Substance P Antagonists as a Novel Intervention for Brain Edema and Raised Intracranial Pressure

Abstract

Increased intracranial pressure (ICP) following acute brain injury requires the accumulation of additional water in the intracranial vault. One source of such water is the vasculature, although the mechanisms associated with control of blood-brain barrier permeability are unclear. We have recently shown that acute brain injury, such as neurotrauma and stroke, results in perivascular accumulation of the neuropeptide, substance P. This accumulation is associated with increased blood-brain barrier permeability and formation of vasogenic edema. Administration of a substance P antagonist targeting the tachykinin NK1 receptor profoundly reduced the increased blood-brain barrier permeability and edema formation, and in small animal models of acute brain injury, improved functional outcome. In a large, ovine model of experimental traumatic brain injury, trauma resulted in a significant increase in ICP. Administration of an NK1 antagonist caused a profound reduction in post--traumatic ICP, with levels returning to normal within 4 h of drug administration. Substance P NK1 antagonists offer a novel therapeutic approach to the treatment of acute brain injury.

Differential effects of aprepitant, a clinically used neurokinin-1 receptor antagonist on the expression of conditioned psychostimulant versus opioid reward

“…Thus, the utility of NK1 directed therapeutics in the clinic is an area of interest in addiction field. Animal studies indicate therapeutic benefits of NK1R antagonists in treating stimulant abuse, depression and cancer (Gabrielian et al 2013; Gonzalez-Nicolini and McGinty 2002; Kramer et al 2004; Lewis et al 2013). Species differences exist with respect to response to non-peptide NK1R antagonists, and rats and mice have amino acid residue changes at antagonist binding sites relative to humans and guinea pigs (Olive 2015; Saria 1999).…”

Substance P: A Novel Target in the Treatment of Cerebral Oedema and Elevated Intracranial Pressure Following Traumatic Brain Injury

“…This animal model incorporates a large gyrencephalic brain with large white matter domains and a significant tentorium cerebelli, features that are comparable to the human brain and essential in order to effectively study cerebral oedema and ICP dynamics. Administration of an NK1 tachykinin receptor antagonist at 30 mins following TBI produced a profound reduction in ICP by 4 h after injury ( Figure 3) as compared to vehicle treated controls [6].…”

“…In this type of cerebral oedema extravasation of plasma proteins occurs followed by a net movement of fluid from the vascular compartment into the brain parenchyma, leading to a disruption of both fluid and ionic homeostasis. Given the increase in the volume of the brain tissue under these circumstances, vasogenic oedema has the potential to markedly alter intracranial pressure dynamics [6] and negatively influence patient outcomes [13]. In addition, the loss of barrier integrity following acute injury to the brain allows peripheral immune cells to cross the barrier and further contribute to and exacerbate in the inflammatory processes within the brain [14].…”

“…Alternatively, if a target is identified that modulates many aspects of secondary injury then this may produce favourable results [5]. Of the secondary injury pathways, disruption to the blood-brain barrier (BBB) and subsequent development of cerebral oedema are of particular concern due to the potential effect on intracranial pressure (ICP) dynamics [6]. In this review, we highlight recent data delineating a potentially crucial role for the neuropeptide substance P (SP) in the pathogenesis of cerebral oedema formation and the development of elevated ICP following TBI, and the multi-potential nature of SP antagonists as a therapeutic intervention.…”

Contralateral extradural hematoma following decompressive craniectomy for acute subdural hematoma (the value of intracranial pressure monitoring): a case report

“…Posttraumatic intracranial mass lesions are commonly seen after severe TBI and are usually involved in the pathophysiology of intracranial hypertension. They may vary from extra-axial mass lesions (acute subdural hematomas, [ASDHs], and extradural hematomas, [EDHs]) to intraparenchymal mass lesions (contusions and intracerebral hematomas) [2-5]. However, EDH following decompressive surgery for ASDH is an uncommon situation with only few cases previously reported in the English medical literature [6-10].…”