The effects of the neuropeptide substance P on outcome following experimental traumatic brain injury in rats

Abstract

Traumatic brain injury (TBI) today remains a major health and social problem for both developed and developing countries. It is the leading cause of death and disability under the age of 40, and despite the significance of this public health problem, no effective therapy exists. While a number of factors have been shown to be associated with the development of irreversible tissue injury after TBI, the formation of oedema and opening of the blood brain barrier (BBB) have been shown to be of major significance to outcome. Oedema formation in the brain, when left uncontrolled, results in increased intracranial pressure that may lead to a decrease in brain tissue perfusion, localised hypoxia and ischemia, and ultimately tissue herniation and death. The mechanisms associated with the development of oedema are largely unclear, and accordingly, current therapies are generally ineffective, often resulting in dehydration, hypotension and renal problems. This thesis describes the characterisation of neurogenic inflammation in the development of post-traumatic brain oedema and functional deficits, and particularly the role of substance P (SP) in mediating their development, using rodent models of both focal and diffuse TBI. Results from this thesis demonstrate that increased SP immunoreactivity, particularly at the level of the vasculature, is a ubiquitous feature of TBI implying a potential role in the breakdown of the blood brain barrier (BBB) following TBI. This was confirmed through the use of the NK[subscript 1] receptor antagonists, which attenuated BBB and oedema formation as well as deleterious morphological events such as dark cell change and axonal injury. The NK[subscript 1] receptor antagonists also resulted in an associated improvement in both motor and cognitive deficits, as assessed using a battery of functional outcome tests. Possible mechanisms of action of the NK[subscript 1] receptor antagonist included effects on the BBB, SP release, intracellular free magnesium concentration and aquaporin-4 channels. Neuroprotection could be facilitated with administration of a non-lipid permeable NK[subscript 1] receptor antagonist in the immediate postinjury period, or up to 12 h after TBI with a lipid permeable NK[subscript 1] receptor antagonist, suggesting that this class of drugs have a clinically viable therapeutic window. We conclude that SP has a significant role in the secondary injury process following TBI and may offer a novel target for the development of interventional pharmacological strategies.