title: Inosine augments the effects of a Nogo receptor blocker and of environmental enrichment to restore skilled forelimb use after stroke.
abstract: Stroke is the leading cause of disability in much of the world, with few treatment options available. Following unilateral stroke in rats, inosine, a naturally occurring purine nucleoside, stimulates the growth of projections from the undamaged hemisphere into denervated areas of the spinal cord and improves skilled use of the impaired forelimb. Inosine augments neurons' intrinsic growth potential by activating Mst3b, a component of the signal transduction pathway through which trophic factors regulate axon outgrowth. The present study investigated whether inosine would complement the effects of treatments that promote plasticity through other mechanisms. Following unilateral stroke in the rat forelimb motor area, inosine combined with NEP1-40, a Nogo receptor antagonist, doubled the number of axon branches extending from neurons in the intact hemisphere into the denervated side of the spinal cord compared with either treatment alone, and restored rats' level of skilled reaching using the impaired forepaw to preoperative levels. Similar functional improvements were seen when inosine was combined with environmental enrichment (EE). The latter effect was associated with changes in gene expression in layer 5 pyramidal neurons of the undamaged cortex well beyond those seen with inosine or EE alone. Inosine is now in clinical trials for other indications, making it an attractive candidate for the treatment of stroke patients.
authors.affiliation: Laboratories for Neuroscience Research in Neurosurgery, Children's Hospital, Boston, Massachusetts 02115, USA.
authors.forename: Laila
authors.initials: L
authors.lastname: Zai
authors.forename: Christina
authors.initials: C
authors.lastname: Ferrari
authors.forename: Carlie
authors.initials: C
authors.lastname: Dice
authors.forename: Sathish
authors.initials: S
authors.lastname: Subbaiah
authors.forename: Leif A
authors.initials: LA
authors.lastname: Havton
authors.forename: Giovanni
authors.initials: G
authors.lastname: Coppola
authors.forename: Daniel
authors.initials: D
authors.lastname: Geschwind
authors.forename: Nina
authors.initials: N
authors.lastname: Irwin
authors.forename: Eric
authors.initials: E
authors.lastname: Huebner
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Strittmatter
authors.forename: Larry I
authors.initials: LI
authors.lastname: Benowitz
mesh_terms: D000818:Animals; D001369:Axons / Q000187:drug effects / Q000502:physiology; D004777:Environment; D005552:Forelimb / Q000187:drug effects* / Q000503:physiopathology; D007288:Inosine / Q000494:pharmacology / Q000627:therapeutic use*; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D009068:Movement / Q000187:drug effects / Q000502:physiology; D009185:Myelin Proteins / Q000494:pharmacology / Q000627:therapeutic use*; D009473:Neuronal Plasticity / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D010446:Peptide Fragments / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D020127:Recovery of Function / Q000187:drug effects* / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013116:Spinal Cord / Q000187:drug effects / Q000503:physiopathology; D020521:Stroke / Q000188:drug therapy* / Q000503:physiopathology
chemical_list: D009185:Myelin Proteins; C457761:NEPI-40 protein, rat; D010446:Peptide Fragments; D007288:Inosine