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Delayed peripheral administration of a GPE analogue induces astrogliosis and angiogenesis and reduces inflammation and brain injury following hypoxia-ischemia in the neonatal rat.

Abstract

Glycine 2-methyl proline glutamate (G-2mPE) is a proline-modified analogue to the naturally existing N-terminal tripeptide glycine-proline-glutamate that is a cleaved product from insulin-like growth factor-1. G-2mPE is designed to be more enzymatically resistant than glycine-proline-glutamate and to increase its bioavailability. The current study has investigated the protective effects of G-2mPE following hypoxic-ischemic brain injury in the neonatal brain. On postnatal day 7, Wistar rats were exposed to hypoxia-ischemia (HI). HI was induced by unilateral ligation of the left carotid artery followed by hypoxia (7.7% O2, 36 degrees C) for 60 min. The drug treatment started 2 h after the insult, and the pups were given either 1.2 mg/kg (bolus), 1.2 mg/ml once a day for 7 days, or vehicle. The degree of brain damage was determined histochemically by thionin/acid fuchsin staining. G-2mPE's anti-inflammatory properties were investigated by IL-1beta, IL-6, and IL-18 ELISA, and effects on apoptosis by caspase 3 activity. Vascularization was determined immunohistochemically by the total length of isolectin-positive blood vessels. Effect on astrocytosis was also determined in the hippocampus. Animals treated with multiple doses of G-2mPE demonstrated reduced overall brain injury 7 days after HI, particularly in the hippocampus and thalamus compared to vehicle-treated rats. The expression of IL-6 was decreased in G-2mPE-treated animals compared to vehicle-treated pups, and both the capillary length and astrogliosis were increased in the drug-treated animals. There was no effect on caspase 3 activity. This study indicates that peripheral administration of G-2mPE, starting 2 h after a hypoxic-ischemic insult, reduces the degree of brain injury in the immature rat brain. The normalization of IL-6 levels and the promotion of both neovascularization and reactive astrocytosis may be potential mechanisms that underlie its protective effects.

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  • Authors+Show Affiliations

    ,

    The Liggins Institute, University of Auckland, Auckland, New Zealand.

    , , , , , ,

    Source

    Developmental neuroscience 29:4-5 2007 pg 393-402

    MeSH

    Animals
    Animals, Newborn
    Apoptosis
    Astrocytes
    Birth Injuries
    Brain
    Caspase 3
    Cerebral Arteries
    Disease Models, Animal
    Drug Administration Schedule
    Encephalitis
    Gliosis
    Hypoxia-Ischemia, Brain
    Interleukins
    Neovascularization, Physiologic
    Nerve Degeneration
    Neuroprotective Agents
    Oligopeptides
    Rats
    Rats, Wistar
    Time Factors
    Treatment Outcome

    Pub Type(s)

    Journal Article
    Research Support, Non-U.S. Gov't

    Language

    eng

    PubMed ID

    17762207

    Citation

    Svedin, Pernilla, et al. "Delayed Peripheral Administration of a GPE Analogue Induces Astrogliosis and Angiogenesis and Reduces Inflammation and Brain Injury Following Hypoxia-ischemia in the Neonatal Rat." Developmental Neuroscience, vol. 29, no. 4-5, 2007, pp. 393-402.
    Svedin P, Guan J, Mathai S, et al. Delayed peripheral administration of a GPE analogue induces astrogliosis and angiogenesis and reduces inflammation and brain injury following hypoxia-ischemia in the neonatal rat. Dev Neurosci. 2007;29(4-5):393-402.
    Svedin, P., Guan, J., Mathai, S., Zhang, R., Wang, X., Gustavsson, M., ... Mallard, C. (2007). Delayed peripheral administration of a GPE analogue induces astrogliosis and angiogenesis and reduces inflammation and brain injury following hypoxia-ischemia in the neonatal rat. Developmental Neuroscience, 29(4-5), pp. 393-402.
    Svedin P, et al. Delayed Peripheral Administration of a GPE Analogue Induces Astrogliosis and Angiogenesis and Reduces Inflammation and Brain Injury Following Hypoxia-ischemia in the Neonatal Rat. Dev Neurosci. 2007;29(4-5):393-402. PubMed PMID: 17762207.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Delayed peripheral administration of a GPE analogue induces astrogliosis and angiogenesis and reduces inflammation and brain injury following hypoxia-ischemia in the neonatal rat. AU - Svedin,Pernilla, AU - Guan,Jian, AU - Mathai,Sam, AU - Zhang,Rong, AU - Wang,Xiaoyang, AU - Gustavsson,Malin, AU - Hagberg,Henrik, AU - Mallard,Carina, PY - 2006/09/12/received PY - 2007/01/05/accepted PY - 2007/9/1/pubmed PY - 2007/10/6/medline PY - 2007/9/1/entrez SP - 393 EP - 402 JF - Developmental neuroscience JO - Dev. Neurosci. VL - 29 IS - 4-5 N2 - Glycine 2-methyl proline glutamate (G-2mPE) is a proline-modified analogue to the naturally existing N-terminal tripeptide glycine-proline-glutamate that is a cleaved product from insulin-like growth factor-1. G-2mPE is designed to be more enzymatically resistant than glycine-proline-glutamate and to increase its bioavailability. The current study has investigated the protective effects of G-2mPE following hypoxic-ischemic brain injury in the neonatal brain. On postnatal day 7, Wistar rats were exposed to hypoxia-ischemia (HI). HI was induced by unilateral ligation of the left carotid artery followed by hypoxia (7.7% O2, 36 degrees C) for 60 min. The drug treatment started 2 h after the insult, and the pups were given either 1.2 mg/kg (bolus), 1.2 mg/ml once a day for 7 days, or vehicle. The degree of brain damage was determined histochemically by thionin/acid fuchsin staining. G-2mPE's anti-inflammatory properties were investigated by IL-1beta, IL-6, and IL-18 ELISA, and effects on apoptosis by caspase 3 activity. Vascularization was determined immunohistochemically by the total length of isolectin-positive blood vessels. Effect on astrocytosis was also determined in the hippocampus. Animals treated with multiple doses of G-2mPE demonstrated reduced overall brain injury 7 days after HI, particularly in the hippocampus and thalamus compared to vehicle-treated rats. The expression of IL-6 was decreased in G-2mPE-treated animals compared to vehicle-treated pups, and both the capillary length and astrogliosis were increased in the drug-treated animals. There was no effect on caspase 3 activity. This study indicates that peripheral administration of G-2mPE, starting 2 h after a hypoxic-ischemic insult, reduces the degree of brain injury in the immature rat brain. The normalization of IL-6 levels and the promotion of both neovascularization and reactive astrocytosis may be potential mechanisms that underlie its protective effects. SN - 1421-9859 UR - https://www.unboundmedicine.com/medline/citation/17762207/Delayed_peripheral_administration_of_a_GPE_analogue_induces_astrogliosis_and_angiogenesis_and_reduces_inflammation_and_brain_injury_following_hypoxia_ischemia_in_the_neonatal_rat_ L2 - https://www.karger.com?DOI=10.1159/000105480 DB - PRIME DP - Unbound Medicine ER -