RESUMEN
The hippocampus has a different vulnerability to ischemia according to the subfields CA1 to CA3 (initials of cornu ammonis). It has been reported that body temperature changes during ischemia affect the degree of neuronal death following transient ischemia. Hypoxiainducible factor 1α (HIF1α) plays a key role in regulating cellular adaptation to low oxygen conditions. In the present study, we investigated the pattern of neuronal death (loss) in CA1 and CA2/3 following 5 min transient forebrain ischemia (TFI) under hyperthermia (39.5±0.2ËC) and the relationship between neuronal death and changes in HIF1α expression using western blot analysis and immunohistochemistry in gerbils. Normothermia or hyperthermia was induced for 30 min before and during the TFI, and neuronal death and HIF1α expression were observed at 0, 3, 6 and 12 h, 1, 2 and 5 days after TFI. Under normothermia, TFIinduced neuronal death of CA1 pyramidal neurons occurred on day 5 after TFI, but CA2/3 pyramidal neurons did not die. In contrast, under hyperthermia, the death of CA1 and CA2/3 pyramidal neurons was observed on day 2 after TFI. Under normothermia, HIF1α expression was significantly elevated in both CA1 and CA2/3 pyramidal neurons at 12 h and 1 day after TFI, and the increased HIF1α immunoreactivity in CA1 was dramatically reduced from 2 days after TFI, but not in CA2/3 pyramidal neurons. Under hyperthermia, the basal expression of HIF1α in the sham group was significantly higher in both CA1 and CA2/3 pyramidal neurons at 0 h after TFI than in the normothermia group. HIF1 expression was continuously higher, peaked at 12 h after TFI, and then significantly decreased from 1 day after TFI. Overall, the present results indicate that resistance to ischemia in CA2/3 pyramidal neurons is closely associated with the persistence of increased expression of HIF1α after ischemic insults and that hyperthermiainduced exacerbation of death of pyramidal neurons is closely related to decreased HIF1α expression after ischemic insults.
Asunto(s)
Hipocampo , Hipertermia Inducida , Animales , Gerbillinae/metabolismo , Hipocampo/metabolismo , Isquemia/metabolismo , Células Piramidales/metabolismoRESUMEN
Altered expression levels of NmethylDaspartate receptor (NMDAR), a ligandgated ion channel, have a harmful effect on cellular survival. Hyperthermia is a proven risk factor of transient forebrain ischemia (tFI) and can cause extensive and severe brain damage associated with mortality. The objective of the present study was to investigate whether hyperthermic preconditioning affected NMDAR1 immunoreactivity associated with deterioration of neuronal function in the gerbil hippocampal CA1 region following tFI via histological and western blot analyses. Hyperthermic preconditioning was performed for 1 h before tFI, which was developed by ligating common carotid arteries for 5 min. tFIinduced cognitive impairment under hyperthermia was worse compared with that under normothermia. Loss (death) of pyramidal neurons in the CA1 region occurred fast and was more severe under hyperthermia compared with that under normothermia. NMDAR1 immunoreactivity was not observed in the somata of pyramidal neurons of sham gerbils with normothermia. However, its immunoreactivity was strong in the somata and processes at 12 h posttFI. Thereafter, NMDAR1 immunoreactivity decreased with time after tFI. On the other hand, NMDAR1 immunoreactivity under hyperthermia was significantly increased in the somata and processes at 6 h posttFI. The change pattern of NMDAR1 immunoreactivity under hyperthermia was different from that under normothermia. Overall, accelerated tFIinduced neuronal death under hyperthermia may be closely associated with altered NMDAR1 expression compared with that under normothermia.
Asunto(s)
Isquemia Encefálica/metabolismo , Regulación de la Expresión Génica , Hipocampo/metabolismo , Hipertermia Inducida , Trastornos de la Memoria/metabolismo , Prosencéfalo/metabolismo , Receptores de N-Metil-D-Aspartato/biosíntesis , Animales , Isquemia Encefálica/patología , Muerte Celular , Gerbillinae , Hipocampo/patología , Masculino , Trastornos de la Memoria/etiología , Trastornos de la Memoria/patología , Neuronas , Prosencéfalo/patologíaRESUMEN
Pycnogenol® (an extract of the bark of French maritime pine tree) is used for dietary supplement and known to have excellent antioxidative efficacy. However, there are few reports on neuroprotective effect of Pycnogenol® supplementation and its mechanisms against ischemic injury following transient forebrain ischemia (TFI) in gerbils. Now, we examined neuroprotective effect and its mechanisms of Pycnogenol® in the gerbils with 5-min TFI, which evokes a significant death (loss) of pyramidal cells located in the cornu ammonis (CA1) region of gerbil hippocampus from 4-5 days post-TFI. Gerbils were pretreated with 30, 40, and 50 mg/kg of Pycnogenol® once a day for 7 days before TFI surgery. Treatment with 50 mg/kg, not 30 or 40 mg/kg, of Pycnogenol® potently protected learning and memory, as well as CA1 pyramidal cells, from ischemic injury. Treatment with 50 mg/kg Pycnogenol® significantly enhanced immunoreactivity of antioxidant enzymes (superoxide dismutases and catalase) in the pyramidal cells before and after TFI induction. Furthermore, the treatment significantly reduced the generation of superoxide anion, ribonucleic acid oxidation and lipid peroxidation in the pyramidal cells. Moreover, interestingly, its neuroprotective effect was abolished by administration of sodium azide (a potent inhibitor of SODs and catalase activities). Taken together, current results clearly indicate that Pycnogenol® supplementation can prevent neurons from ischemic stroke through its potent antioxidative role.
Asunto(s)
Antioxidantes , Región CA1 Hipocampal/citología , Suplementos Dietéticos , Flavonoides/administración & dosificación , Flavonoides/farmacología , Ataque Isquémico Transitorio/complicaciones , Ataque Isquémico Transitorio/patología , Trastornos de la Memoria/etiología , Trastornos de la Memoria/prevención & control , Fármacos Neuroprotectores , Extractos Vegetales/administración & dosificación , Extractos Vegetales/farmacología , Células Piramidales/efectos de los fármacos , Células Piramidales/patología , Animales , Catalasa/metabolismo , Modelos Animales de Enfermedad , Gerbillinae , Peroxidación de Lípido/efectos de los fármacos , Masculino , Células Piramidales/enzimología , Superóxido Dismutasa/metabolismoRESUMEN
Duloxetine (DXT), a serotonin/norepinephrine reuptake inhibitor, is widely used for the treatment of major depressive disorders. In the present study, we investigated the neuroprotective effect of pre-treated DXT in the hippocampal CA1 region following transient global cerebral ischemia. Pre-treatment with 40mg/kg DXT protected pyramidal neurons in the CA1 region from ischemia-reperfusion injury. In addition, pre-treatment with DXT reduced ischemia-induced activations of microglia and astrocytes in the ischemic CA1 region. On the other hand, we found that pre-treatment with DXT did not increase 4-hydroxy-2-noneal (a marker for lipid peroxidation) and significantly increased the expression of Cu, Zn-superoxide dismutase, an antioxidant, in the CA1 pyramidal neurons compared with non-treated those after ischemia-reperfusion. These results indicate that pre-treated DXT has neuroprotective effect against transient global cerebral ischemia and suggest that the neuroprotective effect of DXT may be due to the attenuation of ischemia-induced glial activation as well as the decrease of oxidative stress.