1. ¹Discipline of Pathology, University of Adelaide, Adelaide, South Australia, Australia
2. ²Applied Physics Laboratory, Johns Hopkins University, Laurel, Maryland, USA
3. ³The Hanson Institute Centre for Neurological Diseases, Adelaide, South Australia, Australia

Correspondence: Dr R Vink, Discipline of Pathology, University of Adelaide, Adelaide, SA 5005, Australia. E-mail: Robert.Vink@adelaide.edu.au

Received 16 January 2009; Revised 18 April 2009; Accepted 23 April 2009; Published online 13 May 2009.

Abstract

Brain edema and swelling is a critical factor in the high mortality and morbidity associated with traumatic brain injury (TBI). Despite this, the mechanisms associated with its development are poorly understood and interventions have not changed in over 30 years. Although neuropeptides and neurogenic inflammation have been implicated in peripheral edema formation, their role in the development of central nervous system edema after brain trauma has not been investigated. This study examines the role of the neuropeptide, substance P (SP), in the development of edema and functional deficits after brain trauma in rats. After severe diffuse TBI in adult male rats, neuronal and perivascular SP immunoreactivity were increased markedly. Perivascular SP colocalized with exogenously administered Evans blue, supporting a role for SP in vascular permeability. Inhibition of SP action by administration of the neurokinin-1 (NK₁) antagonist, N-acetyl-L-tryptophan, at 30 mins after trauma attenuated vascular permeability and edema formation. Administration of the NK₁ antagonist also improved both motor and cognitive neurologic outcomes. These findings suggest that SP release is integrally linked to the increased vascular permeability and edema formation after brain trauma, and that treatment with an NK₁ receptor antagonist reduces edema and improves neurologic outcome.