Biology Reference
In-Depth Information
CHAPTER SIX
Rho Signaling and Axon
Regeneration
L. McKerracher
*
,
†
,1
, Gino B. Ferraro
†
, Alyson E. Fournier
†
*BioAxone BioSciences Inc., Fort Lauderdale, Florida, USA
†
Department of Neurology and Neurosurgery, Montreal Neurological Institute, BT-105, McGill University,
Montreal, Quebec, Canada
1
Corresponding author: e-mail address: lmck@bioaxonebio.com
Contents
1. The Growth Inhibitory Proteins in the CNS Signal to Rho
118
1.1 Rho is a key to regeneration
118
1.2 Growth inhibition in the CNS
119
1.3 ROCK and Rho
123
1.4 ROCK and Rho inhibitors
124
1.5 Neurotrauma and Rho activation
125
2. Axon Regeneration and Functional Recovery in Preclinical Studies
126
2.1 Long-distance axon regeneration
126
2.2 Inactivation of Rho and neuroprotection
128
2.3 Inactivation of Rho and functional recovery after SCI
128
2.4 NSAIDs signal to Rho
131
3. Clinical Study with Cethrin
132
4. Summary
133
Disclosures and Acknowledgments
134
References
134
Abstract
Several major advances in our understanding of axon regeneration and functional repair
in the central nervous system (CNS) together with new insights about molecular signal-
ing pathways have led to development of viable drug candidates to treat spinal cord
injury. In this review, we focus on Rho, an intracellular small GTPase that is part of a family
of highly related proteins that are present in all cells as important signaling switches.
Multiple lines of evidence have validated the Rho pathway as important in controlling
axon growth and regeneration after neurotrauma in the CNS. The first part of this review
will provide the evidence that Rho is a convergent point of signaling important for axon
regeneration in the growth inhibitory environment of the adult CNS. The second part of
the review will focus on efforts to target Rho to promote regeneration in vivo. The final
section of the review will summarize clinical results with Cethrin, a Rho inhibitor that has
completed phase I/IIa clinical testing.
