rolipram or the novel PDE4 inhibitor HT-0712

[Guest guest]

This version was published on December 1, 2007

Neurorehabilitation and Neural Repair, Vol. 21, No. 6, 486-496 (2007)

DOI: 10.1177/1545968307305521

© 2007 American Society of Neurorehabilitation

A Novel Phosphodiesterase Type 4 Inhibitor, HT-0712, Enhances

Rehabilitation-Dependent Motor Recovery and Cortical Reorganization

After Focal Cortical Ischemia

Mac

Department of Neuroscience, Canadian Centre for Behavioural

Neuroscience, University of Lethbridge, Lethbridge, Alberta, Canada

Heidi Van der Lee

Department of Neuroscience, Canadian Centre for Behavioural

Neuroscience, University of Lethbridge, Lethbridge, Alberta, Canada

Pocock

Department of Neuroscience, Canadian Centre for Behavioural

Neuroscience, University of Lethbridge, Lethbridge, Alberta, Canada

Christy Cole

Department of Neuroscience, Canadian Centre for Behavioural

Neuroscience, University of Lethbridge, Lethbridge, Alberta, Canada

Nagheme

Department of Neuroscience, Canadian Centre for Behavioural

Neuroscience, University of Lethbridge, Lethbridge, Alberta, Canada,

Department of Neuroscience, University of Florida, Gainsville, Florida

Penny M. VandenBerg, MSc

Department of Neuroscience, Canadian Centre for Behavioural

Neuroscience, University of Lethbridge, Lethbridge, Alberta, Canada

Rusiko Bourtchouladze, PhD

Helicon Therapeutics, Woodbury, New York

A. Kleim, PhD

Department of Neuroscience, Canadian Centre for Behavioural

Neuroscience, University of Lethbridge, Lethbridge, Alberta, Canada,

Department of Neuroscience, University of Florida, Gainsville,

Florida, jkleim@..., Brain Rehabilitation Research Center, Malcom

Randall VA Hospital, Gainesville, Florida

Rehabilitation-dependent motor recovery after cerebral ischemia is

associated with functional reorganization of residual cortical tissue.

Recovery is thought to occur when remaining circuitry surrounding the

lesion is " retrained " to assume some of the lost function. This

reorganization is in turn supported by synaptic plasticity within

cortical circuitry and manipulations that promote plasticity may

enhance recovery. Activation of the cAMP/CREB pathway is a key step

for experience-dependent neural plasticity. Here we examined the

effects of the prototypical phosphodiesterase inhibitor 4 (PDE4)

rolipram and a novel PDE inhibitor (HT-0712), known to enhance

cAMP/CREB signaling and cognitive function, on restoration of motor

skill and cortical function after focal cerebral ischemia. Adult male

rats were trained on a skilled reaching task to establish a baseline

level of motor performance. Intracortical microstimulation was then

used to derive high-resolution maps of forelimb movement

representations within the caudal forelimb area of motor cortex

contralateral to the trained paw. A focal ischemic infarct was created

within approximately 30% of the caudal forelimb area. The effects of

administering either rolipram or the novel PDE4 inhibitor HT-0712

during rehabilitation on motor recovery and restoration of movement

representations within residual motor cortex were examined. Both

compounds significantly enhanced motor recovery and induced an

expansion of distal movement representations that extended beyond

residual motor cortex. The expansion beyond the initial residual

cortex was not observed in vehicle injected controls. Furthermore, the

motor recovery seen in the HT-0712 animals was dose dependent. Our

results suggest that PDE4 inhibitors during motor rehabilitation

facilitate behavioral recovery and cortical reorganization after

ischemic insult to levels significantly greater than that observed

with rehabilitation alone.

Key Words: Phosphodiesterase type 4 inhibitor • Motor recovery •

Rehabilitation • Cerebral ischemia • Cortical plasticity