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.
Highlights
Brain tumors are one of the most devastating forms of cancer, and unlike many other cancer types, their incidence is increasing
The current study demonstrates that perivascular substance P (SP) is significantly increased in the peritumoral region, which is consistent with previous studies demonstrating a role for SP in the genesis of cerebral edema in models of acute brain injury [10,11,22]
Administration of the NK1 antagonist Emend at 3 weeks post-inoculation resulted in a decrease in brain water content and blood-brain barrier (BBB) permeability such that they were no longer significantly different to sham animals within 7 days of treatment
Summary
Brain tumors are one of the most devastating forms of cancer, and unlike many other cancer types, their incidence is increasing. Astrocytomas and metastatic carcinomas are the most common types of brain tumors in adults. Despite recent advances in cancer treatment, brain tumors remain inherently difficult to treat and prognosis for these patients remains extremely poor, with most individuals succumbing to the disease within months of diagnosis. Both aggressive astrocytomas and secondary brain tumors are associated with significant edema formation, which results in substantial morbidity and mortality amongst patients. The disruption to the BBB surrounding tumors is thought to result from defects in these tight junctions, with abnormal expression of tight junction molecules reported to correlate with increasing malignancy [8]. Despite extensive knowledge of the structure of the BBB, molecular mechanisms for the disruption associated with brain tumor growth remains poorly understood
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