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

• 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.

Nyckelord

Animals

Animals

Newborn

Apoptosis

drug effects

physiology

Astrocytes

drug effects

physiology

Birth Injuries

drug therapy

pathology

physiopathology

Brain

blood supply

drug effects

physiopathology

Caspase 3

drug effects

metabolism

Cerebral Arteries

drug effects

growth & development

Disease Models

Animal

Drug Administration Schedule

Encephalitis

drug therapy

pathology

physiopathology

Gliosis

drug therapy

pathology

physiopathology

Hypoxia-Ischemia

Brain

drug therapy

pathology

physiopathology

Interleukins

metabolism

Neovascularization

Physiologic

drug effects

physiology

Nerve Degeneration

drug therapy

pathology

physiopathology

Neuroprotective Agents

pharmacology

therapeutic use

Oligopeptides

pharmacology

therapeutic use

Rats

Rats

Wistar

Time Factors

Treatment Outcome

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