Extracellular signal-regulated kinase 1/2 plays a pro-life role in experimental brain stem death via MAPK signal-interacting kinase at rostral ventrolateral medulla.

Abstract

BACKGROUND:

As the origin of a life-and-death signal detected from systemic arterial pressure, which sequentially increases (pro-life) and decreases (pro-death) to reflect progressive dysfunction of central cardiovascular regulation during the advancement towards brain stem death in critically ill patients, the rostral ventrolateral medulla (RVLM) is a suitable neural substrate for mechanistic delineation of this fatal phenomenon. The present study assessed the hypothesis that extracellular signal-regulated kinase 1/2 (ERK1/2), a member of the mitogen-activated protein kinases (MAPKs) that is important for cell survival and is activated specifically by MAPK kinase 1/2 (MEK1/2), plays a pro-life role in RVLM during brain stem death. We further delineated the participation of MAPK signal-interacting kinase (MNK), a novel substrate of ERK in this process.

METHODS:

An experimental model of brain stem death that employed microinjection of the organophosphate insecticide mevinphos (Mev; 10 nmol) bilaterally into RVLM of Sprague-Dawley rats was used, in conjunction with cardiovascular, pharmacological and biochemical evaluations.

RESULTS:

Results from ELISA showed that whereas the total ERK1/2 was not affected, augmented phosphorylation of ERK1/2 at Thr202 and Tyr204 in RVLM occurred preferentially during the pro-life phase of experimental brain stem death. Furthermore, pretreatment by microinjection into the bilateral RVLM of a specific ERK2 inhibitor, ERK activation inhibitor peptide II (1 nmol); a specific MEK1/2 inhibitor, U0126 (5 pmol); or a specific MNK1/2 inhibitor, CGP57380 (5 pmol) exacerbated the hypotension and blunted the augmented life-and-death signals exhibited during the pro-life phase. Those pretreatments also blocked the upregulated nitric oxide synthase I (NOS I)/protein kinase G (PKG) signaling, the pro-life cascade that sustains central cardiovascular regulatory functions during experimental brain stem death.

CONCLUSIONS:

Our results demonstrated that activation of MEK1/2, ERK1/2 and MNK1/2 in RVLM plays a preferential pro-life role by sustaining the central cardiovascular regulatory machinery during brain stem death via upregulation of NOS I/PKG signaling cascade in RVLM.

• Authors: Samuel H H Chan, Enya Y H Sun, Alice Y W Chang
• Journal: Journal of biomedical science (J Biomed Sci) Vol. 17 Pg. 17 (Mar 15 2010) ISSN: 1423-0127 [Electronic] England
• PMID: 20226096 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Nitric Oxide Synthase Type I
• Protein Serine-Threonine Kinases
• Mitogen-Activated Protein Kinase 1
• Mitogen-Activated Protein Kinase 3
• Mitogen-Activated Protein Kinase Kinases

Topics

• Animals
• Cell Death
• MAP Kinase Signaling System
• Medulla Oblongata (enzymology, metabolism)
• Mitogen-Activated Protein Kinase 1 (metabolism)
• Mitogen-Activated Protein Kinase 3 (metabolism)
• Mitogen-Activated Protein Kinase Kinases (metabolism)
• Nitric Oxide Synthase Type I (metabolism)
• Protein Serine-Threonine Kinases (metabolism)
• Rats
• Rats, Sprague-Dawley