Proteomic Analysis of Hypoxia/Ischemia-Induced Alteration of Cortical Development and Dopamine Neurotransmission in Neonatal Rat

Hu, Xiaoming; Rea, Harriett C.; Wiktorowicz, John E.; Perez‐Polo, J. Regino

doi:10.1021/pr060209x

Cited by 48 publications

(46 citation statements)

References 60 publications

(99 reference statements)

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“…These insults produce long-term aberration in dopamine signaling, release, uptake, and synthesis as well as in dopaminerelated gene expression in animal models. These alterations have been hypothesized to contribute, at least in part, to several pathological behaviors including those typical of schizophrenia (Boksa 2004;Boksa and El-Khodor 2003;Decker and Rye 2002;Hu et al 2006;Schmidt-Kastner et al 2006;Weinberger 2002). Regardless of the aforementioned and in contrast to our finding in the neonatal ventral hippocampal lesion model, protein levels of all three subunits of complex I were unaffected in the prefrontal cortex of rats exposed to the neonatal hypoxic regimen of the present study, both prepubertally and postpubertally.…”

Section: Discussioncontrasting

confidence: 92%

Mitochondrial Complex I Subunits are Altered in Rats with Neonatal Ventral Hippocampal Damage but not in Rats Exposed to Oxygen Restriction at Neonatal Age

et al. 2008

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Several independent lines of evidence suggest mitochondrial dysfunction in schizophrenia in brain and periphery, including mitochondrial hypoplasia, dysfunction of the oxidative phosphorylation system, and altered mitochondrial-related gene expression. In an attempt to decipher whether mitochondrial complex I abnormality in schizophrenia is a core pathophysiological process or is attributable to medication, we studied two animal models of schizophrenia related to the neurodevelopmental hypothesis of this disorder. Protein levels of complex I subunits, 24, 51, and 75 kDa, were assessed in neonatal ventral hippocampal lesion rat model and in rats exposed to hypoxia at a neonatal age. In the prefrontal cortex, a major anatomical substrate of schizophrenia, neonatal ventral hippocampal lesion induced a significant prepubertal increase and postpubertal decrease in all three subunits of complex I as compared to sham-treated rats, while no change was observed in the cingulate cortex. Neonatal exposure to hypoxia did not affect protein levels of any of the three subunits in the prefrontal cortex. An age-dependent increase in the expression of complex I subunits was observed, which was distorted in the prefrontal cortex by the neonatal ventral hippocampal lesion. Complex I alterations in schizophrenia-related neurodevelopmental rat models appear to be brain region and animal model dependent. The results of this study support previous findings suggesting abnormal complex I expression as a pathological characteristic of schizophrenia rather than an effect of medication.

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Section: Discussioncontrasting

confidence: 92%

Mitochondrial Complex I Subunits are Altered in Rats with Neonatal Ventral Hippocampal Damage but not in Rats Exposed to Oxygen Restriction at Neonatal Age

et al. 2008

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“…Proteins were be extracted from samples in destreak Buffer (GE Healthcare Lifesciences, Pittsburgh, PA) as and analyzed by 2DGE as described previously (22–24). After electrophoresis, the gels were fixed (10% methanol, 7% acetic acid in ddH20), and stained with SYPRO-Ruby (Bio-Rad, Hercules, CA) overnight, and destained in Fix Buffer.…”

Section: Methodsmentioning

confidence: 99%

XPO1/CRM1 Inhibition Causes Antitumor Effects by Mitochondrial Accumulation of eIF5A

Miyake

Pradeep

et al. 2015

Clinical Cancer Research

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Purpose XPO1 inhibitors have shown promise for cancer treatment and yet the underlying mechanisms for the antitumor effects are not well understood. In this study, we explored the usefulness of selective inhibitors of nuclear export (SINE) compounds that are specific inhibitors of XPO1. Experimental design We used proteomic analysis in XPO1 inhibitor treated ovarian cancer cell lines, and examined antitumor effects in ovarian and breast cancer mouse models. We also studied the effects of XPO1 inhibitor in combination with chemotherapeutic agents. Results XPO1 inhibitor treatment substantially increased the percentage of apoptotic cells (60%) after 72 hours of incubation. XPO1 inhibitor promoted the accumulation of eIF5A in mitochondria, leading to cancer cell death. Topotecan showed the greatest synergistic effect with XPO1 inhibitor. XPO1 inhibitors prevented the translocation of IGF2BP1 from the nucleus to the cytoplasm, thereby permitting the localization of eIF5A in the mitochondria. This process was p53, RB, and FOXO-independent. Significant anti-tumor effects were observed with XPO1 inhibitor monotherapy in orthotopic ovarian (p < 0.001) and breast (p < 0.001) cancer mouse models, with further decrease in tumor burden observed in combination with topotecan or paclitaxel (p <0.05). This mitochondrial accumulation of eIF5A was highly dependent on the cytoplasmic IGF2BP1 levels. Conclusion We have unveiled a new understanding of the role of eIF5A and IGF2BP1 in XPO1 inhibitor-mediated cell death and support their clinical development for the treatment of ovarian and other cancers. Our data also ascertain the combinations of XPO1 inhibitors with specific chemotherapy drugs for therapeutic trials.

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“…The animals of the HHI group were subsequently subjected to 100% oxygen for 120 min. A more detailed description of this procedure can be found elsewhere (Rice et al, 1981;Grafe, 1994Grafe, , 2008Hu et al, 2003Hu et al, , 2005Hu et al, , 2006.…”

Section: Materials and Methods Animals And Injury Modelmentioning

confidence: 99%

Normobaric hyperoximia increases hypoxia‐induced cerebral injury: DTI study in rats

Bockhorst

Narayana

Dulin

et al. 2009

J of Neuroscience Research

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Perinatal hypoxia affects normal neurological development and can lead to motor, behavioral and cognitive deficits. A common acute treatment for perinatal hypoxia is oxygen resuscitation (hyperoximia), a controversial treatment. Magnetic resonance imaging (MRI), including diffusion tensor imaging (DTI), was performed in a P7 rat model of perinatal hypoxia to determine the effect of hyperoximia. These studies were performed on two groups of animals: 1) animals which were subjected to ischemia followed by hypoxia (HI), and 2) HI followed by hyperoximic treatment (HHI). Lesion volumes on high resolution MRI and DTI derived measures, fractional anisotropy (FA), mean diffusivity (MD), and axial and radial diffusivities (lambda(l) and lambda(t), respectively) were measured in vivo one day, one week, and three weeks after injury. Most significant differences in the MRI and DTI measures were found at three weeks after injury. Specifically, three weeks after HHI injury resulted in significantly larger hyperintense lesion volumes (95.26 +/- 50.42 mm(3)) compared to HI (22.25 +/- 17.62 mm(3)). The radial diffusivity lambda(t) of the genu of corpus callosum was significantly larger in HHI (681 +/- 330 x 10(-6) mm(2)/sec) than in HI (486 +/- 96 x 10(-6) mm(2)/sec). Over all, most significant differences in all the DTI metrics (FA, MD, lambda(t), lambda(l)) at all time points were found in the corpus callosum. Our results suggest that treatment of perinatal hypoxia with normobaric oxygen does not ameliorate, but exacerbates damage.

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Proteomic Analysis of Hypoxia/Ischemia-Induced Alteration of Cortical Development and Dopamine Neurotransmission in Neonatal Rat

Cited by 48 publications

References 60 publications

Mitochondrial Complex I Subunits are Altered in Rats with Neonatal Ventral Hippocampal Damage but not in Rats Exposed to Oxygen Restriction at Neonatal Age

Mitochondrial Complex I Subunits are Altered in Rats with Neonatal Ventral Hippocampal Damage but not in Rats Exposed to Oxygen Restriction at Neonatal Age

XPO1/CRM1 Inhibition Causes Antitumor Effects by Mitochondrial Accumulation of eIF5A

Normobaric hyperoximia increases hypoxia‐induced cerebral injury: DTI study in rats

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