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Sham Vehicle Capsaicin

Fig. 1. Alterations in brain water content at 5h following diffuse traumatic brain injury in rats. Vehicle treated controls showed significantly more (p< 0.001) edema than either sham or capsaicin pre-treated animals.

Yonehara et al., 1987; De and Ghosh, 1990; Laird et al., 2000). It is also well known that SP is the neuropeptide responsible for increased vascular permeability, whereas CGRP is primarily associated with vasodilation. Finally, Kramer et al. (2003) have demonstrated in studies of cardiac is-chaemia that SP release is increased with magnesium depletion; declines in magnesium concentration have been widely described following TBI (Vink et al., 1987, 1988). Therefore it is feasible to propose that drugs acting on SP receptors, and in particular NK1 receptor (Hokfelt et al., 2001), may be beneficial in disease treatment. Studies of neurogenic inflammation following acute brain injury have provided evidence supporting such a possibility.

Acute CNS injury

Virtually all blood vessels of the body are surrounded by sensory nerve fibres that contain both CGRP and SP. Cerebral arteries, in particular, appear to receive a dense supply of these neurones, and it is therefore consistent that these neurones have a role as mediators of the inflammatory process following injury. Studies of migraine (Ferrari, 1998) have indeed demonstrated that neuropeptides are a therapeutic target to reduce vascular permeability. However, only a limited number of studies have demonstrated that

Sham Vehicle Capsaicin

Fig. 1. Alterations in brain water content at 5h following diffuse traumatic brain injury in rats. Vehicle treated controls showed significantly more (p< 0.001) edema than either sham or capsaicin pre-treated animals.

neurogenic inflammation may play a role in acute injury. Significant amounts of SP release has been detected in the nervous system following both peripheral nerve injury (Malcangio et al., 2000), traumatic spinal cord injury (Sharma et al., 1990) and more recently, in vitro studies of endothelium stimulation (Annunziata et al., 2002). In our own TBI studies, perivascular SP immunoreactivity has been shown to increase after TBI (Fig. 2), irrespective of the injury model (focal versus diffuse) or severity of injury. In ischaemia, SP immunore-activity has been shown to increase in GABAergic interneurons around regions of infarction, and transiently expressed in cerebrovenular endotheli-um (Stumm et al., 2001). Our own studies have shown increased SP immunoreactivity following ischaemic brain injury in the rat, which was associated with a significant increase in edema formation (Turner et al., 2006). With respect to the glial response after acute injury, receptor-binding sites for SP have been shown to increase on glia after neuronal injury (Mantyh et al., 1989). Because SP is known to regulate inflammatory and immune responses in peripheral tissue, it therefore may regulate the glial response to injury. Subsequent studies have confirmed that SP receptors are expressed on astrocytes after injury and may therefore be linked to their transformation to reactive astrocytes (Lin, 1995). This increase was not observed in undamaged areas.

Several studies using NK1 receptor antagonists also support a role for SP in neurogenic inflammation following ischaemic injury, although few have been applied to studies of the CNS. For example, in a rodent cerebral stroke model, the NK1 receptor antagonist (SR140333) reduced inf-arct volume after focal ischaemia, implying that that SP might play a role in exacerbating ischaemic damage (Yu et al., 1997). However, despite these positive findings there has been no further work published in this area. Interestingly, serum levels of SP have been measured in humans with both transient ischaemic attack and complete stroke, and these have been found to be significantly elevated compared with controls (Bruno et al., 2003). In other organs, post-ischaemic blockade of tachykinin receptors have been shown to inhibit vascular permeability, neutrophil recruitment, intestinal haemorrhage and neutropaenia following ischaemia and reperfusion of the superior mesenteric artery in the rat (Souza et al., 2002). Similarly, SP antagonists reduced post-ischaemic myocardial injury in rats with dietary Mg deficiency (Kramer et al., 1997), and the authors suggest that SP may play an early critical role in inflammatory/pro-oxidant responses following ischaemia. This finding is of particular interest to TBI as traumatic injury produces sustained decline in intracellular magnesium, implying that SP may significantly contribute to the detrimental effects of magnesium deficiency (Heath and Vink, 1996).

NKi receptor antagonists

A number of groups have hypothesised that tachy-kinin receptor antagonists may have several therapeutic applications (Watling, 1992; Lowe

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