Hye Y Choi

University of Seoul, Sŏul, Seoul, South Korea

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Publications (4)22.57 Total impact

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    ABSTRACT: Ischemia induces blood-brain barrier (BBB) disruption by matrix metalloproteases (MMPs) activation, leading to neuronal cell death. Here, we show that fluoxetine inhibits apoptotic cell death of hippocampal neuron and memory impairment by blocking BBB disruption after transient global ischemia. Fluoxetine treatment (10 mg/kg) after global ischemia significantly inhibited mRNA expression of MMP-2 and -9 and reduced MMP-9 activity. By Evan blue assay, fluoxetine reduced ischemia-induced BBB permeability. In parallel, fluoxetine significantly attenuated the loss of occludin and laminin in the hippocampal area after ischemia. By immunostainning with occludin antibody, fluoxetine preserved the integrity of vascular networks, especially in hippocampal areas after injury. Fluoxetine also prevented the infiltration of macrophages and inhibited the mRNA expression of inflammatory mediators after injury. In addition, the activation of microglia and astrocyte in hippocampal regions was significantly attenuated by fluoxetine. Finally, fluoxetine reduced apoptotic cell death of hippocampal neurons as well as vascular endothelial cell death and improved learning and memory. Thus, our study suggests that the neuroprotective effect of fluoxetine is likely mediated by blocking MMP activation followed BBB disruption after transient global ischemia, and the drug may represent a potential therapeutic agent for preserving BBB integrity following ischemic brain injury in humans.
    Neuropharmacology 12/2013; · 4.11 Impact Factor
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    ABSTRACT: Both oxidative stress and ER stress are known to contribute to secondary injury, ultimately leading to cell death after spinal cord injury (SCI). Here, we showed that valproic acid (VPA) reduced cell death of motor neuron by inhibiting cytochrome c release mediated by oxidative stress and ER stress after SCI. After SCI, rats were immediately injected with VPA (300 mg/kg) subcutaneously and further injected every 12 h for indicated time period. Motor neuron cell death at an early time after SCI was significantly attenuated by VPA treatment. Superoxide anion (O2•-) production and iNOS expression linked to oxidative stress was increased after injury, which was inhibited by VPA. In addition, VPA inhibited c-Jun N-terminal kinase (JNK) activation, which was activated and peaked at early time after SCI. Furthermore, JNK activation and c-Jun phosphorylation were inhibited by a broad-spectrum reactive oxygen species (ROS) scavenger, Mn (III) tetrakis (4-benzoic acid) porphyrin (MnTBAP), indicating that ROS including O2•- increased after SCI probably contribute to JNK activation. VPA also inhibited cytochrome c release and caspase-9 activation, which was significantly inhibited by SP600125, a JNK inhibitor. The levels of phosphorylated Bim and Mcl-1 which is known as downstream targets of JNK were significantly reduced by SP600125. On the other hand, VPA treatment inhibited ER stress-induced caspase-12 activation, which is activated in motor neurons after SCI. In addition, VPA increased Bcl-2/Bax ratio and inhibited CHOP expression. Taken together, our results suggest that cell death of motor neuron after SCI is mediated through oxidative stress and ER stress-mediated cytochrome c release and VPA inhibited cytochrome c release by attenuating ROS-induced JNK activation followed by Mcl-1 and Bim phosphorylation and ER stress-coupled CHOP expression.
    Journal of neurotrauma 12/2013; · 4.25 Impact Factor
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    ABSTRACT: After spinal cord injury, the disruption of blood-spinal cord barrier by activation of matrix metalloprotease is a critical event leading to infiltration of blood cells, inflammatory responses and neuronal cell death, contributing to permanent neurological disability. Recent evidence indicates that fluoxetine, an anti-depressant drug, is shown to have neuroprotective effects in ischaemic brain injury, but the precise mechanism underlying its protective effects is largely unknown. Here, we show that fluoxetine prevented blood-spinal cord barrier disruption via inhibition of matrix metalloprotease activation after spinal cord injury. After a moderate contusion injury at the T9 level of spinal cord with an infinite horizon impactor in the mouse, fluoxetine (10 mg/kg) was injected intraperitoneally and further administered once a day for indicated time points. Fluoxetine treatment significantly inhibited messenger RNA expression of matrix metalloprotease 2, 9 and 12 after spinal cord injury. By zymography and fluorimetric enzyme activity assay, fluoxetine also significantly reduced matrix metalloprotease 2 and matrix metalloprotease 9 activities after injury. In addition, fluoxetine inhibited nuclear factor kappa B-dependent matrix metalloprotease 9 expression in bEnd.3, a brain endothelial cell line, after oxygen-glucose deprivation/reoxygenation. Fluoxetine also attenuated the loss of tight junction molecules such as zona occludens 1 and occludin after injury in vivo as well as in bEnd.3 cultures. By immunofluorescence staining, fluoxetine prevented the breakdown of the tight junction integrity in endothelial cells of blood vessel after injury. Furthermore, fluoxetine inhibited the messenger RNA expression of chemokines such as Groα, MIP1α and 1β, and prevented the infiltration of neutrophils and macrophages, and reduced the expression of inflammatory mediators after injury. Finally, fluoxetine attenuated apoptotic cell death and improved locomotor function after injury. Thus, our results indicate that fluoxetine improved functional recovery in part by inhibiting matrix metalloprotease activation and preventing blood-spinal cord barrier disruption after spinal cord injury. Furthermore, our study suggests that fluoxetine may represent a potential therapeutic agent for preserving blood-brain barrier integrity following ischaemic brain injury and spinal cord injury in humans.
    Brain 07/2012; 135(Pt 8):2375-89. · 10.23 Impact Factor
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    ABSTRACT: The disruption of blood-spinal cord barrier (BSCB) after spinal cord injury (SCI) elicits an intensive local inflammation by the infiltration of blood cells such as neutrophils and macrophages, leading to cell death and permanent neurological disability. SCI activates matrix metalloprotease-9 (MMP-9), which is known to induce BSCB disruption. Here, we examined whether valproic acid (VPA), a histone deacetylase inhibitor, would attenuate BSCB disruption by inhibiting MMP-9 activity, leading to improvement of functional outcome after SCI. After moderate spinal cord contusion injury at T9, VPA (300 mg/kg) were immediately injected subcutaneously and further injected every 12 h for 5 days. Our data show that VPA inhibited MMP-9 activity after injury, and attenuated BSCB permeability and degradation of tight junction molecules such as occludin and ZO-1. In addition, VPA reduced the expression of inflammatory mediators including tumor necrosis factor-α. Furthermore, VPA increased the levels of acetylated histone 3, pAkt, and heat-shock protein 27 and 70, which have anti-apoptotic functions after SCI. Finally, VPA inhibited apoptotic cell death and caspase 3 activation, reduced the lesion volume and improved functional recovery after injury. Thus, our results demonstrated that VPA improves functional recovery by attenuating BSCB disruption via inhibition of MMP-9 activity after SCI.
    Journal of Neurochemistry 03/2012; 121(5):818-29. · 3.97 Impact Factor

Publication Stats

29 Citations
22.57 Total Impact Points

Institutions

  • 2013
    • University of Seoul
      Sŏul, Seoul, South Korea
  • 2012–2013
    • Kyung Hee University
      • • Department of Medicine
      • • Age-Related and Brain Diseases Research Center
      Sŏul, Seoul, South Korea