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Exp Ther Med ; 15(6): 4629-4636, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29805479


The aim of the present study was to identify the effect of heme oxygenase (HO)-1 gene on cerebral ischemia-reperfusion injury. Sprague-Dawley rats were divided randomly into four groups: Sham group, vehicle group, empty adenovirus vector (Ad) group and recombinant HO-1 adenovirus (Ad-HO-1) transfection group. Rats in the vehicle, Ad and Ad-HO-1 groups were respectively injected with saline, Ad or Ad-HO-1 for 3 days prior to cerebral ischemia-reperfusion injury. Subsequently, the middle cerebral artery occlusion method was used to establish the model of cerebral ischemia-reperfusion injury. Following the assessment of neurological function, rats were sacrificed, and the infarction volume and apoptotic index in rat brains were measured. Furthermore, the protein expression levels of HO-1 in brain tissues were detected using western blot analysis. Results indicated that the neurological score of the Ad-HO-1 group was significantly increased compared with the Ad or vehicle groups, respectively (P<0.001). The volume of cerebral infarction and the index score of neuronal apoptosis in the vehicle and Ad groups was significantly increased compared with the Ad-HO-1 group (P<0.01). The death of neuronal cells following cerebral ischemia-reperfusion injury reduced remarkably induced by over-expression of HO-1. These findings suggest a neuroprotective role of HO-1 against brain injury induced by transient cerebral ischemia-reperfusion injury.

Neurosci Lett ; 641: 8-14, 2017 02 22.
Artigo em Inglês | MEDLINE | ID: mdl-28115238


Both nerve growth factor (NGF) and heme oxygenases-1 (HO-1) promotes neuron survival from cerebral ischemic lesions. NGF protects neurons from oxygen-glucose deprivation (OGD), and HO-1 expression can be induced by some growth factors like NGF. This work attempted to identify the contribution of HO-1 on the neuroprotection role of NGF in OGD model, which is an injury simulation of ischemic neuron in vitro. The viability of cortical neurons cells treated with OGD restored significantly by pretreatment with NGF in a dose dependent manner. Moreover, NGF provided obvious protective effects against OGD-induced neurons apoptosis. It identified that NGF could prevent apoptosis and ROS (reactive oxygen species) accumulation in the primary cortical neurons exposed to OGD. NGF could up-regulate the expression level of HO-1, and then afford neuroprotection against OGD insult. In addition, we found that MEK/ERK pathway participated NGF-induced over-expression of HO-1, and was involved in the transcriptional activity or neuroprotection effect of NGF.

Apoptose , Glucose/deficiência , Heme Oxigenase-1/metabolismo , Fatores de Crescimento Neural/metabolismo , Neurônios/metabolismo , Estresse Oxidativo , Oxigênio/metabolismo , Animais , Hipóxia Celular , Sobrevivência Celular , Sistema de Sinalização das MAP Quinases , Fatores de Crescimento Neural/farmacologia , Neurônios/citologia , Neuroproteção , Cultura Primária de Células , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Regulação para Cima
Mol Neurobiol ; 53(6): 3576-3585, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-26099311


Iron overload plays a key role in brain injury after intracerebral hemorrhage (ICH). We explored the roles of ferric iron chelator-deferiprone (DFP)-and ferrous iron chelator-clioquinol (CQ)-in ICH rats through the outcomes, iron deposits, reactive oxygen species (ROS), brain water content, and related iron transporters. One hundred eight Sprague-Dawley rats received intra-striatal infusions of 0.5 U of type IV collagenase to establish ICH models. The rats were randomly assigned to the sham, vehicle, DFP, and CQ groups. We evaluated the outcomes, iron levels, brain water content, and ROS; meanwhile, immunohistochemistry and real-time quantitative polymerase chain reaction (RT-qPCR) were utilized to determine ferritin, transferrin, transferrin receptor, divalent metal transport 1 (DMT1), and ferroportin at 48 and 72 h, 7 and 14 days after surgery. Our results showed ICH induced iron overload, brain edema, ROS formation, and neurological deficits. Both iron chelators decreased iron levels; CQ improved the neurological outcome, attenuated brain edema, and ROS production. DFP reduced iron contents but not brain water content and ROS generation. DFP failed to improve the outcome. ICH initiated endogenous iron chelators and transporters, both exogenous iron chelators enhanced expression of transferrin and transferrin receptor. CQ enhanced expression of ferroportin but not DMT1, while DFP enhanced expression of DMT1 but not ferroportin. Ferrous iron contributed to brain injury, and binding ferrous iron can modestly improve outcome after ICH in rats. The exogenous ferrous iron chelator possibly functioned via endogenous ferrous iron transporters on ICH. Therefore, ferrous iron may be a promising target for ICH in future.

Proteínas de Transporte de Cátions/metabolismo , Hemorragia Cerebral/tratamento farmacológico , Hemorragia Cerebral/metabolismo , Clioquinol/uso terapêutico , Quelantes de Ferro/uso terapêutico , Ferro/metabolismo , Piridonas/uso terapêutico , Animais , Encéfalo/patologia , Edema Encefálico/tratamento farmacológico , Edema Encefálico/patologia , Hemorragia Cerebral/complicações , Hemorragia Cerebral/patologia , Clioquinol/farmacologia , Deferiprona , Ferritinas/metabolismo , Hematoma/complicações , Hematoma/tratamento farmacológico , Hematoma/patologia , Imuno-Histoquímica , Quelantes de Ferro/farmacologia , Masculino , Piridonas/farmacologia , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Análise de Sobrevida , Transferrina/metabolismo , Resultado do Tratamento
Int J Clin Exp Pathol ; 8(9): 10671-9, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26617777


OBJECTIVE: Ferrous iron is a major source inducing oxidative stress after intracerebral hemorrhage (ICH). Divalent metal transporter1 (DMT1) is the important and well-known plasma membrane transport protein which was proved to be involved in the transport of free ferrous iron in mammals. Ferroportin 1 (FPN1) is the unique exporter of ferrous iron from mammalian cells. The role of DMT1 and FPN1 in brain after ICH is still not elucidated. Therefore, we measure the expression of DMT1 and FPN1, to explore the correlations between ferrous iron and its specific transporters after ICH. METHODS: Ninety-six Sprague-Dawley rats received intra-striatal infusions of 0.5 U type IV collagenase to establish ICH model. Ferrous iron content in brain was determined using Turnbull's method. DMT1 and FPN1 expression were examined by immunohistochemical staining and Real-Time quantitative polymerase chain reaction (RT-PCR). With the use of confocal laser microscopy, we determined the colocalization of DMT1 and FPN1 at 1, 3, 7 and 14 days after ICH. RESULTS: Ferrous iron deposition was shown in the perihematomal zone as early as 1 day after ICH; it reached a peak after 7 days and was not elevated within 14 days following ICH. The expression of the DMT1 upregulated and reached to peak at day 7 after ICH. FPN1 reached a plateau at 3 days post-ICH. Expression levels of DMT1 and FPN1 were in parallel with ferrous iron deposition. There was a positive correlation between FPN1 and DMT1. DMT1 mainly localized in the cytoplasm of glias and neurons. FPN1 were mostly distributed on the membrane of endothelial cells and glias. Confocal microscope showed that DMT1 colocalized with FPN1. CONCLUSIONS: DMT1 and FPN1 are positively influenced by ferrous iron status in brain after ICH. DMT1 and FPN1 attenuate iron overload after ICH via increasing transmembrane iron export.

Encéfalo/metabolismo , Proteínas de Transporte de Cátions/metabolismo , Hemorragia Cerebral/metabolismo , Ferro/metabolismo , Animais , Transporte Biológico , Encéfalo/patologia , Proteínas de Transporte de Cátions/genética , Hemorragia Cerebral/induzido quimicamente , Hemorragia Cerebral/genética , Hemorragia Cerebral/patologia , Colagenases , Modelos Animais de Doenças , Masculino , Ratos Sprague-Dawley , Fatores de Tempo
Acta Neurochir (Wien) ; 153(2): 319-25, 2011 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-20686796


BACKGROUND: Heme oxygenase-1 (HO-1), the rate-limiting enzyme for heme catabolism and iron production, its role in intracerebral hemorrhage (ICH) is controversial. The study was to investigate correlations between brain oxidative injury and HO-1 after experimental ICH. METHOD: Sprague-Dawley rats received intra-striatal infusions of 100 µl autologous whole blood as ICH models. HO-1 were examined by immunohistochemical and reverse transcription polymerase chain reaction (RT-PCR) analysis. Brain oxidative stress was quantitated by malondialdehyde (MDA); antioxidation were measured by copper-zinc superoxide dismutase (Cu/Zn-SOD) activity using RT-PCR assay. RESULTS: The expression of the HO-1 upregulated and reached its peak at days 3 and 7 after ICH (P < 0.01). There was a significant increase of MDA and a top at 3-day post-ICH (P < 0.01); Cu/Zn-SOD was upregulated post-ICH and reached the top at day 7 (P < 0.001); HO-1 was correlated significantly with brain MDA content at days 7 and 14 following ICH (r = 0.435-0.501, P < 0.001) but there is no definite correlation between them on 1 to 3 days (P > 0.05); conversely, HO-1 was correlated significantly with Cu/Zn-SOD on 1 to 3 days after ICH (r = 0.433-0.621, P < 0.001) but there is no definite correlation between them at days 7 and 14 (P > 0.05). CONCLUSIONS: HO-1 has both antioxidant and prooxidant properties in ICH. The early upregulation of HO-1 possibly fit with the events and be protective against oxidative stress, whereas its overexpression in the late stages may result in its dysfunction and be toxic. So it should be prudent to intervene ICH with the inhibitor/activator of HO-1.

Hemorragia Cerebral/enzimologia , Heme Oxigenase (Desciclizante)/fisiologia , Degeneração Neural/enzimologia , Estresse Oxidativo/fisiologia , Animais , Hemorragia Cerebral/complicações , Hemorragia Cerebral/patologia , Modelos Animais de Doenças , Feminino , Heme Oxigenase (Desciclizante)/genética , Masculino , Degeneração Neural/etiologia , Degeneração Neural/patologia , Ratos , Ratos Sprague-Dawley , Fatores de Tempo