microglia were differently reacted 5 days after UOCCA. Taken together, a gerbil model of 30 min of UOCCA can be used to study mechanisms of infarction and/or regional selective neuronal death/loss as well as neurological dysfunction following UOCCA.
Asunto(s)
Infarto Encefálico/patología , Estenosis Carotídea/patología , Muerte Celular/fisiología , Gliosis/patología , Neuronas/patología , Animales , Astrocitos/metabolismo , Astrocitos/patología , Infarto Encefálico/etiología , Infarto Encefálico/metabolismo , Proteínas de Unión al Calcio , Arteria Carótida Común , Estenosis Carotídea/complicaciones , Estenosis Carotídea/metabolismo , Proteínas de Unión al ADN/metabolismo , Gerbillinae , Proteína Ácida Fibrilar de la Glía/metabolismo , Gliosis/etiología , Gliosis/metabolismo , Masculino , Proteínas de Microfilamentos , Microglía/metabolismo , Microglía/patología , Neuronas/metabolismoRESUMEN
In recent years, the use of botanical agents to prevent skin damage from solar ultraviolet (UV) irradiation has received considerable attention. Oenanthe javanica is known to exert anti-inflammatory and antioxidant activities. This study investigated photoprotective properties of an Oenanthe javanica extract (OJE) against UVB-induced skin damage in ICR mice. The extent of skin damage was evaluated in three groups: control mice with no UVB, UVB-exposed mice treated with vehicle (saline), and UVB-exposed mice treated with 1% extract. Photoprotective properties were assessed in the dorsal skin using hematoxylin and eosin staining, Masson trichrome staining, immunohistochemical staining, quantitative real-time polymerase chain reaction, and western blotting to analyze the epidermal thickness, collagen expression, and mRNA and protein levels of type I collagen, type III collagen, and interstitial collagenases, including matrix metalloproteinase (MMP)-1 and MMP-3. In addition, tumor necrosis factor (TNF)-α and cyclooxygenase (COX)-2 protein levels were also assessed. In the UVB-exposed mice treated with extract, UV-induced epidermal damage was significantly ameliorated. In this group, productions of collagen types I and III were increased, and expressions of MMP-1 and MMP-3 were decreased. In addition, TNF-α and COX-2 expressions were reduced. Based on these findings, we conclude that OJE displays photoprotective effects against UVB-induced collagen disruption and inflammation and suggest that Oenanthe javanica can be used as a natural product for the treatment of photodamaged skin.
Asunto(s)
Colágeno/metabolismo , Oenanthe/química , Extractos Vegetales/farmacología , Sustancias Protectoras/farmacología , Piel/efectos de los fármacos , Piel/metabolismo , Piel/efectos de la radiación , Rayos Ultravioleta/efectos adversos , Animales , Biomarcadores , Biopsia , Dermatitis/tratamiento farmacológico , Dermatitis/etiología , Dermatitis/metabolismo , Modelos Animales de Enfermedad , Expresión Génica , Inmunohistoquímica/métodos , Ratones , Extractos Vegetales/química , Sustancias Protectoras/químicaRESUMEN
Fucoidan, a natural sulfated polysaccharide, displays various biological activities including antioxidant properties. We examined the neuroprotective effect of fucoidan against transient global cerebral ischemia (tGCI) in high-fat diet (HFD)-induced obese gerbils and its related mechanisms. Gerbils received HFD for 12 weeks and fucoidan (50 mg/kg) daily for the last 5 days during HFD exposure, and they were subjected to 5-min tGCI. Pyramidal cell death was observed only in the CA 1 area (CA1) of the hippocampus in non-obese gerbils 5 days after tGCI. However, in obese gerbils, pyramidal cell death in the CA1 and CA2/3 occurred at 2 days and 5 days, respectively, after tGCI. In the obese gerbils, oxidative stress indicators (dihydroethidium, 8-hydroxyguanine and 4-hydroxy-2-nonenal) were significantly enhanced and antioxidant enzymes (SOD1 and SOD2) were significantly reduced in pre- and post-ischemic phases compared to the non-obese gerbils. Fucoidan treatment attenuated acceleration and exacerbation of tGCI-induced neuronal death in the CA1â»3, showing that oxidative stress was significantly reduced, and antioxidant enzymes were significantly increased in pre- and post-ischemic phases. These findings indicate that pretreated fucoidan can relieve the acceleration and exacerbation of ischemic brain injury in an obese state via the attenuation of obesity-induced severe oxidative damage.
Asunto(s)
Antioxidantes/uso terapéutico , Hipocampo/patología , Ataque Isquémico Transitorio/tratamiento farmacológico , Neuronas/patología , Obesidad/tratamiento farmacológico , Polisacáridos/uso terapéutico , Aldehídos/metabolismo , Animales , Antioxidantes/farmacología , Muerte Celular/efectos de los fármacos , Dieta Alta en Grasa , Gerbillinae , Ataque Isquémico Transitorio/metabolismo , Ataque Isquémico Transitorio/patología , Masculino , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Neuroprotección/efectos de los fármacos , Obesidad/patología , Estrés Oxidativo/efectos de los fármacos , Polisacáridos/farmacología , Superóxido Dismutasa/metabolismoRESUMEN
Neuronal death and reactive gliosis are major features of brain tissue damage following transient global cerebral ischemia (tgCI). This study investigated long-term changes in neuronal death and astrogliosis in the gerbil hippocampus for 180 days after 5 min of tgCI. A massive loss of pyramidal neurons was found in the hippocampal CA1 area (CA1) area between 5 and 30 days after tgCI by Fluoro-Jade B (FJB, a marker for neuronal degeneration) histofluorescence staining, but pyramidal neurons in the CA2/3 area did not die. The reaction of astrocytes (astrogliosis) was examined by glial fibrillary acidic protein (GFAP) immunohistochemistry. Morphological change or degeneration (death) of the astrocytes was found in the CA1 area after tgCI, but, in the CA2/3 area, astrogliosis was hardly shown. GFAP immunoreactive astrocytes in the CA1 area was significantly increased in number with time and peaked at 30 days after tgCI, and they began to be degenerated or dead from 40 days after tgCI. The effect was examined by double immunofluorescence staining for FJB and GFAP. The number of FJB/GFAP⺠cells (degenerating astrocytes) was gradually increased with time after tgCI. At 180 days after tgCI, FJB/GFAP⺠cells were significantly decreased, but FJB⺠cells (dead astrocytes) were significantly increased. In brief, 5 min of tgCI induced a progressive degeneration of CA1 pyramidal neurons from 5 until 30 days with an increase of reactive astrocytes, and, thereafter, astrocytes were degenerated with time and dead at later times. This phenomenon might be shown due to the death of neurons.
Asunto(s)
Astrocitos/patología , Linaje de la Célula , Gerbillinae/fisiología , Hipocampo/patología , Ataque Isquémico Transitorio/patología , Animales , Astrocitos/metabolismo , Proteína Ácida Fibrilar de la Glía/metabolismo , Ataque Isquémico Transitorio/metabolismo , Masculino , Coloración y EtiquetadoRESUMEN
Macrophage inflammatory protein-3α (MIP-3α) and its sole receptor, CCR6, play pivotal roles in neuroinflammatory processes induced by brain ischemic insults. In this study, we investigated transient ischemia-induced changes in MIP-3α and CCR6 protein expressions in the hippocampal CA1 area following 5 min of transient global cerebral ischemia (tgCI) in gerbils. Both MIP-3α and CCR6 immunoreactivities were very strongly expressed in pyramidal neurons of the CA1 area from 6 h to 1 day after tgCI and were hardly shown 4 days after tgCI. In addition, strong MIP-3α immunoreactivity was newly expressed in astrocytes 6 h after tgCI. These results indicate that tgCI causes apparent changes in MIP-3α and CCR6 expressions in pyramidal neurons and astrocytes in the hippocampal CA1 area and suggest that tgCI-induced changes in MIP-3α and CCR6 expressions might be closely associated with neuroinflammatory processes in brain ischemic regions.
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Astrocitos/metabolismo , Quimiocina CCL20/metabolismo , Ataque Isquémico Transitorio/metabolismo , Animales , Región CA1 Hipocampal/metabolismo , Muerte Celular/fisiología , Gerbillinae , Masculino , Neuronas/metabolismo , Células Piramidales/metabolismo , Receptores CCR6/metabolismo , Factores de TiempoRESUMEN
(1) Background: By 2050, it is estimated that 130 million people will be diagnosed with dementia, and currently approved medicines only slow the progression. So preventive intervention is important to treat dementia. Mild cognitive impairment is a condition characterized by some deterioration in cognitive function and increased risk of progressing to dementia. Therefore, the treatment of mild cognitive impairment (MCI) is a possible way to prevent dementia. Angelica gigas reduces neuroinflammation, improves circulation, and inhibits cholinesterase, which can be effective in the prevention of Alzheimer's disease and vascular dementia and the progression of mild cognitive impairment. (2) Methods: Angelica gigas (AG) extract 1 mg/kg was administered to mildly cognitive impaired mice, models based on mild traumatic brain injury and chronic mild stress. Then, spatial, working, and object recognition and fear memory were measured. (3) Result: Angelica gigas improved spatial learning, working memory, and suppressed fear memory in the mild traumatic brain injury model. It also improved spatial learning and suppressed cued fear memory in the chronic mild stress model animals. (4) Conclusions: Angelica gigas can improve cognitive symptoms in mild cognitive impairment model mice.
Asunto(s)
Angelica/fisiología , Disfunción Cognitiva/tratamiento farmacológico , Memoria/efectos de los fármacos , Extractos Vegetales/uso terapéutico , Animales , Condicionamiento Psicológico , Miedo , Masculino , Ratones , Ratones Endogámicos C57BL , Extractos Vegetales/farmacología , Distribución Aleatoria , Estrés FisiológicoRESUMEN
To examine the effects of Populus tomentiglandulosa (PT) extract on the expressions of antioxidant enzymes and neurotrophic factors in the cornu ammonis 1 (CA1) region of the hippocampus at 5 min after inducing transient global cerebral ischemia (TGCI) in gerbils, TGCI was induced by occlusion of common carotid arteries for 5 min. Before ischemic surgery, 200 mg·kg-1 PT extract was orally administrated once daily for 7 d. We performed neuronal nuclear antigen immunohistochemistry and Fluoro-Jade B staining. Furthermore, we determined in situ production of superoxide anion radical, expression levels of SOD1 and SOD2 as antioxidant enzymes and brain-derived neurotrophic factor (BDNF) and insulin-like growth factor I (IGF-I) as neurotrophic factors. Pretreatment with 200 mg·kg-1 PT extract prevented neuronal death (loss). Furthermore, pretreatment with 200 mg·kg-1 PT extract significantly inhibited the production of superoxide anion radical, increased expressions of SODs and maintained expressions of BDNF and IGF-I. Such increased expressions of SODs were maintained in the neurons after IRI. In summary, pretreated PT extract can significantly increase levels of SODs and protect the neurons against TGCI, suggesting that PT can be a useful natural agent to protect against TGCI.
Asunto(s)
Factor Neurotrófico Derivado del Encéfalo/metabolismo , Región CA1 Hipocampal/efectos de los fármacos , Factor I del Crecimiento Similar a la Insulina/metabolismo , Extractos Vegetales/administración & dosificación , Populus/química , Células Piramidales/efectos de los fármacos , Daño por Reperfusión/tratamiento farmacológico , Superóxido Dismutasa/metabolismo , Animales , Factor Neurotrófico Derivado del Encéfalo/genética , Región CA1 Hipocampal/metabolismo , Gerbillinae , Humanos , Factor I del Crecimiento Similar a la Insulina/genética , Masculino , Fármacos Neuroprotectores/administración & dosificación , Células Piramidales/metabolismo , Daño por Reperfusión/genética , Daño por Reperfusión/metabolismo , Superóxido Dismutasa/genética , Regulación hacia Arriba/efectos de los fármacosRESUMEN
Fucoidan is a sulfated polysaccharide derived from brown algae and possesses various beneficial activities, including antioxidant property. Previous studies have shown that fucoidan displays protective effect against ischemia-reperfusion injury in some organs. However, few studies have been reported regarding the protective effect of fucoidan against transient cerebral ischemic insults and its related mechanisms. Therefore, in this study, we examined the neuroprotective effect of fucoidan against transient global cerebral ischemia (tGCI), as well as underlying its mechanism using a gerbil model of tGCI which shows a loss of pyramidal neurons in the hippocampal cornu ammonis 1 (CA1) area after 5 min of tGCI. Fucoidan (25 and 50 mg/kg) was intraperitoneally administered once daily for 5 days before tGCI. Pretreatment with 50 mg/kg of fucoidan, not 25 mg/kg of fucoidan, attenuated tGCI-induced hyperactivity and protected CA1 pyramidal neurons from tGCI. In addition, pretreatment with 50 mg/kg of fucoidan inhibited activations of astrocytes and microglia in the ischemic CA1 area. Furthermore, pretreatment with 50 mg/kg of fucoidan significantly reduced the increased 4-hydroxy-2-noneal and superoxide anion radical production in the ischemic CA1 area and significantly increased expressions of SOD1 and SOD2 in the CA1 pyramidal neurons before and after tGCI. Additionally, treatment with diethyldithiocarbamate (an inhibitor of SODs) to the fucoidan-treated gerbils notably abolished the fucoidan-mediated neuroprotection. In brief, our present results indicate that fucoidan can effectively protect neurons from tGCI through attenuation of activated glial cells and reduction of oxidative stress via increase of SODs. Thus, we strongly suggest that fucoidan can be used as a useful preventive agent in cerebral ischemia.
Asunto(s)
Anticoagulantes/administración & dosificación , Región CA1 Hipocampal/efectos de los fármacos , Ataque Isquémico Transitorio/prevención & control , Fármacos Neuroprotectores/administración & dosificación , Estrés Oxidativo/efectos de los fármacos , Polisacáridos/administración & dosificación , Animales , Región CA1 Hipocampal/metabolismo , Región CA1 Hipocampal/patología , Gerbillinae , Ataque Isquémico Transitorio/metabolismo , Ataque Isquémico Transitorio/patología , Masculino , Estrés Oxidativo/fisiología , Distribución AleatoriaRESUMEN
Intermittent fasting (ImF) is known to reduce oxidative stress and affects adult neurogenesis in the hippocampal dentate gyrus. However, it is unknown how ImF affects endogenous antioxidants expressions, cell proliferation, and neuroblast differentiation and their dendrite remodeling over 3 months in the dentate gyrus of adult gerbils. The present study subjected 6month old male gerbils to a normal diet or alternateday ImF for 1, 2 and 3 months. Changes in body weight were not significantly different between gerbils fed a normal diet and on ImF. The present study also investigated the effects of ImF on antioxidant enzymes [superoxide dismutase (SOD)1, SOD2 and catalase] using immunohistochemistry, and endogenous cell proliferation, neuroblast differentiation and neuroblast dendrite complexity by using Ki67 (a cell proliferation marker) and doublecortin (neuroblast differentiation marker) immunohistochemistry in the dentate gyrus. SOD1, SOD2 and CAT immunoreactivities were shown in cells in the granule cell and polymorphic layers. SOD1, SOD2 and catalase immunoreactivity in the cells peaked at 2, 1 and 1 month, respectively, following ImF. Cell proliferation was ~250, 129 and 186% of the control, at 1, 2 and 3 months of ImF, respectively. Neuroblast differentiation was ~41, 32 and 12% of the control, at 1, 2 and 3 months of ImF, respectively, indicating that dendrites of neuroblasts were more arborized and developed at 3 months of ImF. Taken together, these results indicate that ImF for 3 months improves endogenous SOD1, SOD2 and catalase expressions and enhances cell proliferation, and neuroblast dendrites complexity and maturation in the adult gerbil dentate gyrus.
Asunto(s)
Diferenciación Celular/genética , Dendritas/genética , Gerbillinae/genética , Neurogénesis/genética , Animales , Antioxidantes/metabolismo , Catalasa/genética , Proliferación Celular/genética , Dendritas/metabolismo , Giro Dentado/crecimiento & desarrollo , Ayuno/metabolismo , Gerbillinae/crecimiento & desarrollo , Hipocampo/crecimiento & desarrollo , Hipocampo/metabolismo , Humanos , Células-Madre Neurales/metabolismo , Neuronas/metabolismo , Estrés Oxidativo/genética , Superóxido Dismutasa/genética , Superóxido Dismutasa-1/genéticaRESUMEN
Transient ischemia in the whole brain leads to neuronal loss/death in vulnerable brain regions. The striatum, neocortex and hippocampus selectively loose specific neurons after transient ischemia. Just 5 minutes of transient ischemia can cause pyramidal neuronal death in the hippocampal cornu ammonis (CA) 1 field at 4 days after transient ischemia. In this study, we investigated the effects of 5-minute (mild), 15-minute (severe), and 20-minute (lethal) transient ischemia by bilateral common carotid artery occlusion (BCCAO) on behavioral change and neuronal death and gliosis (astrocytosis and microgliosis) in gerbil hippocampal subregions (CA1-3 region and dentate gyrus). We performed spontaneous motor activity test to evaluate gerbil locomotor activity, cresyl violet staining to detect cellular distribution, neuronal nuclei immunohistochemistry to detect neuronal distribution, and Fluoro-Jade B histofluorescence to evaluate neuronal death. We also conducted immunohistochemical staining for glial fibrillary acidic protein and ionized calcium-binding adapter molecule 1 (Iba1) to evaluate astrocytosis and microgliosis, respectively. Animals subjected to 20-minute BCCAO died in at least 2 days. BCCAO for 15 minutes led to pyramidal cell death in hippocampal CA1-3 region 2 days later and granule cell death in hippocampal dentate gyrus 5 days later. Similar results were not found in animals subjected to 5-minute BCCAO. Gliosis was much more rapidly and severely progressed in animals subjected to 15-minute BCCAO than in those subjected to 5-minute BCCAO. Our results indicate that neuronal loss in the hippocampal formation following transient ischemia is significantly different according to regions and severity of transient ischemia. The experimental protocol was approved by Institutional Animal Care and Use Committee (AICUC) of Kangwon National University (approval No. KW-180124-1) on May 22, 2018.
RESUMEN
Although multiple reports using animal models have confirmed that melatonin appears to promote neuroprotective effects following ischemia/reperfusion-induced brain injury, the relationship between its protective effects and activation of autophagy in Purkinje cells following asphyxial cardiac arrest and cardiopulmonary resuscitation (CA/CPR) remains unclear. Rats used in this study were randomly assigned to 6 groups as follows; vehicle-treated sham operated group, vehicle-treated asphyxial CA/CPR operated group, melatonin-treated sham operated group, melatonin-treated asphyxial CA/CPR operated group, PDOT (a MT2 melatonin receptor antagonist) plus (+) melatonin-treated sham operated group and PDOT+melatonin-treated asphyxial CA/CPR operated group. Melatonin (20â¯mg/kg, i.p., 4 times before CA and 3 times after CA) treatment significantly improved survival rate and neurological deficit compared with the vehicle-treated asphyxial CA/CPR rats (survival rates ≥40% vs 10%), showing that melatonin treatment exhibited protective effect against asphyxial CA/CPR-induced Purkinje cell death. The protective effect of melatonin against CA/CPR-induced Purkinje cell death paralleled a remarkable attenuation of autophagy-like processes (Beclin-1, Atg7 and LC3), as well as a dramatic reduction in superoxide anion radical (O2·-), intense enhancements of CuZn superoxide dismutase (SOD1) and MnSOD (SOD2) expressions. Furthermore, the protective effect was notably reversed by treatment with PDOT, which is a selective MT2 antagonist. In brief, melatonin conferred neuroprotection against asphyxial CA/CPR-induced Purkinje cell death via inhibiting autophagic activation by reducing expressions of O2·- and increasing expressions of antioxidant enzymes, and suggests that MT2 is involved in neuroprotective effect of melatonin against Purkinje cell death caused by asphyxial CA/CPR.
Asunto(s)
Antioxidantes/farmacología , Paro Cardíaco/patología , Melatonina/farmacología , Estrés Oxidativo/efectos de los fármacos , Células de Purkinje/efectos de los fármacos , Animales , Asfixia/etiología , Autofagia/efectos de los fármacos , Paro Cardíaco/complicaciones , Masculino , Fármacos Neuroprotectores/farmacología , Células de Purkinje/metabolismo , Células de Purkinje/patología , Distribución Aleatoria , Ratas , Ratas Sprague-Dawley , Receptor de Melatonina MT2/metabolismoRESUMEN
A brief episode of transient ischemia (TI) can confer cerebral ischemic tolerance against a subsequent severer TI under standard condition. The brain under obesity's conditions is more sensitive to ischemic injury. However, the impact of a brief episode of TI under obesity's conditions has not been fully addressed yet. Thus, the objective of this study was to determine the effect of a brief TI in the hippocampus of high-fat diet (HFD)-induced obese gerbils and related mechanisms. Gerbils were maintained on HFD or normal diet (ND) for 12 weeks and subjected to 2 min TI. HFD gerbils were heavier, with higher blood glucose, serum total cholesterol, triglycerides, and leptin levels. Massive loss of pyramidal neurons occurred in the hippocampal cornu ammonis 1 (CA1) field of HFD animals at 5 days after 2 min of TI, but 2 min of TI did not elicit death of pyramidal neurons in ND gerbils. The HFD group showed significantly increased levels of oxidative stress indicators (dihydroethidium and 4-hydroxynonenal) and proinflammatory cytokines (tumor necrosis factor-α and interleukin-1ß) and microglial activation in pre- and/or post-ischemic phases compared to the ND group. Levels of mammalian target of rapamycin (mTOR) and phosphorylated-mTOR in the CA1 field of the HFD group were also significantly higher than the ND group. On the other hand, inhibition of mTOR activation by rapamycin (an allosteric mTOR inhibitor) significantly attenuated neuronal death induced by HFD, showing reduction of HFD-induced increases of oxidative stress indicators and proinflammatory cytokines, and microglia activation. Taken together, a brief episode of TI can evoke neuronal death under obesity's conditions. It might be closely associated with an abnormal increase of mTOR activation-mediated, severe oxidative stress and neuroinflammation in pre- and/or post-ischemic phases.
Asunto(s)
Hipocampo/patología , Ataque Isquémico Transitorio/complicaciones , Obesidad/metabolismo , Obesidad/patología , Serina-Treonina Quinasas TOR/metabolismo , Animales , Estudios de Casos y Controles , Muerte Celular , Dieta Alta en Grasa/efectos adversos , Modelos Animales de Enfermedad , Gerbillinae , Hipocampo/citología , Hipocampo/metabolismo , Interleucina-1beta/metabolismo , Ataque Isquémico Transitorio/metabolismo , Ataque Isquémico Transitorio/patología , Masculino , Neuronas/citología , Neuronas/metabolismo , Obesidad/inducido químicamente , Estrés Oxidativo/efectos de los fármacos , Fosforilación , Sirolimus/farmacología , Factor de Necrosis Tumoral alfa/metabolismo , Regulación hacia ArribaRESUMEN
Coping is a strategic approach to dealing with stressful situations. Those who use proactive coping strategies tend to accept changes and act before changes are expected. In contrast, those who use reactive coping are less flexible and more likely to act in response to changes. However, little research has assessed how coping style changes with age. This study investigated age-related changes in coping strategies and stress responsiveness and the influence of age on the processing of conditioned fear memory in 2-, 12- and 23-month-old male mice. Coping strategy was measured by comparing the escape latency in an active avoidance test and by comparing responses to a shock prod. The results showed that proactivity in coping response gradually decreased with age. Stress responsiveness, measured by stress-induced concentration of corticosterone, was also highest in 2-month-old mice and decreased with age. Consolidation of fear memory was highest in 12-month-old mice and was negatively correlated with the degree of stress responsiveness and proactivity in coping. Fear extinction did not differ among age groups and was not correlated with stress responsiveness or the proactivity of coping. However, the maintenance of extinct fear memory, which was best in 2-month-old mice and worst in 12-month-old mice, was negatively correlated with stress responsiveness but not with coping style. Age-dependent changes in the expression of glucocorticoid receptor (GR) and its regulatory co-chaperones, which are accepted mechanisms for stress hormone stimulation, were measured in the hippocampus. The expression of GR was increased at 12 months compared to other age groups. There were no differences in Hsp70 and BAG1 expression by age. These results can be summarized as follows: (1) stress responsiveness and proactivity in coping decreased with age class; (2) consolidation of fear memory was negatively correlated with both stress responsiveness and proactivity; however, maintenance of extinct fear memory was negatively correlated with stress responsiveness only; and (3) consolidation and maintenance of extinct fear memory appeared to be more influenced by factors other than stress reactivity and proactivity in coping, such as the amount of hippocampal glucocorticoid expression.
RESUMEN
Nuclear receptor related-1 protein (Nurr1) serves important roles in hippocampal-dependent cognitive process. In the present study, the protein expression of Nurr1 was compared in the hippocampi of young [postnatal month 3 (PM 3)], adult (PM 12) and aged (PM 24) gerbils using western blot analysis and immunohistochemistry. Results indicated that the protein level of Nurr1 was significantly and gradually decreased in the gerbil hippocampus with increasing age. In addition, strong Nurr1 immunoreactivity was primarily observed in pyramidal neurons and granule cells of the hippocampus in the young group, which was determined to be reduced in the adult group and to a greater extent in the aged group. Collectively the data demonstrated that Nurr1 immunoreactivity was gradually and markedly decreased during normal aging. These results indicate that gradual decrease of Nurr1 expression in the hippocampus may be associated with the normal aging process and a decline in hippocampus-dependent cognitive function.
RESUMEN
Animal models of scopolamine-induced amnesia are widely used to study underlying mechanisms and treatment of cognitive impairment in neurodegenerative diseases such as Alzheimer's disease (AD). Previous studies have identified that melatonin improves cognitive dysfunction in animal models. In this study, using a mouse model of scopolamine-induced amnesia, we assessed spatial and short-term memory functions for 4 weeks, investigated the expression of myelin-basic protein (MBP) in the dentate gyrus, and examined whether melatonin and scopolamine cotreatment could keep cognitive function and MBP expression. In addition, to study functions of melatonin for keeping cognitive function and MBP expression, we examined expressions of brain-derived neurotrophic factor (BDNF) and tropomycin receptor kinase B (TrkB) in the mouse dentate gyrus. Scopolamine (1â¯mg/kg) and melatonin (10â¯mg/kg) were intraperitoneally treated for 2 and 4 weeks. Two and 4 weeks after scopolamine treatment, mice showed significant cognitive impairment; however, melatonin and scopolamine cotreatment recovered cognitive impairment. Two and 4 weeks of scopolamine treatment, the density of MBP immunoreactive myelinated nerve fibers was significantly decreased in the dentate gyrus; however, scopolamine and melatonin cotreatment significantly increased the scopolamine-induced reduction of MBP expression in the dentate gyrus. Furthermore, the cotreatment of scopolamine and melatonin significantly increased the scopolamine-induced decrease of BDNF and TrKB immunoreactivity in the dentate gyrus. Taken together, our results indicate that melatonin treatment exerts anti-amnesic effect and restores the scopolamine-induced reduction of MBP expression through increasing BDNF and TrkB expressions in the mouse dentate gyrus.
Asunto(s)
Factor Neurotrófico Derivado del Encéfalo/metabolismo , Disfunción Cognitiva , Enfermedades Desmielinizantes/prevención & control , Melatonina/farmacología , Melatonina/uso terapéutico , Glicoproteínas de Membrana/metabolismo , Receptor trkB/metabolismo , Transducción de Señal/efectos de los fármacos , Animales , Antioxidantes/farmacología , Antioxidantes/uso terapéutico , Cognición/efectos de los fármacos , Disfunción Cognitiva/inducido químicamente , Disfunción Cognitiva/tratamiento farmacológico , Giro Dentado/efectos de los fármacos , Giro Dentado/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Masculino , Ratones , Proteína Básica de Mielina/genética , EscopolaminaRESUMEN
Intermittent fasting has been shown to have neuroprotective effects against transient focal cerebral ischemic insults. However, the effects of intermittent fasting on transient global ischemic insult has not been studied much yet. The present study examined effects of intermittent fasting on endogenous antioxidant enzyme expression levels in the hippocampus and investigated whether the fasting protects neurons 5 days after 5 min of transient global cerebral ischemia. Gerbils were randomly subjected to either ad libitum or alternateday intermittent fasting for two months and assigned to sham surgery or transient ischemia. Changes of antioxidant enzymes were examined using immunohistochemistry for cytoplasmic superoxide dismutase 1 (SOD1), mitochondrial (SOD2), catalase (CAT), and glutathione peroxidase (GPX). The effects of intermittent fasting on ischemiainduced antioxidant changes, neuronal damage/degeneration and glial activation were examined. The weight of fasting gerbils was not different from that of control gerbils. In controls, SOD1 and GPX immunoreactivities were strong in pyramidal neurons of filed cornu ammonis 1 (CA1). Transient ischemia in controls significantly decreased expressions of SOD1 and GPX in CA1 pyramidal neurons. Intermittent fasting resulted in increased expressions of SOD2 and CAT, not of SOD1 and GPX, in CA1 pyramidal neurons. Nevertheless, CA1 pyramidal neurons were not protected in gerbils subjected to fasting after transient ischemia, and inhibition of glialcell activation was not observed in the gerbils. In summary, intermittent fasting for two months increased SOD2 and CAT immunoreactivities in hippocampal CA1 pyramidal neurons. However, fasting did not protect the CA1 pyramidal neurons from transient cerebral ischemia. The results of the present study indicate that intermittent fasting may increase certain antioxidants, but not protect neurons from transient global ischemic insult.
Asunto(s)
Catalasa/metabolismo , Ayuno/metabolismo , Gerbillinae/metabolismo , Hipocampo/irrigación sanguínea , Hipocampo/metabolismo , Isquemia/metabolismo , Neuronas/metabolismo , Superóxido Dismutasa/metabolismo , Animales , Antioxidantes/metabolismo , Biomarcadores , Peso Corporal , Muerte Celular , Gerbillinae/genética , Inmunohistoquímica , Isquemia/genética , Masculino , Neuroglía/metabolismo , Neuronas/patología , Oxidación-Reducción , Células Piramidales/metabolismo , Células Piramidales/patología , Superóxido Dismutasa/genéticaRESUMEN
Recent studies have shown that obesity and its related metabolic dysfunction exacerbate outcomes of ischemic brain injuries in some brain areas, such as the hippocampus and cerebral cortex when they are subjected to transient ischemia. However, the impact of obesity in the striatum after brief transient ischemia has not yet been addressed. The objective of this study was to investigate effects of obesity on neuronal damage and inflammation in the striatum after transient ischemia and to examine the role of mTOR which is involved in the pathogenesis of metabolic and neurological diseases. Gerbils were fed with normal diet (ND) or high-fat diet (HFD) for 12 weeks and subjected to 5â¯min of transient ischemia. HFD-fed gerbils showed significant increase in body weight, blood glucose level, serum triglycerides, total cholesterol and low-density lipoprotein cholesterol without affecting food intake. Neuronal death/loss in the HFD-fed gerbils occurred in the dorsolateral striatum 2 days after transient ischemia, and neuronal loss was increased 5 days after transient ischemia, although no neuronal loss was observed in ND-fed gerbils at any time after transient ischemia. The HFD-fed gerbils showed hypertrophied microglia and further increased expressions of tumor necrosis factor-alpha, interukin-1beta, mammalian target of rapamycin (mTOR) and phosphorylated-mTOR during pre- and post-ischemic phases compared with the ND-fed gerbils. Additionally, we found that treatment with mTOR inhibitor rapamycin in the HFD-fed gerbils significantly attenuated transient ischemia-induced neuronal death in the dorsolateral striatum. These findings reveal that chronic HFD-induced obesity results in severe neuroinflammation and significant increase of mTOR activation, which could contribute to neuronal death in the stratum following 5â¯min of transient ischemia. Especially, abnormal mTOR activation would play a key role in mediating obesity-induced severe ischemic brain injury.
Asunto(s)
Cuerpo Estriado/metabolismo , Citocinas/biosíntesis , Dieta Alta en Grasa/efectos adversos , Ataque Isquémico Transitorio/metabolismo , Obesidad/metabolismo , Serina-Treonina Quinasas TOR/metabolismo , Animales , Muerte Celular/fisiología , Cuerpo Estriado/patología , Dieta Alta en Grasa/tendencias , Gerbillinae , Mediadores de Inflamación/metabolismo , Ataque Isquémico Transitorio/patología , Masculino , Neuronas/metabolismo , Neuronas/patología , Obesidad/patologíaRESUMEN
Neurofilaments (NFs) including neurofilament200 kDa (NFH), neurofilament165 kDa (NFM) and neurofilament68 kDa (NFL) are major protein constituents of the brain, and serve important roles in the regulation of axonal transport. NF alteration is a key feature in the pathogenesis of neurological disorders involving cognitive dysfunction. In the present study, cognitive impairments were investigated, via assessments using the Morris water maze and passive avoidance tests, in mice following chronic systemic treatment with 1 mg/kg scopolamine (SCO) for 4 weeks. SCOinduced cognitive impairments were significantly observed 1 week following the SCO treatment, and these cognitive deficits were maintained for 4 weeks. However, the NF immunoreactivities and levels were altered differently according to the hippocampal subregion following SCO treatment. NFH immunoreactivity and levels were markedly altered in all hippocampal subregions, and were significantly increased 1 week following the SCO treatment; thereafter, the immunoreactivity and levels significantly decreased with time. NFM immunoreactivity and levels gradually decreased in the hippocampus and were significantly decreased 4 weeks following SCO treatment. NFL immunoreactivity and levels gradually decreased in the hippocampus, and were significantly decreased 2 and 4 weeks following SCO treatment. In conclusion, the results of the present study demonstrated that chronic systemic treatment with SCO induced cognitive impairment from 1 week following SCO treatment, and NF expression was diversely altered according to the hippocampal subregion from 1 week following SCO treatment. These results suggest that SCOinduced changes in NF expression may be associated with cognitive impairment.
Asunto(s)
Disfunción Cognitiva/tratamiento farmacológico , Hipocampo/efectos de los fármacos , Filamentos Intermedios/patología , Antagonistas Muscarínicos/uso terapéutico , Proteínas de Neurofilamentos/análisis , Escopolamina/uso terapéutico , Animales , Disfunción Cognitiva/patología , Hipocampo/patología , Masculino , Ratones , Ratones Endogámicos ICRRESUMEN
Rufinamide is a novel antiepileptic drug and commonly used in the treatment of Lennox-Gastaut syndrome. In the present study, we investigated effects of rufinamide on cognitive function using passive avoidance test and neurogenesis in the hippocampal dentate gyrus using Ki-67 (a marker for cell proliferation), doublecortin (DCX, a marker for neuroblast) and BrdU/NeuN (markers for newly generated mature neurons) immunohistochemistry in aged gerbils. Aged gerbils (24-month old) were treated with 1â¯mg/kg and 3â¯mg/kg rufinamide for 4 weeks. Treatment with 3â¯mg/kg rufinamide, not 1â¯mg/kg rufinamide, significantly improved cognitive function and increased neurogenesis, showing that proliferating cells (Ki-67-immunoreactive cells), differentiating neuroblasts (DCX-immunoreactive neuroblasts) and mature neurons (BrdU/NeuN-immunoreactive cells) in the aged dentate gyrus compared with those in the control group. When we examined its mechanisms, rufinamide significantly increased immunoreactivities of insulin-like growth factor-1 (IGF-1), its receptor (IGF-1R), and phosphorylated cAMP response element binding protein (p-CREB). However, rufinamide did not show any increase in immunoreactivities of brain-derived neurotrophic factor and its receptor. Therefore, our results indicate that rufinamide can improve cognitive function and increase neurogenesis in the hippocampus of the aged gerbil via increasing expressions of IGF-1, IGF-1R and p-CREB.