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

Abstract

It has recently been shown that substance P (SP) plays a major role in the secondary injury process following traumatic brain injury (TBI), particularly with respect to neuroinflammation, increased blood–brain barrier (BBB) permeability, and edema formation. Edema formation is associated with the development of increased intracranial pressure (ICP) that has been widely associated with increased mortality and morbidity after neurotrauma. However, a pharmacological intervention to specifically reduce ICP is yet to be developed, with current interventions limited to osmotic therapy rather than addressing the cause of increased ICP. Given that previous publications have shown that SP, NK1 receptor antagonists reduce edema after TBI, more recent studies have examined whether these compounds might also reduce ICP and improve brain oxygenation after TBI. We discuss the results of these studies, which demonstrate that NK1 antagonists reduce posttraumatic ICP to near normal levels within 4 h of drug administration, as well as restoring brain oxygenation to near normal levels in the same time frame. The improvements in these parameters occurred in association with an improvement in BBB integrity to serum proteins, suggesting that SP-mediated increases in vascular permeability significantly contribute to the development of increased ICP after acute brain injury. NK1 antagonists may therefore provide a novel, mechanistically targeted approach to the management of increased ICP.

Direct activation of tachykinin receptors within baroreflex afferent pathway and neurocontrol of blood pressure regulation

“…The key feature of SP is to induce vasodilation that would benefit its inflammatory processes on the one hand and to promote inflammatory cells’ migration to the sites through endothelium on the other . Vasodilation may also modulate BP by competing with sympathetic nerve activity and cause a local circulation disturbance after brain injury. Since NKRs’ expression in the NG is closely associated with estrogen, whether direct activation of these NKRs by microinjection of SP into NG can induce paralleled changes in BP became our immediate focus.…”

“…The sexual dimorphic release of SP from the NG and in other brain regions has also been reported. The release of SP as a neurotransmitter and neuromodulator has been involved in neurogenic inflammation, which is a local inflammatory response to certain types of injury and pain . SP is a key first responder to most noxious stimuli (stressors), by which to compromise potentially any biological integrity.…”

Posttraumatic Headache: Basic Mechanisms and Therapeutic Targets

“…Regardless of these levels, it will be important to investigate the potential efficacy for PTH of CGRP peptide or receptor antibodies, or small molecule CGRP receptor antagonists, when these medications become available. 88 It is a primary mediator of the phenomenon of neurogenic inflammation via its activation of neurokinin (NK) receptors. 81 Increased expression of PACAP was also found in glia surrounding traumatic lesions in humans.…”

“…Substance P.-Substance P is released in response to traumatic brain injury and has been proposed to play a role in edema, increased permeability of the blood brain barrier, and functional consequences of TBI. 88 It is a primary mediator of the phenomenon of neurogenic inflammation via its activation of neurokinin (NK) receptors. 89 Based on the role of substance P in animal models it was investigated as a potential therapeutic target for migraine, with negative results.…”

Truncation of neurokinin-1 receptor—Negative regulation of substance P signaling

“…in 1971 . Since this initial seminal discovery, by Leeman and her colleagues, SP expression has been identified in different organs and cell systems, including the central and peripheral nervous systems, as well as the immune system …”