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The Journal of Neuroscience, June 24, 2009, 29(25):8187-8197; doi:10.1523/JNEUROSCI.0414-09.2009

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Development/Plasticity/Repair
Inosine Alters Gene Expression and Axonal Projections in Neurons Contralateral to a Cortical Infarct and Improves Skilled Use of the Impaired Limb

Laila Zai,^1,2 Christina Ferrari,¹ Sathish Subbaiah,^1,4 Leif A. Havton,⁵ Giovanni Coppola,⁵ Stephen Strittmatter,⁶ Nina Irwin,^1,2,4 Daniel Geschwind,⁵ and Larry I. Benowitz^1,2,3,4

¹Laboratories for Neuroscience Research in Neurosurgery and ²F. M. Kirby Neurobiology Center, Children's Hospital Boston, and ³Program in Neuroscience and ⁴Department of Surgery, Harvard Medical School, Boston, Massachusetts 02115, ⁵Program in Neurogenetics, Department of Neurology, University of California, Los Angeles, Los Angeles, California 90095, and ⁶Department of Neurology, Yale University School of Medicine, New Haven, Connecticut 06510

Correspondence should be addressed to Dr. Larry Benowitz, Laboratories for Neuroscience Research in Neurosurgery, Children's Hospital Boston, 300 Longwood Avenue, Boston, MA 02115. Email: larry.benowitz{at}childrens.harvard.edu

Recovery after stroke and other types of brain injury is restricted in part by the limited ability of undamaged neurons to form compensatory connections. Inosine, a naturally occurring purine nucleoside, stimulates neurons to extend axons in culture and, in vivo, enhances the ability of undamaged neurons to form axon collaterals after brain damage. The molecular changes induced by inosine are unknown, as is the ability of inosine to restore complex functions associated with a specific cortical area. Using a unilateral injury model limited to the sensorimotor cortex, we show that inosine triples the number of corticospinal tract axons that project from the unaffected hemisphere and form synaptic bouton-like structures in the denervated half of the spinal cord. These changes correlate with improved recovery in animals' ability to grasp and consume food pellets with the affected forepaw. Studies using laser-capture microdissection and microarray analysis show that inosine profoundly affects gene expression in corticospinal neurons contralateral to the injury. Inosine attenuates transcriptional changes caused by the stroke, while upregulating the expression of genes associated with axon growth and the complement cascade. Thus, inosine alters gene expression in neurons contralateral to a stroke, enhances the ability of these neurons to form connections on the denervated side of the spinal cord, and improves performance with the impaired limb.

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Received Jan. 26, 2009; revised March 29, 2009; accepted May 18, 2009.

Correspondence should be addressed to Dr. Larry Benowitz, Laboratories for Neuroscience Research in Neurosurgery, Children's Hospital Boston, 300 Longwood Avenue, Boston, MA 02115. Email: larry.benowitz{at}childrens.harvard.edu

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