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ROCK inhibition with Y27632 activates astrocytes and increases their expression of neurite growth‐inhibitory chondroitin sulfate proteoglycans
Author(s) -
Chan Carmen C. M.,
Wong Angel K.,
Liu Jie,
Steeves John D.,
Tetzlaff Wolfram
Publication year - 2007
Publication title -
glia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.954
H-Index - 164
eISSN - 1098-1136
pISSN - 0894-1491
DOI - 10.1002/glia.20466
Subject(s) - chondroitin sulfate proteoglycan , neurite , glial scar , microbiology and biotechnology , rho associated protein kinase , chondroitin sulfate , inhibitory postsynaptic potential , biology , chemistry , neuroscience , extracellular matrix , astrocyte , anatomy , biochemistry , proteoglycan , signal transduction , central nervous system , glycosaminoglycan , in vitro
Inhibition of Rho‐kinase (ROCK) with Y27632 stimulates sprouting by injured corticospinal tract and dorsal column tract axons, and accelerates functional recovery. However, regeneration of these axons across the glial scar was not observed. Here we examined the effects of Y27632 treatment on chondroitin sulfate proteoglycan (CSPG) expression by astrocytes, which are a key component of the reactive gliosis inhibiting axonal regeneration. In vivo, rats underwent a dorsal column transection and were treated with Y27632 via intrathecal pump infusion. Compared with controls, Y27632‐treated injury sites displayed exaggerated upregulation of glial fibrillary acid protein and neurocan immunoreactivity along the lesion edge. In vitro, astrocytes assumed a reactive morphology (stellate shape) and increased their expression of CSPGs after Y27632 treatment. Neurite growth by dissociated cortical neurons decreased when cultured on the extracellular matrix (ECM) derived from Y27632‐treated astrocytes. This decrease in neurite growth was reversed with chondroitinase‐ABC (ChABC) digestion, indicating that the inhibition was due to CSPG depositions within the ECM. Interestingly, conditioned medium (CM) from untreated astrocytes was inhibitory to neurite growth, which was overcome by ChABC digestion. Such inhibitory activity was not found in the CM of Y27632‐treated astrocytes. Taken together, these data support a model where ROCK inhibition by Y27632 modifies astrocytic processing of CSPGs, and increases the presence of CSPGs within the ECM while reduces CSPGs in the CM (cerebrospinal fluid in vivo). This increased expression of inhibitory CSPGs in the ECM of the glial scar may counteract the growth promoting effects of ROCK inhibition on axonal growth cones. © 2006 Wiley‐Liss, Inc.