Altered biosynthesis of neuropeptide processing enzyme carboxypeptidase E after brain ischemia: molecular mechanism and implication.

Abstract

In this study, using both in vivo and in vitro ischemia models, the authors investigated the impact of brain ischemia on the biosynthesis of a key neuropeptide-processing enzyme, carboxypeptidase E (CPE). The response to brain ischemia of animals that lacked an active CPE was also examined. Combined in situ hybridization and immunocytochemical analyses for CPE showed reciprocal changes of CPE mRNA and protein, respectively, in the same cortical cells in rat brains after focal cerebral ischemia. Western blot analysis revealed an accumulation of the precursor protein of CPE in the ischemic cortex in vivo and in ischemic cortical neurons in vitro. Detailed metabolic labeling experiments on ischemic cortical neurons showed that ischemic stress caused a blockade in the proteolytic processing of CPE. When mice lacking an active CPE protease were subjected to a sublethal episode of focal cerebral ischemia, abundant TUNEL-positive cells were seen in the ischemic cortex whereas only a few were seen in the cortex of wild-type animals. These findings suggest that ischemia has an adverse impact on the neuropeptide-processing system in the brain and that the lack of an active neuropeptide-processing enzyme exacerbates ischemic brain injury.

• Authors: An Zhou, Manabu Minami, Xiaoman Zhu, Sylvia Bae, John Minthorne, Jingquan Lan, Zhi-Gang Xiong, Roger P Simon
• 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. 24 Issue 6 Pg. 612-22 (Jun 2004) ISSN: 0271-678X [Print] United States
• PMID: 15181368 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Neuropeptides
• Protein Precursors
• Carboxypeptidase H

Topics

• Animals
• Astrocytes (cytology, metabolism)
• Brain (cytology, metabolism, pathology)
• Brain Ischemia (metabolism, pathology, physiopathology)
• Carboxypeptidase H (biosynthesis, genetics)
• Cells, Cultured
• In Situ Hybridization
• In Situ Nick-End Labeling
• Male
• Mice
• Mice, Knockout
• Neurons (cytology, metabolism)
• Neuropeptides (metabolism)
• Protein Precursors (metabolism)
• Rats
• Rats, Sprague-Dawley