Abstract
BackgroundRhoA and Rho kinase inhibitors overcome the inhibition of axonal regeneration posed by central nervous system (CNS) substrates.MethodsTo investigate if inhibition of the Rho pathway augments the neurite extension that naturally occurs in the peripheral nervous system (PNS) following nerve damage, dorsal root ganglion neurons and Schwann cell co-cultures were incubated with culture medium, C3 fusion toxin, and the Rho kinase (ROCK) inhibitors Y27632 and H1152. The longest neurite per neuron were measured and compared. Incubation with Y27632 and H1152 resulted in significantly longer neurites than controls when the neurons were in contact with Schwann cells. When separated by a porous P.E.T. membrane, only the group incubated with H1152 developed significantly longer neurites. This work demonstrates that Rho kinase inhibition augments neurite elongation in the presence of contact with a PNS-like substrate.
Highlights
RhoA and Rho kinase inhibitors overcome the inhibition of axonal regeneration posed by central nervous system (CNS) substrates
The CNS inhibitory substrates such as NOGO mediate their effect by binding to the p75 nerve growth factor (p75NTR) this binding causes the activation of RhoA and the inhibition of axonal regeneration [12,7]
C3 fusion toxin and the Rho kinase inhibitors Y27632 and H1152 increase neurite length in neuron-enriched cultures Dissociated DRG neuron cultures incubated overnight with 10 ng/ml of nerve growth factor (NGF) followed by an 8 h incubation with C3 fusion toxin and the ROCK inhibitors Y27632 and H1152 showed an increase in the average length of their longest neurites when compared to the control group
Summary
RhoA and Rho kinase inhibitors overcome the inhibition of axonal regeneration posed by central nervous system (CNS) substrates. The CNS is an environment normally hostile to nerve regeneration due to the presence of axonal inhibitory substrates like chondroitin sulphate proteoglycans (CSPGs) – present in both the glial scar and in myelin – NOGO and myelin associated glycopeptide (MAG) [1]. These substances inhibit axonal regeneration by activating on RhoA, a member of the Rho GTPase family. The CNS inhibitory substrates such as NOGO mediate their effect by binding to the p75NTR this binding causes the activation of RhoA and the inhibition of axonal regeneration [12,7]
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