Delayed Gelatinase Inhibition Induces Reticulon 4 Receptor Expression in the Peri-Infarct Cortex.

Abstract

Matrix metalloproteinase (MMP) inhibition can potentially prevent hemorrhagic transformation following cerebral infarction; however, delayed-phase MMP activity is also necessary for functional recovery after experimental stroke. We sought to identify potential mechanisms responsible for the impaired recovery associated with subacute MMP inhibition in a transient middle cerebral artery occlusion model of focal ischemia in CD rats. Gelatinase inhibition was achieved by intracerebral injection of the Fn-439 MMP inhibitor 7 days after stroke. Treatment efficacy was determined on day 9 by in situ gelatin zymography. The peri-infarct cortex was identified by triphenyl tetrazolium chloride staining, and tissue samples were dissected for TaqMan array gene-expression study. Of 84 genes known to influence poststroke regeneration, we found upregulation of mRNA for the reticulon 4 receptor (Rtn4r), a major inhibitor of regenerative nerve growth in the adult CNS, and borderline expression changes for 3 additional genes (DCC, Jun, and Ngfr). Western blot confirmed increased Rtn4r protein in the peri-infarct cortex of treated animals, and double immunolabeling showed colocalization primarily with the S100 astrocyte marker. These data suggest that increased Rtn4 receptor expression in the perilesional cortex may contribute to the impaired regeneration associated with MMP inhibition in the subacute phase of cerebral infarction.

• Authors: Sándor Nardai, Arpád Dobolyi, Judit Skopál, Kinga Lakatos, Béla Merkely, Zoltán Nagy
• Journal: Journal of neuropathology and experimental neurology (J Neuropathol Exp Neurol) Vol. 75 Issue 4 Pg. 379-85 (Apr 2016) ISSN: 1554-6578 [Electronic] England
• PMID: 26945033 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2016 American Association of Neuropathologists, Inc. All rights reserved.

Chemical References

• 4-aminobenzoyl-glycyl-prolyl-leucyl-alanine hydroxamic acid
• Enzyme Inhibitors
• GPI-Linked Proteins
• Hydroxamic Acids
• Myelin Proteins
• Nerve Tissue Proteins
• Nogo Receptor 1
• Oligopeptides
• RNA, Messenger
• Receptors, Cell Surface
• Rtn4r protein, rat
• Gelatinases
• Matrix Metalloproteinases

Topics

• Animals
• Brain Infarction (metabolism, pathology)
• Cerebral Cortex (drug effects, metabolism)
• Disease Models, Animal
• Enzyme Inhibitors (pharmacology)
• GPI-Linked Proteins (genetics, metabolism)
• Gelatinases (metabolism)
• Gene Expression Regulation (drug effects, physiology)
• Hydroxamic Acids (pharmacology)
• Infarction, Middle Cerebral Artery (complications)
• Laser-Doppler Flowmetry
• Matrix Metalloproteinases (genetics, metabolism)
• Myelin Proteins (genetics, metabolism)
• Nerve Tissue Proteins (genetics, metabolism)
• Nogo Receptor 1
• Oligopeptides (pharmacology)
• RNA, Messenger (metabolism)
• Rats
• Receptors, Cell Surface (genetics, metabolism)