Activation of NF-kB and ERK1/2 after permanent focal ischemia is abolished by simvastatin treatment.

Abstract

We investigated the effects of simvastatin treatment on the expression of IL-1beta and MCP-1, the activity of NF-kB, and the signaling pathways related to NF-kB activation in a rat model of permanent middle cerebral artery occlusion (pMCAO). IL-1beta and MCP-1 expression, determined using RT-PCR, was enhanced by pMCAO; this effect was inhibited by the administration of simvastatin before ischemia. Pre-treatment with simvastatin abolished the ischemia-induced activation of NF-kB observed in vehicle-treated animals. The evaluation of signal transduction pathways, including extracellular signal-regulated kinase (ERK1/2), SAPK/JNK 46/54 and p38, indicated that only ERK1/2 phosphorylation was enhanced by ischemia, and this activation was prevented by simvastatin. ERK1/2-inhibitor, U0126, reduced brain ischemia but not cytokine induction. These results provide evidence that the HMG-CoA reductase inhibitor induces its effect in the protection of ischemic brain damage with a more complex mechanism which also involve anti-inflammatory properties rather than simple inhibition of ERK1/2 signaling pathway.

• Authors: Luigi Sironi, Cristina Banfi, Maura Brioschi, Paolo Gelosa, Uliano Guerrini, Elena Nobili, Anita Gianella, Rodolfo Paoletti, Elena Tremoli, Mauro Cimino
• Journal: Neurobiology of disease (Neurobiol Dis) Vol. 22 Issue 2 Pg. 445-51 (May 2006) ISSN: 0969-9961 [Print] United States
• PMID: 16480888 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Ccl2 protein, rat
• Chemokine CCL2
• Enzyme Inhibitors
• Hydroxymethylglutaryl-CoA Reductase Inhibitors
• Interleukin-1
• NF-kappa B
• Simvastatin
• Mitogen-Activated Protein Kinase 3

Topics

• Animals
• Brain (drug effects, metabolism, physiopathology)
• Brain Ischemia (drug therapy, metabolism, physiopathology)
• Chemokine CCL2 (drug effects, metabolism)
• Disease Models, Animal
• Down-Regulation (drug effects, physiology)
• Encephalitis (drug therapy, physiopathology, prevention & control)
• Enzyme Activation (drug effects, physiology)
• Enzyme Inhibitors (pharmacology)
• Hydroxymethylglutaryl-CoA Reductase Inhibitors (pharmacology, therapeutic use)
• Infarction, Middle Cerebral Artery (drug therapy, metabolism, physiopathology)
• Interleukin-1 (metabolism)
• MAP Kinase Signaling System (drug effects, physiology)
• Male
• Mitogen-Activated Protein Kinase 3 (drug effects, metabolism)
• NF-kappa B (drug effects, metabolism)
• Rats
• Rats, Sprague-Dawley
• Simvastatin (pharmacology, therapeutic use)
• Up-Regulation (drug effects, physiology)