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

Laboratories for Neuroscience Research in Neurosurgery and F. M. Kirby Neurobiology Center, Children's Hospital Boston, Boston, Massachusetts 02115, USA.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 07/2009; 29(25):8187-97. DOI: 10.1523/JNEUROSCI.0414-09.2009
Source: PubMed


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.

Download full-text


Available from: Stephen M Strittmatter
    • "Indeed, inosine-treated rats showed a faster recovery in their ability to retrieve food pellets with the paw contralateral to the infarct (Zai et al., 2009). At the anatomical level, this effect was accompanied by an enhanced sprouting of corticospinal tract from the healthy hemisphere into the denervated half of the spinal cord (Zai et al., 2009). Finally, neuromodulatory techniques may be successfully used to boost the therapeutic effects of rehabilitation. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Ischemic injuries within the motor cortex results in functional deficits that may profoundly impact activities of daily living in patients. Current rehabilitation protocols achieve only limited recovery of motor abilities. The brain reorganizes spontaneously after injury, and it is believed that appropriately boosting these neuroplastic processes may restore function via recruitment of spared areas and pathways. Here I review studies on circuit reorganization, neuronal and glial plasticity and axonal sprouting following ischemic damage to the forelimb motor cortex, with a particular focus on rodent models. I discuss evidence pointing to compensatory take-over of lost functions by adjacent peri-lesional areas and the role of the contralesional hemisphere in recovery. One key issue is the need to distinguish "true" recovery (i.e. re-establishment of original movement patterns) from compensation in the assessment of post-stroke functional gains. I also consider the effects of physical rehabilitation, including robot-assisted therapy, and the potential mechanisms by which motor training induces recovery. Finally, I describe experimental approaches in which training is coupled with delivery of plasticising drugs that render the remaining, undamaged pathways more sensitive to experience-dependent modifications. These combinatorial strategies hold promise for the definition of more effective rehabilitation paradigms that can be translated into clinical practice.
    No preview · Article · Oct 2015 · Neuroscience
  • Source
    • "Another compound that has proven effective is inosine, a compound that regulates axon outgrowth through changes in gene expression. Several studies have shown that inosine stimulates the projection of new axons from the undamaged side of the brain to denervated areas of midbrain and spinal cord (Chen et al., 2002; Smith et al., 2007; Zai et al., 2009). "
    [Show abstract] [Hide abstract]
    ABSTRACT: A fundamental property of the brain is its capacity to change with a wide variety of experiences, including injury. Although there are spontaneous reparative changes following injury, these changes are rarely sufficient to support significant functional recovery. Research on the basic principles of brain plasticity is leading to new approaches to treating the injured brain. We review factors that affect synaptic organization in the normal brain, evidence of spontaneous neuroplasticity after injury, and the evidence that factors including postinjury experience, pharmacotherapy, and cell-based therapies, can form the basis of rehabilitation strategies after brain injuries early in life and in adulthood.
    Full-text · Article · Jun 2014 · Frontiers in Human Neuroscience
  • Source
    • "Furthermore, the combinatorial treatment of acutely applied anti-Nogo-A antibody followed by delayed Chondroitinase ABC treatment starting 3 weeks after spinal cord injury, and forelimb grasp training starting at 4 weeks was much more effective in terms of functional recovery, sprouting and axonal regeneration than the single treatments (Rehme et al., 2011). In rats with large cortical strokes, inosine, a substance which was shown to improve fine motor control after stroke (Zai et al., 2009), augmented the effects of the Nogo receptor blocker NEP1-40 in the restoration of skilled reaching abilities in rats. Similar functional improvements were seen when inosine was combined with environmental enrichment (Zai et al., 2011). "
    [Show abstract] [Hide abstract]
    ABSTRACT: After stroke the central nervous system reveals a spectrum of intrinsic capacities to react as a highly dynamic system which can change the properties of its circuits, form new contacts, erase others, and remap related cortical and spinal cord regions. This plasticity can lead to a surprising degree of spontaneous recovery. It includes the activation of neuronal molecular mechanisms of growth and of extrinsic growth promoting factors and guidance signals in the tissue. Rehabilitative training and pharmacological interventions may modify and boost these neuronal processes, but almost nothing is known on the optimal timing of the different processes and therapeutic interventions and on their detailed interactions. Finding optimal rehabilitation paradigms requires an optimal orchestration of the internal processes of re-organization and the therapeutic interventions in accordance with defined plastic time windows. In this review we summarize the mechanisms of spontaneous plasticity after stroke and experimental interventions to enhance growth and plasticity, with an emphasis on anti-Nogo-A immunotherapy. We highlight critical time windows of growth and of rehabilitative training and consider different approaches of combinatorial rehabilitative schedules. Finally, we discuss potential future strategies for designing repair and rehabilitation paradigms by introducing a "3 step model": determination of the metabolic and plastic status of the brain, pharmacological enhancement of its plastic mechanisms, and stabilization of newly formed functional connections by rehabilitative training.
    Full-text · Article · Jun 2014 · Frontiers in Human Neuroscience
Show more