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Type: Thesis
Title: The role of substance P in experimental intracerebral haemorrhage.
Author: Kleinig, Timothy John
Issue Date: 2010
School/Discipline: School of Medical Sciences
Abstract: Background: Elevated levels of substance P (SP) have previously been found following ischaemic stroke and traumatic brain injury. Inhibiting the main SP receptor (neurokinin-1 (NK1)) reduces oedema and improves functional outcome in both settings. As this thesis details, we hypothesised that SP plays a similarly deleterious role following intracerebral haemorrhage (ICH). We further hypothesised that the post-ICH effects of intracerebral thrombin (which is known to play a major role in post-ICH secondary injury) are at least partly SP-mediated. Thrombin, similarly to SP, is known to play a deleterious role following both ischaemic stroke and traumatic brain injury. Previous research has also demonstrated that thrombin causes cutaneous oedema by an SP-dependent mechanism. Methods: Three hundred and forty three male Sprague-Dawley rats were used, and variously subjected to collagenase ICH, autologous ICH, intracerebral thrombin injection and intracerebral injection of SP. The sequelae of these various injuries was assessed, as well as the effect of antagonists to the main substance P receptor (NK1R), using functional testing, histological analysis, ELISA, real-time RT-PCR, wet-weight dry weight (for assessment of oedema) and Evans blue (for assessment of blood-brain barrier integrity). The effect of prior splenectomy on oedema following ICH was also assessed. Results: Elevated levels of SP were demonstrated post-ICH in the two different ICH models, and localised to astrocytes. Following collagenase ICH, two structurally unrelated NK1R antagonists reduced oedema and blood-brain barrier (BBB) dysfunction, but failed to reduce cellular inflammation, brain lesion volume and functional deficits. Stereotactic thrombin injections caused both oedema and elevated intracerebral SP, however, NK1R antagonism post-intracerebral thrombin failed to reduce brain oedema, largely disproving the hypothesis that thrombin causes intracerebral oedema post-ICH by a SP-dependent mechanism. Supraphysiological levels of SP injected stereotactically caused surprisingly little oedema and BBB dysfunction. Additional exploratory experiments demonstrated that NK1R antagonism did not reduce oedema caused by autologous ICH and also that the oedema-reducing effects of NK1R antagonism following collagenase ICH were abrogated by prior splenectomy. Conclusion: These results demonstrate that the oedematogenic actions of substance P following ICH are complex, and may predominantly be peripherally-mediated. Future experiments are planned to characterise further the role of SP in neuroinflammatory conditions.
Advisor: Vink, Robert
Blumbergs, Peter Charles
Dissertation Note: Thesis (Ph.D.) -- University of Adelaide, School of Medical Sciences, 2010
Keywords: substance P; intracerebral haemorrhage; oedema; inflammation
Appears in Collections:Research Theses

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