Substance P as a Mediator of Neurogenic Inflammation after Balloon Compression Induced Spinal Cord Injury

Abstract

Authors may also deposit this version on his/her funder's or funder's designated repository at the funder's request or as a result of a legal obligation, provided it is not made publicly available until 12 months after official publication. Such an open environment precludes the measurement of intrathecal pressure (ITP), whose increase after SCI has been linked to the development of greater tissue damage and functional deficits. Raised ITP may be potentiated by edema, which we have recently shown to be associated with substance P (SP) induced neurogenic inflammation in both traumatic brain injury and stroke. The present study investigates whether SP plays a similar role as a mediator of neurogenic inflammation after SCI. A closed balloon compression injury was induced at T10 in New Zealand white rabbits. Animals were thereafter assessed for blood spinal cord barrier (BSCB) permeability, edema, ITP, histological outcome, and functional outcome from 5 h to 2 weeks post-SCI. The balloon compression model produced significant increases in BSCB permeability, edema, and ITP along with significant functional deficits that persisted for 2 weeks. Histological assessment demonstrated decreased SP immunoreactivity in the injured spinal cord while NK1 receptor immunoreactivity initially increased before returning to sham levels. In addition, aquaporin 4 immunoreactivity increased early post-SCI, implicating this water channel in the development of edema after SCI. The changes described in the present study support a role for SP as a mediator of neurogenic inflammation after SCI.

Treatment with the NK1 Antagonist Emend Reduces Blood Brain Barrier Dysfunction and Edema Formation in an Experimental Model of Brain Tumors

“…However, one limitation of the use of these animals is the translational potential of research carried out in immune deficient species. Nonetheless, the results of the present study using immunocompromised mice are consistent with previous studies performed in immune competent animals, suggesting a dominant role for SP and the NK1 receptor in neurogenic inflammation in a variety of models of CNS disease [30]–[32]. Furthermore, the pattern of SP immunoreactivity, as well as the observed decreases in BBB permeability and brain water content are consistent among these studies [10], [12], highlighting the reproducibility of these results in both immune-competent and deficient species, and thus the translational potential of SP antagonists as a therapy for cerebral edema.…”

Aquaporins in the Spinal Cord

“…This increase in AQP4 was observed throughout the nine-month study period [78]. Similarly, a significant increase in AQP4 immunoreactivity at 5 h, 24 h, three days and 14 days post SCI was also observed in a rat spinal cord compression model [79]. However, despite overall AQP4 up-regulation in chronically affected spinal cords, astrocytes forming the glia limitans externa exhibited markedly decreased AQP4 levels [77].…”

The Role of Substance P in Secondary Pathophysiology after Traumatic Brain Injury

“…In studies of TBI, inhibition of posttraumatic neurogenic inflammation by prior depletion of sensory neuropeptides using chronic capsaicin pretreatment attenuated increased BBB permeability, and the development of edema and functional deficits (60, 61), with subsequent studies demonstrating that ACE inhibitors exacerbated histological damage and functional deficits after TBI (62). Further studies in stroke established that reversible ischemic stroke resulted in increased brain perivascular immunoreactivity to SP with associated edema formation (63), while decreased SP immunoreactivity in association with increased NK1 immunoreactivity in both rat and human spinal cord injury suggested a role for neurogenic inflammation in this form of CNS injury (64, 65). Finally, activation of the multimodal TRPV1 receptor that is linked to SP release initiates neurogenic inflammation and is associated with increased BBB permeability, an effect abolished by the TRPV1 antagonist capsazepine and by an NK1 antagonist (66).…”