Alan J. Nimmo

Multifunctional drugs for head injury

SummaryTraumatic brain injury (TBI) remains one of the leading causes of mortality and morbidity worldwide in individuals under the age of 45 years, and, despite extensive efforts to develop neuroprotective therapies, there has been no successful outcome in any trial of neuroprotection to date. In addition to recognizing that many TBI clinical trials have not been optimally designed to detect potential efficacy, the failures can be attributed largely to the fact that most of the therapies investigated have been targeted toward an individual injury factor. The contemporary view of TBI is that of a very heterogenous type of injury, one that varies widely in etiology, clinical presentation, severity, and pathophysiology. The mechanisms involved in neuronal cell death after TBI involve an interaction of acute and delayed anatomic, molecular, biochemical, and physiological events that are both complex and multifaceted. Accordingly, neuropharmacotherapies need to be targeted at the multiple injury factors that contribute to the secondary injury cascade, and, in so doing, maximize the likelihood of a successful outcome. This review focuses on a number of such multifunctional compounds that have shown considerable success in experimental studies and that show maximum promise for success in clinical trials.

Substance P is associated with the development of brain edema and functional deficits after traumatic brain injury

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 (NIC,) antagonist, N-acetyl-l-tryptophan, at 30 mins after trauma attenuated vascular permeability and edema formation. Administration of the NIC, 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 NIC, receptor antagonist reduces edema and improves neurologic outcome.

Neurogenic inflammation is associated with development of edema and functional deficits following traumatic brain injury in rats

The present study has used capsaicin-induced neuropeptide depletion to examine the role of neurogenic inflammation in the development of edema and functional deficits following traumatic brain injury (TBI). Adult, male rats were treated with capsaicin (neuropeptide-depleted) or equal volume vehicle (controls) 14 days prior to induction of moderate/severe diffuse TBI. Injury in vehicle treated control animals resulted in acute (4-5 h) edema formation, which was confirmed as being vasogenic in origin by diffusion weighted magnetic resonance imaging and the presence of increased permeability of the blood-brain barrier (BBB) to Evans blue dye. There was also a significant decline in brain magnesium concentration, as assessed by phosphorus magnetic resonance spectroscopy, and the development of profound motor and cognitive deficits. In contrast, capsaicin pre-treatment resulted in a significant reduction in post-traumatic edema formation (p < 0.001), BBB permeability (p < 0.001), free magnesium decline (p < 0.01) and both motor and cognitive deficits (p < 0.001). We conclude that neurogenic inflammation may play an integral role in the development of edema and functional deficits following TBI, and that neuropeptides may be a novel target for development of interventional pharmacological strategies.

Magnesium attenuates persistent functional deficits following diffuse traumatic brain injury in rats

Although a number of studies have demonstrated that magnesium improves acute motor and cognitive outcome after traumatic brain injury, others have failed to show positive effects on cognitive outcome and none have examined persistent functional deficits. The present study shows that severe impact-acceleration induced, diffuse traumatic brain injury in rats produced profound motor and cognitive deficits that persisted for at least 4 weeks after trauma. Intravenous administration of magnesium sulfate (250 micromoles/kg) at 30 min after injury significantly improved rotarod (sensorimotor) and open field (stress/anxiety) performance, and led to a faster rate of recovery in the Barnes maze (learning). We conclude that posttraumatic magnesium administration attenuates long-term motor and cognitive deficits after traumatic brain injury, and that this improvement may include some reduction of post-traumatic stress and anxiety.

Magnesium attenuates post-traumatic depression/anxiety following diffuse traumatic brain injury in rats

Objective: Magnesium (Mg) declines after traumatic brain injury (TBI), a decline believed associated with ensuing neuronal cell death and subsequent functional impairment. While Mg’s effects on motor and cognitive deficits following TBI have been well studied, few studies have addressed post-traumatic depression as an outcome parameter, despite its being a major clinical problem with an incidence of between 6 and 77%. We investigated the incidence of post-traumatic depression/anxiety in an animal model of diffuse TBI, and explored the use of magnesium sulfate (MgSO4) as an interventional treatment. Methods: Diffuse TBI was induced in 32 anesthetized, adult, male Sprague-Dawley rats, using the 2 m impact-acceleration model of injury. At 30 min after injury, half of the rats received 250 μmol/kg i.v. MgSO4; the other half served as non-treated controls. Before and for 6 weeks after injury, the open-field, spontaneous activity test was used to determine post-traumatic depression/anxiety relative to pre-injury. In this test, animals are placed in a 1-meter square box with 100 squares marked on the base. The number of squares entered in a 5-min period is recorded. Incidence of post-traumatic depression/anxiety was defined as the number of animals demonstrating a reduction in spontaneous activity to less than 100 squares in 5 min. Prior to injury, rats typically entered a mean of 201 ± 12 (SEM) squares over a 5 min observation period. Results: At 1 week after injury, non-treated animals had a mean core of 62 ± 13. The incidence of post-traumatic depression/anxiety in these animals was 61%, which is similar to that observed clinically. In contrast, animals treated with MgSO4 had a mean activity score of 144 ± 23 at 1 week after TBI and an incidence of depression/anxiety of less than 30%. The significant difference between groups persisted for the entire 6-week observation period. Conclusions: The improvement in post-traumatic depression/anxiety conferred by Mg adds further weight to available evidence of Mg’s benefit as a neuroprotective agent after TBI.

An Overview Of New And Novel Pharmacotherapies For Use In Traumatic Brain Injury

1. Although a number of interventional pharmacotherapies have undergone clinical trial in traumatic brain injury (TBI), none has shown considerable promise. The present short review will examine some of the more novel compounds that have been proposed recently as potential therapeutic agents for use in TBI.

Recent patents in CNS drug discovery: the management of inflammation in the central nervous system.

In recent years, one of the major advances in terms of our understanding of the pathology underlying many neurological conditions has been the realisation that inflammation may play a major role in many acute and chronic conditions. Inflammation is not only involved in acute CNS conditions, such as stroke and traumatic injury, but it is also a central factor in chronic and neurodegenerative conditions such as Alzheimers disease, Parkinsons disease and multiple sclerosis. There are some key differences between inflammatory processes within the CNS (neuroinflammation) and peripheral inflammation, partly due to the natural compartmentation of the brain by the blood-brain barrier. As a result of these differences, the classical anti-inflammatory agents (steroids and NSAIDs) have not played a major role in the management of CNS inflammatory conditions. In order to address this clinical need, there is significant interest in developing novel anti-inflammatory agents that may help prevent or ameliorate CNS inflammation. In this review, the authors focus on disclosures from the patent literature to give a broad overview of the different approaches that are being taken to try and develop more effective and selective anti-inflammatory agents to manage acute and chronic inflammation in the CNS. A variety of approaches are discussed including modulating the activity of various inflammatory mediators such as cytokines, chemokines and kinins, targeting toll-like receptors as a possible therapeutic intervention, and novel approaches to managing the actions of eicosanoids in neuroinflammation.

Neuropeptide release influences brain edema formation after diffuse traumatic brain injury.

The mechanisms associated with edema formation after traumatic brain injury (TBI) have not been fully elucidated. In peripheral tissue injury, the neurogenic component of inflammation plays a significant role in increased vascular permeability and edema formation. However, few studies have examined the role of neuropeptide induced neurogenic inflammation following TBI. Adult male Sprague-Dawley rats were either left untreated, or pre-treated with capsaicin (125 mg/kg s.c.) or equal volume vehicle, and injured 14 days later using the 2-meter impact-acceleration model. Subgroups of animals were assessed for blood brain barrier (BBB) permeability (Evans Blue), brain edema (wet weight/dry weight) and functional outcome (Barnes maze and Rotarod) for up to 2 weeks post-trauma. Increased BBB permeability was present in untreated animals between 3 and 6 h after injury but not at later time-points. Edema was maximal at 5 h after trauma, declined and then significantly increased over the 5 days post-trauma. In contrast, capsaicin pre-treated, neuropeptide-depleted animals exhibited no significant increase in BBB permeability or edema compared to vehicle treated animals after injury. Notably, motor and cognitive impairments were significantly reduced in the capsaicin-pretreated animals. We conclude that neurogenic inflammation contributes to the development of edema and posttraumatic deficits after diffuse TBI.

Novel therapies in development for the treatment of traumatic brain injury.

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.

Effects of daily versus weekly testing and pre-training on the assessment of neurologic impairment following diffuse traumatic brain injury in rats

A number of test paradigms have been used to determine acute and chronic motor and cognitive deficits after experimental traumatic brain injury (TBI). Some involve daily testing of either trained or untrained animals whereas others utilize periodic testing over extended time periods. Which test paradigm is the most appropriate for the assessment of motor and cognitive deficits is, however, unclear. In the current study, we have used both daily and weekly testing in trained and untrained animals to ascertain which assessment protocol is most suited for the detection of functional deficits after diffuse TBI in rats. Animals were subjected to severe injury using the impact-acceleration model of diffuse TBI. An equal number of animals were also prepared surgically but not subject to injury (shams). The rotarod device and the Barnes Maze were used for motor and cognitive assessment respectively, with half of the animals being pre-trained on each test for 10 days prior to injury. The open field test was used to assess spontaneous exploratory activity (stress). Following injury, animals were assessed for neurologic deficits either on a daily basis (for 10 days) or a weekly basis (for 4 weeks). In trained animals, the greatest differences in neurologic outcome between injured and sham animals were observed early after injury. In contrast, in untrained animals, greatest differences between injured and sham animals were observed at later time points. Pre-injury training did not improve the rate of cognitive recover, or the rate of motor recovery in the weekly test paradigm, but did improve the rate of motor recovery in the daily assessment paradigm. Daily assessment promoted rapid functional recovery whereas weekly assessments did not significantly affect outcome in injured animals over the 4-week assessment period. Spontaneous exploratory activity was decreased after TBI and was not influenced by task exposure. These studies demonstrate that the functional assessment paradigm needs to be considered when quantifying functional deficits following diffuse TBI in rats.