Novel therapies in development for the treatment of traumatic brain injury

Abstract

In industrialised countries, the mean per capita incidence of traumatic brain injury (TBI) that results in a hospital presentation is 250 per 100,000. In Europe and North America alone, this translates to > 2 million TBI presentations annually. Approximately 25% of these presentations are admitted for hospitalisation. Despite the significance of these figures, there is no single interventional pharmacotherapy that has shown efficacy in the treatment of clinical TBI. This lack of efficacy in clinical trials may be due, in part, to the inherent heterogeneity of the traumatic brain injury population. However, it is the multifactorial nature of secondary injury that also poses a major hurdle, particularly for those therapies that have been designed to specifically target an individual injury factor. It is now becoming increasingly recognised that any successful TBI therapy may have to simultaneously affect multiple injury factors, somewhat analogous to other broad spectrum interventions. Recent efforts in experimental TBI have therefore focussed on developing novel pharmacotherapies that may affect multiple injury factors and thus improve the likelihood of a successful outcome. While a number of interventions are noteworthy in this regard, this review will focus on three novel compounds that show particular promise: magnesium, substance P antagonists and cyclosporin A.

The effects of magnesium sulfate on blood-brain barrier disruption caused by intracarotid injection of hyperosmolar mannitol in rats

“…# P b 0.05 compared with control and magnesium. supported by reports on the protective effects of magnesium on neuropathologic changes (Cotton et al, 1992;Vink and Nimmo, 2002;Esen et al, 2003). Intraarterial or intraperitoneal usage of magnesium has recently been reported as an alternative approach to protect the BBB against several pathological conditions (Muir, 1998;Fortin et al, 2000;Kaya et al, 2001;Esen et al, 2003).…”

“…One of the major possible mechanisms of BBB protection caused by magnesium could be its own direct action on the BBB through suppression of endothelial cell function. Magnesium can reach the brain through the BBB in larger amounts following high doses of magnesium (Fuchs-Buder et al, 1997;Vink and Nimmo, 2002). Increased magnesium levels in either cerebrospinal fluid or brain could be sufficient to suppress the activity of neurons (van der Hel et al, 1998).…”

Pathophysiology of Cerebral Ischemia and Brain Trauma: Similarities and Differences

“…Although the location and severity of the primary insult are important factors determining the impact of individual injury processes, excitotoxicity, calcium-mediated events, free radicals, mitochondrial damage, inflammation, and apoptosis are commonly discussed as possible targets for therapeutic interventions. Indeed, much progress has been made developing novel pharmaceutical therapies to treat these injuries including glutamate receptor antagonists, calcium channel blockers, radical scavengers, as well as anti-inflammatory and anti-apoptotic agents (Vink and Nimmo, 2002;Chauhan et al, 2003;Fisher, 1999). Despite the identification of these processes and the development of novel pharmacological agents, clinical trials in stroke and TBI have met with little success (Doppenberg and Bullock, 1997;Gladstone et al, 2002).…”

Multifunctional Drugs for Head Injury

“…[143][144][145] Briefly, brain magnesium decline is a ubiquitous feature of TBI and is associated with the development of motor and cognitive deficits. Experimentally, parenteral administration of magnesium up to 12 h post trauma restores brain magnesium homeostasis and profoundly improves both motor and cognitive outcome.…”