QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

HOME  |   SEARCH  |   ARCHIVE  |   SUBSCRIBE  |   CONTACT  |   HELP

The Journal of Neuroscience, July 16, 2008, 28(29):7293-7303; doi:10.1523/JNEUROSCI.1826-08.2008

This Article Full Text Full Text (PDF) Submit an eLetter Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Nakashima, S. Articles by Hagg, T. Search for Related Content PubMed PubMed Citation Articles by Nakashima, S. Articles by Hagg, T.

 Previous Article  |  Next Article 

Development/Plasticity/Repair
Small-Molecule Protein Tyrosine Phosphatase Inhibition as a Neuroprotective Treatment after Spinal Cord Injury in Adult Rats

Shojiro Nakashima,^1,4 Sheila A. Arnold,^2,4 Edward T. Mahoney,^1,4 Srinivas D. Sithu,^3,4 Y. Ping Zhang,^1,4 Stanley E. D'Souza,^3,4 Christopher B. Shields,^1,4 and Theo Hagg^1,2,4

Departments of ¹Neurological Surgery, ²Pharmacology and Toxicology, and ³Physiology and Biophysics, and ⁴Kentucky Spinal Cord Injury Research Center, University of Louisville, Louisville, Kentucky 40292

Correspondence should be addressed to Theo Hagg, Kentucky Spinal Cord Injury Research Center, 511 South Floyd Street, MDR Building Room 616, University of Louisville, Louisville, KY 40292. Email: theo.hagg{at}louisville.edu

Spinal cord injury causes progressive secondary tissue degeneration, leaving many injured people with neurological disabilities. There are no satisfactory neuroprotective treatments. Protein tyrosine phosphatases inactivate neurotrophic factor receptors and downstream intracellular signaling molecules. Thus, we tested whether the peroxovanadium compound potassium bisperoxo(1,10-phenanthroline)oxovanadate (V) [bpV(phen)], a stable, potent and selective protein tyrosine phosphatase inhibitor, would be neuroprotective after a thoracic spinal cord contusion in adult rats. Intrathecal bpV(phen) infusions through a lumbar puncture rescued dorsal column sensory axons innervating the nucleus gracilis and white matter at the injury epicenter. At the most effective dose, essentially all of these axons and most of the white matter at the epicenter were spared (vs 60% with control infusions). bpV(phen) treatments started 4 h after contusion were fully effective. This treatment greatly improved and normalized sensorimotor function in a grid-walking test and provided complete axonal protection over 6 weeks. The treatment rescued sensory-evoked potentials that disappeared after dorsal column transection. bpV(phen) affected early degenerative mechanisms, because the main effects were seen at 7 d and lasted beyond the treatment period. The neuroprotection appeared to be mediated by rescue of blood vessels. bpV(phen) reduced apoptosis of cultured endothelial cells. These results show that a small molecule, used in a clinically relevant manner, reduces loss of long-projecting axons, myelin, blood vessels, and function in a model relevant to the most common type of spinal cord injury in humans. They reveal a novel mechanism of spinal cord degeneration involving protein tyrosine phosphatases that can be targeted with therapeutic drugs.

Key words: axon; blood vessel; degeneration; myelin; neuroprotection; sensory

---

Received Nov. 16, 2007; accepted May 20, 2008.

Correspondence should be addressed to Theo Hagg, Kentucky Spinal Cord Injury Research Center, 511 South Floyd Street, MDR Building Room 616, University of Louisville, Louisville, KY 40292. Email: theo.hagg{at}louisville.edu

Home  |   Search  |   Archive  |   Subscribe  |   Contact  |   Help