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

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.