Transforming growth factor-alpha acting at the epidermal growth factor receptor reduces infarct volume after permanent middle cerebral artery occlusion in rats.

Abstract

Transforming growth factor-alpha (TGF-alpha) is a ligand for the epidermal growth factor (EGF) receptor (EGFR), and is more abundant than EGF in the brain. The authors studied whether administration of exogenous TGF-alpha into the brain can protect neurons against ischemia in a model of permanent middle cerebral artery (MCA) occlusion in the rat, and whether any effect of TGF-alpha was mediated by EGFR by administering 4,5-dianilinophthalimide (DAPH), a protein-tyrosine kinase inhibitor with high selectivity for EGFR. Rats received either TGF-alpha (10 or 25 ng), DAPH (100 ng), DAPH plus TGF-alpha (25 ng), or vehicle in the ipsilateral first ventricle. Drugs were administered twice: 30 minutes before and 30 minutes after MCA occlusion, and infarct volume was evaluated 24 hours later. Transforming growth factor-alpha at the dose of 25 ng caused a statistically significant reduction of infarct volume (60%) in relation to ischemic rats administered vehicle. This reduction was no longer seen when TGF-alpha was administered in combination with DAPH. The present results show that TGF-alpha can protect neurons from ischemic damage, and that this effect is mediated by EGFR. It is suggested that activation of EGFR-mediated intracellular signalling pathways contributes to the survival of neural cells susceptible to ischemic injury.

• Authors: C Justicia, A M Planas
• 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. 19 Issue 2 Pg. 128-32 (Feb 1999) ISSN: 0271-678X [Print] United States
• PMID: 10027766 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Drug Combinations
• Enzyme Inhibitors
• Neuroprotective Agents
• Phthalimides
• Transforming Growth Factor alpha
• ErbB Receptors
• 4,5-dianilinophthalimide

Topics

• Animals
• Arterial Occlusive Diseases (complications)
• Brain Edema (pathology)
• Cerebral Arteries
• Cerebral Infarction (etiology, pathology)
• Dose-Response Relationship, Drug
• Drug Combinations
• Enzyme Inhibitors (pharmacology)
• ErbB Receptors (drug effects, physiology)
• Image Processing, Computer-Assisted
• Male
• Neuroprotective Agents (pharmacology)
• Phthalimides (pharmacology)
• Rats
• Rats, Sprague-Dawley
• Transforming Growth Factor alpha (pharmacology)