Spinal Endothelin Content is Elevated after Moderate Local Trauma in the Rat to Levels Associated with Locomotor Dysfunction after Intrathecal Injection

Abstract

The role of endothelin (ET) in the pathophysiology of secondary neural damage after experimental spinal cord injury (SCI) was examined in a rat model of weight-drop contusion injury. Initial studies demonstrated a significant increase in spinal ET concentrations in a 7.5-mm segment of tissue (centered at the impact site) at 30 min, 4 h, and 24 h after a moderate (50 g-cm) contusion injury. Subsequent experiments were aimed at reproducing these elevations by the intrathecal (i.t.) administration of ET and observing the effect on locomotor function. These studies showed that i.t. dosage of 9.6 ng produced spinal cord elevations of ET similar to those seen 30 min after moderate SCI as well as mild locomotor deficits. A 48 ng dose of ET resulted in moderate to severe locomotor deficits that were associated with spinal ET elevations much greater than those seen after injury. The mild deficits attributable to the lower dose of ET could contribute to the pathophysiological actions of other purported secondary injury mediators. The more pronounced locomotor deficits associated with the higher dose could be of relevance for severe SCI.

Intraspinal Application of Endothelin Results in Focal Ischemic Injury of Spinal Gray Matter and Restricts the Differentiation of Engrafted Neural Stem Cells

“…This is consistent with findings demonstrating the correlation between spinal levels of ET-1 and pathology following traumatic SCI (20)(21)(22)(23)34). The causal relationship between spinal levels of ET-1 and pathophysiology following SCI is supported by the finding that selective ET-1 antagonism attenuates dysfunction following injury (24).…”

“…Following traumatic SCI, CSF, plasma, and tissue levels of ET-1 are significantly increased (20)(21)(22), with a concomitant upregulation of ET A and ET B receptors (22,23). This induction appears to have pathological consequences, as antagonism of ET-1 receptors results in improved tissue sparing following experimental SCI (24).…”

“…When applied to cortical tissue by direct injection, tissue perfusion is significantly reduced acutely, with significant autolysis and histopathology observed chronically (31,32). Similar approaches have been used to elicit local reduction in blood flow in the spinal cord with intrathecal application of ET-1 (22,33,34) but this approach to inducing transient spinal cord ischemia has proven to be problematic due to significant mortality following intrathecal application of ET-1, presumably due to lethal cardiovascular responses to the intraspinal binding of high doses of the peptide (35). To date, no data exist regarding the effect of intraparenchymally administered ET-1 in the mammalian spinal cord.…”

The Genomic Response to Retinal Disease and Injury: Evidence for Endothelin Signaling from Photoreceptors to Glia

“…For example, after transection of the rabbit or rat optic nerve, a twofold elevation in EDNRB is first observed at 7 or 60 d after injury, respectively (Rogers et al, 1997). In contrast, light damage in the BALB/c retina induces a ϳ12-fold elevation in retinal EDNRB within 1 d. One study of spinal cord compression injury in rats reported a 1.5-fold increase in tissue endothelin within 30 min, followed by a return to the baseline level over the next 48 h (Salzman et al, 1996). However, a different study of spinal cord transection in rats reported a 30-fold increase in tissue endothelin levels at 24 h, with accumulation beginning within several hours of injury (Ue- Figure 7.…”

Inhibition of endothelin-1 by the competitive ET A receptor antagonist Ro 61-1790 reduces lesion volume after cold injury in the rat

“…High plasma levels of ETs are found in humans after stroke or subarachnoid haemorrhage [23,28]. Furthermore, the cerebral tissue concentration of ET-1 is increased after brain injury or ischaemia [3,15,21,26]. ET-1 might thus be a mediator of secondary brain damage by virtue of its high potency and extremely long-lasting action in both small and large brain vessels.…”