Inosine alters gene expression and axonal projections in neurons contralateral to a cortical infarct and improves skilled use of the impaired limb.
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.
Zai
Laila
L
Laboratories for Neuroscience Research in Neurosurgery and F. M. Kirby Neurobiology Center, Children's Hospital Boston, Boston, Massachusetts 02115, USA.
Ferrari
Christina
C
Subbaiah
Sathish
S
Havton
Leif A
LA
Coppola
Giovanni
G
Strittmatter
Stephen
S
Irwin
Nina
N
Geschwind
Daniel
D
Benowitz
Larry I
LI
D000818:Animals; D001369:Axons / Q000187:drug effects*; D020520:Brain Infarction / Q000150:complications / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology*; D015922:Complement C1q / Q000235:genetics / Q000378:metabolism; D003176:Complement C3 / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005121:Extremities / Q000503:physiopathology*; D007839:Functional Laterality / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects*; D006360:Heat-Shock Proteins / Q000235:genetics; D007150:Immunohistochemistry; D007276:Injections, Intraventricular; D007288:Inosine / Q000008:administration & dosage / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D046988:Proteasome Endopeptidase Complex / Q000235:genetics; D012333:RNA, Messenger; D051381:Rats; D017207:Rats, Sprague-Dawley; D020127:Recovery of Function / Q000187:drug effects; D016896:Treatment Outcome; D054875:Ubiquitination / Q000235:genetics
D003176:Complement C3; D006360:Heat-Shock Proteins; D012333:RNA, Messenger; D007288:Inosine; D015922:Complement C1q; C088875:PSMB6 protein, human; D046988:Proteasome Endopeptidase Complex