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

Abstract

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 ϳ60% 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.

Vascular Endothelial Growth Factor and Spinal Cord Injury Pain

“…The increased abundance of SMI-31-labeled axons in VEGF 165 -treated SCI rats indicates two possibilities: (1) VEGF 165 spared axons after SCI, consistent with other reports of the neuroprotective effects of VEGF (Zachary, 2005), and/ or (2) VEGF 165 induced excessive axonal regeneration/ sprouting of surviving axons, a finding in agreement with previous reports of the effects of VEGF on axonal growth (Zachary, 2005). Given that lesions of DC axons can cause motor deficits, while sparing of DC axons improves locomotor recovery after SCI (Brodal, 1992;Nakashima et al, 2008), and that motor recovery of SCI rats treated with VEGF 165 did not improve (Fig. 2B), we conclude that increased SMI-31 labeling in VEGF 165 -treated SCI rats reflected predominantly nonspecific, aberrant sprouting of myelinated axons, although some axonal sparing could not be excluded.…”

Controlled enzymatic production of astrocytic hydrogen peroxide protects neurons from oxidative stress via an Nrf2-independent pathway

“…6 A-C), mimicking the H 2 O 2 effect. In fact, PTP inhibition has been shown to be neuroprotective in spinal cord injury (37), suggesting that PTPs are potential candidates in mediating H 2 O 2 's astrocytic neuroprotective effect. PTP inhibition-mediated astrocytic neuroprotection was not restricted to a 7-h time-window, as seen with low-level H 2 O 2 .…”

Intravenous Infusion of Magnesium Chloride Improves Epicenter Blood Flow during the Acute Stage of Contusive Spinal Cord Injury in Rats

“…The rats were also tested in a sensorimotor grid walk test, which is particularly sensitive to dorsal column injury. 20 Rats walked voluntarily on a 114 · 114 cm grid with 3.8 cm holes. The number of hindlimb footfalls were counted by two observers from different sides and recorded by a third person.…”

“…20,21 Endothelial cell loss might be caused by pathological calcium influx or lipid peroxidation, which can be reduced by magnesium treatment in brain injury. 19,22,23 It remains to be determined whether microvascular endothelial cells can be protected following resolution of vasospasm, as reperfusion injury might be detrimental following SCI.…”

“…[25][26][27][28] Microscopic histological analyses of LEA + microvessels provide a measure of the perfusion status of microvessels that are lined with endothelial cells at the injury epicenter and penumbra, two areas where therapeutic intervention is needed during the acute stage of injury. 20,21,29 Here, we determined the temporal changes in the number of perfused and endothelial-lined microvasculature over 2 days following contusive SCI in adult rats. We also tested continuous intravenous magnesium infusion to improve blood flow and survival of endothelial cells in the injury epicenter and penumbra, and potential exacerbating effects on hemorrhage.…”