Inosine Alters Gene Expression and Axonal Projections in Neurons Contralateral to a Cortical Infarct and Improves Skilled Use of the Impaired Limb
Open accessAbstract
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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Axonal sprouting after stroke shares similarities with the neuronal morphology changes in learning and memory paradigms, optic nerve and spinal cord regeneration and neurodevelopment.
“Axonal sprouting after stroke shares similarities with the neuronal morphology changes in learning and memory paradigms, optic nerve and spinal cord regeneration and neurodevelopment36,37.”
From GDF10 is a signal for axonal sprouting and functional recovery after stroke (2015) · cites this paper as [37]
The Introduction and Discussion (§ Anatomical reorganization; page unavailable) describe axonal reorganization after stroke and say it is consistent with reports following other CNS injuries, including spinal cord injury. Our copy does not make the claimed comparison with morphology changes in learning and memory paradigms, optic nerve regeneration, or neurodevelopment. (LLM, conf=0.82)
Experimental — accuracy not yet measuredPTEN inhibition potentiates axonal sprouting in optic nerve injury and spinal cord injury, through induction of PI3kinase signaling and activation of mTOR.
“PTEN inhibition potentiates axonal sprouting in optic nerve injury and spinal cord injury, through induction of PI3kinase signaling and activation of mTOR.”
From GDF10 is a signal for axonal sprouting and functional recovery after stroke (2015) · cites this paper as [37]
The Introduction and Results discuss inosine-induced axonal sprouting after cortical stroke, while the Discussion’s “Mechanisms of action” section describes inosine activating Mst3b. Searches for PTEN, PI3kinase, and mTOR found no passage addressing whether PTEN inhibition promotes sprouting after optic nerve or spinal cord injury through that pathway. The copy therefore does not verify the attributed claim. (LLM, conf=0.76)
Experimental — accuracy not yet measuredInhibition of SOCS3 further promotes axonal sprouting on top of PTEN inhibition.
“Inhibition of SOCS3 further promotes axonal sprouting on top of PTEN inhibition8,37,38.”
From GDF10 is a signal for axonal sprouting and functional recovery after stroke (2015) · cites this paper as [37]
The Results section reports increased corticospinal axon sprouting after inosine treatment, and the Discussion’s “Mechanisms of action” section describes inosine and Mst3b. Neither passage addresses SOCS3 inhibition, PTEN inhibition, or their combined effect. Searches for SOCS3/PTEN and their expanded names found no passage supporting the attributed claim; page numbers were not available in our copy. (LLM, conf=0.76)
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Cited by
Sorted by citations
An age-related sprouting transcriptome provides molecular control of axonal sprouting after stroke
Li, S., Overman, J. J., Katsman, D., Kozlov, S. V., Donnelly, C. J., Twiss, J. L., Giger, R. J., Coppola, G., Geschwind, D. H., & Carmichael, S. T. (2010) · Nature Neuroscience · doi:10.1038/nn.2674 · Cited by 329 · see citing works
Self-citationGDF10 is a signal for axonal sprouting and functional recovery after stroke
Li, S., Nie, E. H., Yin, Y., Benowitz, L. I., Tung, S., Vinters, H. V., Bahjat, F. R., Stenzel-Poore, M. P., Kawaguchi, R., Coppola, G., et al. (2015) · Nature Neuroscience · doi:10.1038/nn.4146 · Cited by 181 · see citing works
“After stroke, axonal sprouting has been demonstrated in mice, rats and non-human primates 1–4,10,38 .”
Self-citationTranslating the frontiers of brain repair to treatments: Starting not to break the rules
Carmichael, S. T. (2010) · Neurobiology of Disease · doi:10.1016/j.nbd.2009.09.005 · Cited by 35 · see citing works
- Authors
- Zai, L., Ferrari, C., Subbaiah, S., Havton, L. A., Coppola, G., Strittmatter, S., Irwin, N., Geschwind, D., & Benowitz, L. I.
- Affiliations
- Boston Children's Hospital (US)
- Harvard University (US)
- University of California, Los Angeles (US)
- Yale University (US)
- Corresponding author
- Benowitz, L. I.
- Venue
- Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2009-06-24
- Volume
- 29
- Issue
- 25
- Pages
- 8187-8197
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC2856695
- OpenAlex
- W2038995683
- Cited by
- 104
- References
- 3
- Citations by year
- 2026: 1 · 2025: 6 · 2024: 6 · 2023: 4 · 2022: 3 · 2021: 6 · 2020: 7 · 2019: 6 · 2018: 6 · 2017: 6 · 2016: 6 · 2015: 6 · 2014: 7 · 2013: 8 · 2012: 6
- FWCI
- 3.60
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Neuroscience (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Dr. Miriam and Sheldon G. Adelson Medical Research Foundation
- National Institutes of Health (HD018655)
- National Institute of Neurological Disorders and Stroke (R01NS042304, R01NS039962, R01NS047446, R37NS033020, R01NS056485)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (P30HD018655)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nerve injury and regeneration
- Health Sciences › Medicine › Rehabilitation › Stroke Rehabilitation and Recovery
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Keywords
- inosine, stroke recovery, corticospinal tract, axon regeneration, sensorimotor cortex, gene expression, complement system, denervation, synaptic boutons
- MeSH terms
- Animals, Axons, Cerebral Cortex, Complement C3, Disease Models, Animal, Extremities, Gene Expression Regulation, Heat-Shock Proteins, Immunohistochemistry, Injections, Intraventricular, Inosine, Functional Laterality, Neurons, RNA, Messenger, Complement C1q, Treatment Outcome, Rats, Sprague-Dawley, Recovery of Function, Oligonucleotide Array Sequence Analysis, Brain Infarction, Proteasome Endopeptidase Complex, Rats, Ubiquitination
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