Small-molecule protein tyrosine phosphatase inhibition as a neuroprotective treatment after spinal cord injury in adult rats.
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 approximately 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.
Nakashima
Shojiro
S
Department of Neurological Surgery, Kentucky Spinal Cord Injury Research Center, University of Louisville, Louisville, Kentucky 40292, USA.
Arnold
Sheila A
SA
Mahoney
Edward T
ET
Sithu
Srinivas D
SD
Zhang
Y Ping
YP
D'Souza
Stanley E
SE
Shields
Christopher B
CB
Hagg
Theo
T
D000818:Animals; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D016503:Drug Delivery Systems / Q000379:methods; D004730:Endothelium, Vascular / Q000187:drug effects / Q000473:pathology; D005260:Female; D006801:Humans; D018836:Inflammation Mediators / Q000008:administration & dosage / Q000627:therapeutic use; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D009942:Organometallic Compounds / Q000008:administration & dosage / Q000627:therapeutic use*; D010618:Phenanthrolines / Q000008:administration & dosage / Q000627:therapeutic use*; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013119:Spinal Cord Injuries / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology
D018836:Inflammation Mediators; D018696:Neuroprotective Agents; D009942:Organometallic Compounds; D010618:Phenanthrolines; C102120:bisperoxo(1,10-phenanthroline)oxovanadate(1-); D017027:Protein Tyrosine Phosphatases