Characterising the role of the neuropeptide substance P in experimental subarachnoid haemorrhage.

Abstract

Background: Raised intracranial pressure (ICP) following SAH predicts poor outcome and is due to hemorrhage volume and possibly brain oedema, hydrocephalus and increased volume of circulating intracranial blood. Interventions that reduce oedema may therefore reduce ICP and improve outcome. The neuropeptide substance P (SP) mediates vasogenic oedema formation in animal models of ischemic stroke, intracerebral hemorrhage and brain trauma, and may contribute to the development of increased ICP. Blockade of the SP NK1 tachykinin receptor using n-acetyl-l-tryptophan (NAT) reduces brain oedema and improves outcome in these models. This intervention had not previously been tested in models of SAH. This study therefore assessed whether SP mediates oedema formation in experimental SAH, and whether NAT treatment impacted on ICP and functional outcome. Methods: SAH was induced in adult male Sprague-Dawley rats by either injection of autologous blood into the prechiasmatic cistern (injection SAH) or by endovascular arterial puncture of the Circle of Willis (filament SAH). NAT was injected (i.v.) at 30 minutes after induction of SAH. Subgroups were assessed for brain water content, immunoreactivity to SP, albumin immunoreactivity and functional outcome at 5, 24 and 48 hours, or ICP and cerebral perfusion pressure during SAH and over the following 5 hours. Results: In both models a primary ICP increase occurred during SAH and a secondary ICP increase occurred within 2 hours. Injection SAH was followed by a non-significant increase in brain water content and caused no functional deficits. In contrast, brain oedema followed filament SAH (p < 0.001) and correlated with functional deficits (r = 0.8, p < 0.01). Increased albumin immunoreactivity (p < 0.001) indicated vasogenic brain oedema. Cerebral perfusion pressure was diminished after filament SAH and some animals demonstrated plateau waves of ICP. NAT treatment did not improve ICP, oedema or outcome. Conclusion: SAH produced secondary ICP elevation, vasogenic brain oedema and functional deficits, but it is unclear if oedema contributed to ICP. Blockade of SP did not improve any outcome parameters, suggesting that SP-mediated neurogenic inflammation may be less critical to outcome than other factors in these models.