The effects of insulin-like growth factor (IGF)-1, IGF-2, and des-IGF-1 on neuronal loss after hypoxic-ischemic brain injury in adult rats: evidence for a role for IGF binding proteins.

Guan, Jian; Williams, Christopher E.; Skinner, S. J. M.; Mallard, Carina; Gluckman, P. D.

doi:10.1210/endo.137.3.8603600

Cited by 96 publications

(58 citation statements)

References 35 publications

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“…In infant rats there is a marked change in IGFBP expression after unilateral hypoxic-ischemic brain injury (21,22,50) and IGFBP-2 is expressed together with IGF-1 during myelin regeneration after spinal cord injury (51). Recent studies suggest that the IGFBPs are important determinants of the neuronal rescue effects of IGF-1 (52). Moreover, in sheep choroid plexus cells IGFBP2 has been shown to enhance the biological actions of IGF-1 at low concentrations, but to inhibit the actions of IGF-1 at high concentrations (53).…”

Section: Discussionmentioning

confidence: 99%

Insulin-like growth factor-1 is a potent neuronal rescue agent after hypoxic-ischemic injury in fetal lambs.

Johnston

Mallard²,

Williams³

et al. 1996

J. Clin. Invest.

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181

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This study was designed to determine the potential of IGF-1 as a neuronal rescue agent after cerebral ischemia. Unanesthetized late gestation fetal sheep were subjected to 30-min cerebral ischemia by inflation of carotid artery occluder cuffs. 2 h later either 0.1 g rhIGF-1, 1 g rhIGF-1, 10 g rhIGF-1, or vehicle was infused into a lateral cerebral ventricle over 1 h. Histologic outcome was assessed 5 d later. Overall neuronal loss was reduced with 0.1 g ( P Ͻ 0.05) and 1 g ( P Ͻ 0.002) rhIGF-1, but treatment with 10 g was not effective. With 1 g rhIGF-1 neuronal loss scores were significantly lower in brain regions examined including cortex, hippocampus, and striatum, whereas with 0.1 g rhIGF-1 the parietal cortex and thalamus were not improved and the improvement seen in other regions was less than with 1 g rhIGF-1. Treatment with 1 g rhIGF-1 also delayed the onset of seizures and reduced their incidence. Moreover, the secondary phase of cytotoxic edema was reduced and delayed in onset. We conclude that low dose rhIGF-1 therapy promotes neuronal rescue after cerebral hypoxic-ischemic injury in utero, but the effect is dose dependent. Importantly, rhIGF-1 is effective and nontoxic when administered 2 h after the hypoxic ischemic insult.

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Section: Discussionmentioning

confidence: 99%

Insulin-like growth factor-1 is a potent neuronal rescue agent after hypoxic-ischemic injury in fetal lambs.

Johnston

Mallard²,

Williams³

et al. 1996

J. Clin. Invest.

Self Cite

181

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“…IGF and IGFBP gene expression can be induced in response to hypoxia/ischemia and play a role in neuroprotection. 21 Thus, the corresponding evidence of decreased glycolytic enzymes, electron transport chain transcripts/proteins (see below) and increased INS signaling implies abnormal brain glucose utilization/regulation, and is in keeping with increased oxidative stress and perhaps hypoxic conditions within the prefrontal cortex of schizophrenia (Figures 2a and b). Biological systems limited in their supply of glucose as an energy source are forced to alter their gene expression in order to utilize alternate energy sources.…”

Section: D-digementioning

confidence: 93%

Mitochondrial dysfunction in schizophrenia: evidence for compromised brain metabolism and oxidative stress

et al. 2004

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The etiology and pathophysiology of schizophrenia remain unknown. A parallel transcriptomics, proteomics and metabolomics approach was employed on human brain tissue to explore the molecular disease signatures. Almost half the altered proteins identified by proteomics were associated with mitochondrial function and oxidative stress responses. This was mirrored by transcriptional and metabolite perturbations. Cluster analysis of transcriptional alterations showed that genes related to energy metabolism and oxidative stress differentiated almost 90% of schizophrenia patients from controls, while confounding drug effects could be ruled out. We propose that oxidative stress and the ensuing cellular adaptations are linked to the schizophrenia disease process and hope that this new disease concept may advance the approach to treatment, diagnosis and disease prevention of schizophrenia and related syndromes.

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“…The results in Figure 2 show that colony formation in semi-solid agar (Figure 2a), IGF-I-induced proliferation, as measured by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide thiazolyl blue (MTT) assay (Figure 2b), and IGF-Iinduced migration, as determined by a Boyden chamber migration assay (Figure 2c), were all significantly reduced in CLAS cells as compared to either parental or mock-transfected H-59 cells. To rule out the possibility that the reduced sensitivity to IGF-I in these cells was due to its altered association with IGF binding proteins (IGFBPs) (Zwad et al, 2002;Gordon et al, 2005), we also compared the response of CLAS and control cells to Des-IGF-I, an IGF-I analog with a mutation in the NH 2 -terminal domain (deletion of residues 1-3) that has a reduced affinity for IGFBP (Guan et al, 1996). The results in Figure 2d show that there was no difference between the responsiveness of either control or CLAS cells to IGF-I and Des-IGF-I, suggesting that the impaired IGF-I sensitivity was independent of IGF-I association with its binding proteins.…”

Section: Loss Of Igf-ir-mediated Functions In Cells Expressing Reducementioning

confidence: 99%

Loss of responsiveness to IGF-I in cells with reduced cathepsin L expression levels

et al. 2008

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The lysosomal cysteine proteinase cathepsin L is involved in proteolytic processing of internalized proteins. In transformed cells, where it is frequently overexpressed, its intracellular localization and functions can be altered. Previously, we reported that treatment of highly metastatic, murine carcinoma H-59 cells with small molecule cysteine proteinase inhibitors altered the responsiveness of the type I insulin-like growth factor (IGF-I) receptor and consequently reduced cell invasion and metastasis. To assess more specifically the role of cathepsin L in IGF-I-induced signaling and tumorigenicity, we generated H-59 subclones with reduced cathepsin L expression levels. These clonal lines showed an altered responsiveness to IGF-I in vitro, as evidenced by (i) loss of IGF-I-induced receptor phosphorylation and Shc recruitment, (ii) reduced IGF-I (but not IGF-II)-induced cellular proliferation and migration, (iii) decreased anchorage-independent growth and (iv) reduced plasma membrane levels of IGF-IR. These changes resulted in increased apoptosis in vivo and an impaired ability of the cells to form liver metastases. The results demonstrate that cathepsin L expression levels regulate cell responsiveness to IGF-I and thereby identify a novel function for cathepsin L in the control of the tumorigenic/metastatic phenotype.

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The effects of insulin-like growth factor (IGF)-1, IGF-2, and des-IGF-1 on neuronal loss after hypoxic-ischemic brain injury in adult rats: evidence for a role for IGF binding proteins.

Cited by 96 publications

References 35 publications

Insulin-like growth factor-1 is a potent neuronal rescue agent after hypoxic-ischemic injury in fetal lambs.

Insulin-like growth factor-1 is a potent neuronal rescue agent after hypoxic-ischemic injury in fetal lambs.

Mitochondrial dysfunction in schizophrenia: evidence for compromised brain metabolism and oxidative stress

Loss of responsiveness to IGF-I in cells with reduced cathepsin L expression levels

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