Neuroprotective effects of insulin-like growth factor-binding protein ligand inhibitors in vitro and in vivo.

Abstract

The role of brain insulin-like growth factors (IGFs) and IGF binding proteins (IGFBPs) in neuroprotection was further investigated using in vitro and in vivo models of cerebral ischemia by assessing the effects of IGF-I, IGF-II, and high affinity IGFBP ligand inhibitors (the peptide [Leu24, 59, 60, Ala31]hIGF-I (IGFBP-LI) and the small molecule NBI-31772 (1-(3,4-dihydroxybenzoyl)-3-hydroxycarbonyl-6, 7-dihydroxyisoquinoline), which pharmacologically displace and elevate endogenous, bioactive IGFs from IGFBPs. Treatment with IGF-I, IGF-II, or IGFBP-LI (2 microg/mL) significantly (P < 0.05) reduced CA1 damage in organotypic hippocampal cultures resulting from 35 minutes of oxygen and glucose deprivation by 71%, 60%, and 40%, respectively. In the subtemporal middle cerebral artery occlusion (MCAO) model of focal ischemia, intracerebroventricular (icv) administration of IGF-I and IGF-II at the time of artery occlusion reduced ischemic brain damage in a dose-dependent manner, with maximum reductions in total infarct size of 37% (P < 0.01) and 38% (P < 0.01), respectively. In this model of MCAO, i.c.v. administration of NBI-31772 at the time of ischemia onset also dose-dependently reduced infarct size, and the highest dose (100 microg) significantly reduced both total (by 40%, P < 0.01) and cortical (by 43%, P < 0.05) infarct volume. In the intraluminal suture MCAO model, administration of NBI-31772 (50 microg i.c.v.) at the time of artery occlusion reduced both cortical infarct volume (by 40%, P < 0.01) and brain swelling (by 24%, P < 0.05), and it was still effective when treatment was delayed up to 3 hours after the induction of ischemia. These results further define the neuroprotective properties of IGFs and IGFBP ligand inhibitors in experimental models of cerebral ischemia.

• Authors: Kenneth B Mackay, Sarah A Loddick, Gregory S Naeve, Alicia M Vana, Gail M Verge, Alan C Foster
• Journal: Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism (J Cereb Blood Flow Metab) Vol. 23 Issue 10 Pg. 1160-7 (Oct 2003) ISSN: 0271-678X [Print] United States
• PMID: 14526226 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Catechols
• Insulin-Like Growth Factor Binding Proteins
• Isoquinolines
• NBI 31772
• Neuroprotective Agents
• Insulin-Like Growth Factor I
• Insulin-Like Growth Factor II

Topics

• Animals
• Brain Ischemia (drug therapy, metabolism)
• Catechols (metabolism, pharmacology)
• Hippocampus (cytology, metabolism)
• Infarction, Middle Cerebral Artery (drug therapy, metabolism)
• Insulin-Like Growth Factor Binding Proteins (metabolism)
• Insulin-Like Growth Factor I (metabolism, pharmacology)
• Insulin-Like Growth Factor II (metabolism, pharmacology)
• Isoquinolines (metabolism, pharmacology)
• Neuroprotective Agents (metabolism, pharmacology)
• Organ Culture Techniques
• Rats
• Rats, Sprague-Dawley