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A Novel Phosphodiesterase Type 4 Inhibitor, HT-0712, Enhances Rehabilitation-Dependent Motor Recovery and Cortical Reorganization After Focal Cortical Ischemia
Erin MacDonald
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
David 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 Thomas
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
Jeffrey 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{at}ufl.edu, 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
References
- Monfils MH, Plautz EJ, Kleim JA In search of the motor engram: motor map plasticity as a mechanism for encoding motor experience. Neuroscientist. 2005;11:471-483.[Abstract/Free Full Text]
- Duncan PW, Jorgensen HS, Wade DT Outcome measures in acute stroke trials: a systematic review and some recommendations to improve practice. Stroke. 2000;31:1429-1438.[Abstract/Free Full Text]
- Gladstone DJ, Danells CJ, Armesto A., et al. Subacute therapy with amphetamine and rehabilitation for stroke study investigators. Physiotherapy coupled with dextroamphetamine for rehabilitation after hemiparetic stroke: a randomized, double-blind, placebo-controlled trial. Stroke. 2006;37:179-185.[Abstract/Free Full Text]
- Nudo RJ, Wise BM, SiFuentes F., et al. Neural substrates for the effects of rehabilitative training on motor recovery after ischemic infarct. Science. 1996;272:1791-1794.[Abstract]
- Butefisch CM Plasticity in the human cerebral cortex: lessons from the normal brain and from stroke. Neuroscientist. 2004; 10:163-173.[Abstract/Free Full Text]
- Conner JM, Chiba AA, Tuszynski MH The basal forebrain cholinergic system is essential for cortical plasticity and functional recovery following brain injury. Neuron. 2005;46:173-179.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Friel KM, Heddings AA, Nudo RJ Effects of postlesion experience on behavioral recovery and neurophysiologic reorganization after cortical injury in primates. Neurorehabil Neural Repair. 2000;14:187-198.[Web of Science][Medline]
[Order article via Infotrieve]
- Kleim JA, Bruneau R., VandenBerg P., et al. Motor cortex stimulation enhances motor recovery and reduces peri-infarct dysfunction following ischemic insult. Neurol Res. 2003; 25:789-793.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Frost SB, Barbay S., Friel KM, et al. Reorganization of remote cortical regions after ischemic brain injury: a potential substrate for stroke recovery. J Neurophysiol. 2003;89:3205-3214.[Abstract/Free Full Text]
- Hess G., Donoghue JP Long-term potentiation of horizontal connections provides a mechanism to reorganize cortical motor maps. J Neurophysiol. 1994;71:2543-2547.[Abstract/Free Full Text]
- Kleim JA, Barbay S., Cooper NR, et al. Motor learning-dependent synaptogenesis is localized to functionally reorganized motor cortex. Neurobiol Learn Mem. 2002;77:63-77.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Kleim JA, Hogg TM, VandenBerg PM, et al. Cortical synaptogenesis and motor map reorganization occur during late, but not early, phase of motor skill learning. J Neurosci. 2004;24:628-633.[Abstract/Free Full Text]
- Monfils MH, VandenBerg PM, Kleim JA, et al. Long-term potentiation induces expanded movement representations and dendritic hypertrophy in layer V of rat sensorimotor neocortex. Cereb Cortex. 2004;14:586-593.[Abstract/Free Full Text]
- Hodgson RA, Ji Z., Standish S., et al. Training-induced and electrically induced potentiation in the neocortex. Neurobiol Learn Mem. 2005;83:22-32.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Teskey GC, Young NA, van Rooyen F., et al. Induction of neocortical long-term depression results in smaller movement representations, fewer excitatory perforated synapses, and more inhibitory synapses. Cereb Cortex. 2007;17:434-442. Epub 2006, Mar 17.[CrossRef][Medline]
[Order article via Infotrieve]
- Dash PK, Hochner B., Kandel ER Injection of the cAMP-responsive element into the nucleus of Aplysia sensory neurons blocks long-term facilitation. Nature. 1990;345:718-721.[CrossRef][Medline]
[Order article via Infotrieve]
- Yin JC, Wallach JS, Del Vecchio M, et al. Induction of a dominant negative CREB transgene specifically blocks long-term memory in Drosophila. Cell. 1994;79:49-58.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Frey U., Huang YY, Kandel ER Effects of cAMP simulate a late stage of LTP in hippocampal CA1 neurons. Science. 1993;260: 1661-1664.[Abstract/Free Full Text]
- Huang YY, Kandel ER D1/D5 receptor agonists induce a protein synthesis-dependent late potentiation in the CA1 region of the hippocampus. Proc Natl Acad Sci USA. 1995;92:2446-2450.[Abstract/Free Full Text]
- Barad M., Bourtchouladze R., Winder DG, et al. Rolipram, a type IV-specific phosphodiesterase inhibitor, facilitates the establishment of long-lasting long-term potentiation and improves memory. Proc Natl Acad Sci USA. 1998;95:15020-15025.[Abstract/Free Full Text]
- Josselyn SA, Kida S., Silva AJ Inducible repression of CREB function disrupts amygdala-dependent memory. Neurobiol Learn Mem. 2004;82:159-163.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Barco A., Alarcon JM, Kandel ER Expression of constitutively active CREB protein facilitates the late phase of long-term potentiation by enhancing synaptic capture. Cell. 2002;108:689-703.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Pittenger C., Huang YY, Paletzki RF, et al. Reversible inhibition of CREB/ATF transcription factors in region CA1 of the dorsal hippocampus disrupts hippocampus-dependent spatial memory. Neuron. 2002;34:447-462.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Vitolo OV, Sant'Angelo A., Costanzo V., et al. Amyloid beta-peptide inhibition of the PKA/CREB pathway and long-term potentiation: reversibility by drugs that enhance cAMP signaling. Proc Natl Acad Sci USA. 2002;99:13217-13221.[Abstract/Free Full Text]
- Bourtchouladze R., Abel T., Berman N., et al. Different training procedures recruit either one or two critical periods for contextual memory consolidation, each of which requires protein synthesis and PKA. Learn Mem. 1998;5:365-374.[Abstract/Free Full Text]
- Schafe GE, LeDoux JE Memory consolidation of auditory Pavlovian fear conditioning requires protein synthesis and protein kinase A in the amygdala. J Neurosci. 2000;20:RC96.[Abstract/Free Full Text]
- Koh MT, Thiele TE, Bernstein IL Inhibition of protein kinase A activity interferes with long-term, but not short-term, memory of conditioned taste aversions. Behav Neurosci. 2002;116:1070-1074.[CrossRef][Medline]
[Order article via Infotrieve]
- Tully T., Bourtchouladze R., Scott R., et al. Targeting the CREB pathway for memory enhancers. Nat Rev Drug Discov. 2003; 2:267-277.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Monti B., Berteotti C., Contestabile A. Subchronic rolipram delivery activates hippocampal CREB and Arc, enhances retention and slows down extinction of conditioned fear. Neuropsychopharmacology. 2006;31:278-286.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Zhang HT, Huang Y., Suvarna NU, et al. Effects of the novel PDE4 inhibitors MEM1018 and MEM1091 on memory in the radial-arm maze and inhibitory avoidance tests in rats. Psychopharmacology (Berl). 2005;179:613-619.[CrossRef][Medline]
[Order article via Infotrieve]
- Bourtchouladze R., Lidge R., Catapano R., et al. A mouse model of Rubinstein-Taybi syndrome: defective long-term memory is ameliorated by inhibitors of phosphodiesterase 4. Proc Natl Acad Sci USA. 2003;100:10518-10522.[Abstract/Free Full Text]
- Gong B., Vitolo OV, Trinchese F., Liu S., Shelanski M., Arancio O. Persistent improvement in synaptic and cognitive functions in an Alzheimer mouse model after rolipram treatment. J Clin Invest. 2004;114:1624-1634.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Liao DS, Mower AF, Neve RL, et al. Different mechanisms for loss and recovery of binocularity in the visual cortex. J Neurosci. 2002;22:9015-9023.[Abstract/Free Full Text]
- Mower AF, Liao DS, Nestler EJ, et al. cAMP/Ca2+ response element-binding protein function is essential for ocular dominance plasticity. J Neurosci. 2002;22:2237-2245.[Abstract/Free Full Text]
- Pham TA, Graham SJ, Suzuki S., et al. A semi-persistent adult ocular dominance plasticity in visual cortex is stabilized by activated CREB. Learn Mem. 2004;11:738-747.[Abstract/Free Full Text]
- Glazewski S., Barth AL, Wallace H., et al. Impaired experience-dependent plasticity in barrel cortex of mice lacking the alpha and delta isoforms of CREB. Cereb Cortex. 1999;9:249-256.[Abstract/Free Full Text]
- Barth AL, McKenna M., Glazewski S., et al. Upregulation of cAMP response element-mediated gene expression during experience-dependent plasticity in adult neocortex. J Neurosci. 2000;20: 4206-4216.[Abstract/Free Full Text]
- Hess G. Synaptic plasticity of local connections in rat motor cortex. Acta Neurobiol Exp (Wars). 2004;64:271-276.[Medline]
[Order article via Infotrieve]
- Ying SW, Futter M., Rosenblum K., et al. Brain-derived neurotrophic factor induces long-term potentiation in intact adult hippocampus: requirement for ERK activation coupled to CREB and upregulation of Arc synthesis. J Neurosci. 2002;22:1532-1540.[Abstract/Free Full Text]
- Kleim JA, Chan S., Pringle E., et al. BDNF va166met polymorphism is associated with modified experience-dependent plasticity in human motor cortex. Nat Neurosci. 2006;9:735-737. Epub 2006, May 7.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Whishaw IQ, Pellis SM The structure of skilled forelimb reaching in the rat: a proximally driven movement with a single distal rotatory component. Behav Brain Res. 1990;41:49-59.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Kleim, JA, Barbay, S., Nudo R.J. Functional reorganization of the rat motor cortex following motor skill learning. J Neurophys. 1998;8:3321-3325.
- Kleim, JA, Cooper NR, VandenBerg, P. Exercise induces angiogenesis but does not alter movement representations within rat motor cortex. Brain Res. 2002;934:1-6.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Remple MS, Bruneau RM, VandenBerg PM, et al. Sensitivity of cortical movement representations to motor experience: evidence that skill learning but not strength training induces functional organization. Behav Brain Res 2001;123:133-141.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Teskey GC, Monfils M., VandenBerg PM, et al. Expansion of movement representations within rat motor cortex following kindling. Cereb Cortex. 2002;12:98-105.[Abstract/Free Full Text]
- Goertzen C., Yamagishi K., VandenBerg PM, Kleim JA Behavioural and functional compensation following ischemic infarct in rat motor cortex is dependent upon the nature of the motor rehabilitation experience. Soc Neurosci Abstr. 2001; 27:761.10.
This version was published on December
1, 2007
Neurorehabilitation and Neural Repair, Vol. 21, No. 6,
486-496 (2007)
DOI: 10.1177/1545968307305521
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