title: A novel phosphodiesterase type 4 inhibitor, HT-0712, enhances rehabilitation-dependent motor recovery and cortical reorganization after focal cortical ischemia.
abstract: 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.
authors.affiliation: Department of Neuroscience, Canadian Centre for Behavioural Neuroscience, University of Lethbridge, Lethbridge, Alberta, Canada.
authors.forename: Erin
authors.initials: E
authors.lastname: MacDonald
authors.forename: Heidi
authors.initials: H
authors.lastname: Van der Lee
authors.forename: David
authors.initials: D
authors.lastname: Pocock
authors.forename: Christy
authors.initials: C
authors.lastname: Cole
authors.forename: Nagheme
authors.initials: N
authors.lastname: Thomas
authors.forename: Penny M
authors.initials: PM
authors.lastname: VandenBerg
authors.forename: Rusiko
authors.initials: R
authors.lastname: Bourtchouladze
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Kleim
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000188:drug therapy* / Q000503:physiopathology / Q000534:rehabilitation*; D001931:Brain Mapping; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000378:metabolism; D005552:Forelimb / Q000294:innervation; D008297:Male; D009044:Motor Cortex / Q000201:enzymology / Q000502:physiology; D009046:Motor Neurons / Q000201:enzymology; D009473:Neuronal Plasticity / Q000187:drug effects; D058988:Phosphodiesterase 4 Inhibitors; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010881:Piperidones / Q000494:pharmacology*; D051381:Rats; D020318:Rats, Long-Evans; D020127:Recovery of Function / Q000187:drug effects*