Chapter 22 - Neuroprotection for traumatic brain injury

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Abstract

Traumatic brain injury (TBI) is a major cause of mortality and morbidity worldwide. Despite extensive preclinical research supporting the effectiveness of neuroprotective therapies for brain trauma, there have been no successful randomized controlled clinical trials to date. TBI results in delayed secondary tissue injury due to neurochemical, metabolic and cellular changes; modulating such effects has provided the basis for neuroprotective interventions. To establish more effective neuroprotective treatments for TBI it is essential to better understand the complex cellular and molecular events that contribute to secondary injury. Here we critically review relevant research related to causes and modulation of delayed tissue damage, with particular emphasis on cell death mechanisms and post-traumatic neuroinflammation. We discuss the concept of utilizing multipotential drugs that target multiple secondary injury pathways, rather than more specific “laser”-targeted strategies that have uniformly failed in clinical trials. Moreover, we assess data supporting use of neuroprotective drugs that are currently being evaluated in human clinical trials for TBI, as well as promising emerging experimental multipotential drug treatment strategies. Finally, we describe key challenges and provide suggestions to improve the likelihood of successful clinical translation.

Introduction

Traumatic brain injury (TBI) is a major cause of mortality and morbidity, particularly at the two ends of the age spectrum, with large direct and indirect costs to society (see Ch. 1). The US Centers for Disease Control and Prevention (CDC) estimate that more than 1.7 million individuals in the US suffer a TBI annually (Faul et al., 2010), and the annual burden of TBI has been estimated at over US$60 billion based upon year 2000 dollars (Finkelstein et al., 2006). Yet even these numbers markedly underestimate the incidence and costs as the CDC data do not include reports of sports-related concussions (estimated incidence of 1.6–3.8 million per year (Langlois et al., 2006)) or military-related blast injuries (it is estimated that between 2000 and 2011 some 229 106 US service members suffered TBI in military conflict zones (Magnuson et al., 2012)). Globally, the incidence of TBI is also increasing, particularly in developing countries where road traffic accidents have increased as a result of greater motor vehicle use (Maas et al., 2008).

TBI is a highly complex disorder that is caused by both primary and secondary injury mechanisms (Loane and Faden, 2010) (see Ch. 5). Primary injury mechanisms result from the mechanical damage that occurs at the time of trauma to neurons, axons, glia and blood vessels as a result of shearing, tearing or stretching (see Ch. 7). Collectively, these effects induce secondary injury mechanisms that evolve over minutes to days and even months after the initial traumatic insult and result from delayed neurochemical, metabolic and cellular changes (Fig. 22.1) (see Ch. 42). These secondary injury events are thought to account for the development of many of the neurologic deficits observed after TBI, and their delayed nature suggests that there is a window for therapeutic intervention (pharmacologic or other) to prevent progressive tissue damage and improve functional recovery after injury. Implicated secondary injury mechanisms include disturbances of ionic homeostasis (Gentile and McIntosh, 1993), release of neurotransmitters (e.g., glutamate excitotoxicity) (Faden et al., 1989), mitochondrial dysfunction (Xiong et al., 1997), neuronal apoptosis (Yakovlev et al., 1997), lipid degradation (Hall et al., 2004), and initiation of inflammatory and immune responses (Morganti-Kossmann et al., 2007), among others. These neurochemical events induce toxic and proinflammatory molecules such as prostaglandins, oxidative metabolites, chemokines and proinflammatory cytokines, which lead to lipid peroxidation, blood–brain barrier (BBB) disruption, and the development of cerebral edema. The associated increase in intracranial pressure can contribute to local hypoxia and ischemia as well as secondary hemorrhage and herniation, leading to initiation and execution of multiple neuronal cell death mechanisms (Andriessen et al., 2010). Furthermore, secondary injury mechanisms may be highly interactive and often occur in parallel, thereby adding to the complexity of this disorder.

Considerable research has sought to elucidate secondary injury mechanisms in order to develop neuroprotective treatments. Although preclinical studies have suggested many promising pharmacologic agents, more than 30 phase III prospective clinical trials have failed to show significance for their primary end point (Narayan et al., 2002, Schouten, 2007, Maas et al., 2010). Most of these trials targeted single factors proposed to mediate secondary injury. But the complexity and diversity of secondary injury mechanisms have led to calls to target multiple delayed injury factors (Margulies and Hicks, 2009, Stoica et al., 2009, Vink and Nimmo, 2009), either by combining agents that have complementary effects or by using multipotential drugs that modulate multiple injury mechanisms. Whereas the multidrug approach has long been successfully employed for the treatment of cancer and infectious diseases, it is less likely to gain traction for neuroprotection because of the costs associated with establishing the efficacy of even a single agent. This recognition has led to the recent emphasis on multipotential treatments for TBI (Vink and Nimmo, 2009, Loane and Faden, 2010), several of which are now in clinical trials and others that are showing considerable promise in preclinical studies.

Neuroprotection approaches for both acute and chronic neurodegenerative disorders have historically been dominated by a neuronocentric view, in which modification of neuronal-based injury mechanisms is viewed as the primary focus of the neuroprotective strategy. However, increasing evidence in the literature underscores the importance of viewing injury more broadly to include endothelial cells, astrocytes, microglia, oligodendrocytes, and precursor cells. More recent neuroprotection approaches have recognized this complex structure and interplay, emphasizing therapeutic strategies that promote the recovery and optimal functioning of non-neuronal cells in addition to more directly inhibiting mechanisms of neuronal cell death (Stoica and Faden, 2010b). Thus, developing effective neuroprotective strategies for TBI requires an understanding of the complex cellular and molecular events that contribute to secondary injury. Mechanisms of neuronal cell death and post-traumatic neuroinflammation will be addressed in the following sections as well as a discussion on the many challenges translating promising preclinical neuroprotection therapeutic strategies to the clinic. Finally, we will critically review developing preclinical multipotential drug treatment strategies for TBI that show promise for successful clinical translation for head injury.

Section snippets

Neuronal cell death: morphology versus mechanism

Neuronal cell death is a major cause of neurologic dysfunction following TBI. For many years, it was believed that all or most cell death following brain trauma reflected a passive and unregulated form of neuronal death due to energy failure and related loss of ionic homeostasis, which was commonly called necrosis. However, over the past 15 years additional neuronal death phenotypes have been described based upon either morphologic or molecular features. Yet, despite the efforts of many

Caspase-dependent neuronal cell death pathways

Multiple groups have shown that neuronal cell death involving caspase-dependent mechanisms occurs after experimental TBI (Rink et al., 1995; Yakovlev et al., 1997; Conti et al., 1998). Some studies have shown that FAS death receptors contributed to caspase activation following experimental and clinical TBI and that caspase-8 deletion protects against experimental TBI, thus supporting a role for extrinsic apoptosis after such injury (Qiu et al., 2002, Krajewska et al., 2011). Other studies have

Conclusion

TBI is a highly complex disorder, which is characterized by multiple interacting secondary injury cascades. The focus on highly selective “laser-guided” neuroprotective strategies has given way to the concept of multipotential drugs that modulate multiple secondary injury pathways. The potential limitations of using single models and species for preclinical screening of neuroprotective agents has been increasingly underscored, as have the methodologic differences between clinical and

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