TITLE:
A Cell-Penetrating Peptide for Inhibiting MAPKAP Kinase 2-Mediated Inflammatory Cytokine Release Following Glial Cell Activation
AUTHORS:
James R. Wodicka, Nnadozie I. Onunkwo, Andrew J. Woolley, Alyssa Panitch, Kevin J. Otto
KEYWORDS:
Injury, Mitigation, Treatment, Drug, MK2i
JOURNAL NAME:
World Journal of Neuroscience,
Vol.5 No.2,
May
25,
2015
ABSTRACT: Central nervous system
(CNS) injury initializes a reactive tissue response, which is characterized by
a cascade of signals that result in inflammatory cytokine release and
neuroinflammation. These signals are induced in part by activated microglia
that migrates to the injury site in an attempt to remove dead tissue and
promote healing. The ability to control the reactive tissue response is of
significant importance to a variety of applications, such as neuroprostheses,
whose functional lifespan is limited by glial cell activation. A possible
strategy to mitigate glial cell activation is to reduce the release of inflammatory
cytokines following a brain injury. One pathway that facilitates inflammatory
cytokine release is the mitogen-activated protein kinase-activated protein
kinase 2 (MK2) pathway, which increases cytokine mRNA synthesis, stability and
translation following activation. Therefore, inhibiting MK2-mediated cytokine
release can reduce microglial activationfollowing CNS injury. Throughin vitrostudies, we demonstrate the ability of
a cell-penetrating peptide inhibitor of MK2 (MK2i) to reduce MK2-mediated cytokine
release in mixed cortical cultures.Immunocytochemistry,
enzyme-linked immunosorbent assay (ELISA), and cytotoxicity assays in 7- -10-day-old
E17 Sprague-Dawley rat mixed cortical cultures showed that MK2i treatment
significantly lowered inflammatory cytokine production and increased cortical
cell viability followingglial
cell activation with tumor necrosis factor-α(TNF-α) and
lipopolysaccharide (LPS). Results suggest that MK2i may reduce damage caused by
activated glia in the inflamed CNS.