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

Abstract

The neuropeptide substance P (SP) has been implicated in the disruption of the blood-brain barrier (BBB) and development of cerebral edema in acute brain injury. Cerebral edema accumulates rapidly around brain tumors and has been linked to several tumor-associated deficits. Currently, the standard treatment for peritumoral edema is the corticosteroid dexamethasone, prolonged use of which is associated with a number of deleterious side effects. As SP is reported to increase in many cancer types, this study examined whether SP plays a role in the genesis of brain peritumoral edema. A-375 human melanoma cells were injected into the right striatum of male Balb/c nude mice to induce brain tumor growth, with culture medium injected in animals serving as controls. At 2, 3 or 4 weeks following tumor cell inoculation, non-treated animals were perfusion fixed for immunohistochemical detection of Albumin, SP and NK1 receptor. A further subgroup of animals was treated with a daily injection of the NK1 antagonist Emend (3 mg/kg), dexamethasone (8 mg/kg) or saline vehicle at 3 weeks post-inoculation. Animals were sacrificed a week later to determine BBB permeability using Evan's Blue and brain water content. Non-treated animals demonstrated a significant increase in albumin, SP and NK1 receptor immunoreactivity in the peritumoral area as well as increased perivascular staining in the surrounding brain tissue. Brain water content and BBB permeability was significantly increased in tumor-inoculated animals when compared to controls (p<0.05). Treatment with Emend and dexamethasone reduced BBB permeability and brain water content when compared to vehicle-treated tumor-inoculated mice. The increase in peritumoral staining for both SP and the NK1 receptor, coupled with the reduction in brain water content and BBB permeability seen following treatment with the NK1 antagonist Emend, suggests that SP plays a role in the genesis of peritumoral edema, and thus warrants further investigation as a potential anti-edematous treatment.

Peripheral blood occludin level as a biomarker for preoperative cerebral edema in patients with brain tumors

“…Importantly, this study revealed a relationship between the serum level of occludin and the severity of brain edema in patients with brain tumors. Previous investigations have con rmed that PBTE is vascular edema caused by damage to the BBB [17][18][19] . Occludin is an important component of the tight junctions that constitute the BBB.…”

Paeoniflorin inhibits proliferation and promotes apoptosis of multiple myeloma cells via its effects on microRNA-29b and matrix metalloproteinase-2

“…MMP-2 is usually located in the cytoplasm of tumor cells, and is often detected in the endothelial cells of the vascular basement membrane, thus suggesting that during the invasion of astrocytoma, MMP-2 and vascular endothelial growth factor have a synergistic role in regulating the angiogenesis of tumor vessels in MM (24,25). The structure of newly formed tumor vasculature is incomplete, and easily leaks, thus affecting the integrity of the blood-brain barrier (BBB); plasma and other macromolecules may penetrate into the cells through the damaged BBB and gather around the tumor, forming extensive peritumoral edema (26). Furthermore, MMP-2 may directly degrade the extracellular matrix of the basement membrane of blood vessels, loosening the structure, which is conducive to the invasion of tumor cells along the basement membrane (27).…”

The Neurokinin-1 Receptor Antagonist Aprepitant, a New Drug for the Treatment of Hematological Malignancies: Focus on Acute Myeloid Leukemia

“…and exerts an antitumor action [22,86]. Moreover, aprepitant activates the caspase-3 dependent apoptotic pathway by altering the expression of the apoptosis-related genes, increases the sensitization of certain tumor cells to the cytotoxic action of vincristine/arsenic trioxide (ATO) and decreases the expression of liver stemness markers blood-brain barrier permeability and brain water content [48,87,88].…”