Neuroinflammation after traumatic brain injury: Opportunities for therapeutic intervention

Abstract

Traumatic brain injury (TBI) remains one of the leading causes of mortality and morbidity worldwide, yet despite extensive efforts to develop neuroprotective therapies for this devastating disorder there have been no successful outcomes in human clinical trials to date. Following the primary mechanical insult TBI results in delayed secondary injury events due to neurochemical, metabolic and cellular changes that account for many of the neurological deficits observed after TBI. The development of secondary injury represents a window of opportunity for therapeutic intervention to prevent progressive tissue damage and loss of function after injury. To establish effective neuroprotective treatments for TBI it is essential to fully understand the complex cellular and molecular events that contribute to secondary injury. Neuroinflammation is well established as a key secondary injury mechanism after TBI, and it has been long considered to contribute to the damage sustained following brain injury. However, experimental and clinical research indicates that neuroinflammation after TBI can have both detrimental and beneficial effects, and these likely differ in the acute and delayed phases after injury. The key to developing future anti-inflammatory based neuroprotective treatments for TBI is to minimize the detrimental and neurotoxic effects of neuroinflammation while promoting the beneficial and neurotrophic effects, thereby creating optimal conditions for regeneration and repair after injury. This review outlines how post-traumatic neuroinflammation contributes to secondary injury after TBI, and discusses the complex and varied responses of the primary innate immune cells of the brain, microglia, to injury. In addition, emerging experimental anti-inflammatory and multipotential drug treatment strategies for TBI are discussed, as well as some of the challenges faced by the research community to translate promising neuroprotective drug treatments to the clinic.

Introduction

Traumatic brain injury (TBI) is associated with significant morbidity and mortality; this devastating disorder has substantial direct, and indirect, costs to society. The Center for Disease Control and Prevention (CDC) estimate that more than 1.7 million individuals in the United States suffer a TBI annually (Faul et al., 2010). These numbers, however, greatly underestimate the real incidence, and costs, of TBI as the CDC data does not include reports of sports-related concussions or repeated mild TBI from military conflict zones. Globally, the incidence of TBI is also increasing, particularly in developing countries where road traffic accidents are on the increase as a result of widespread 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, McIntosh et al., 1996). 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. 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. These secondary injury events are thought to account for the development of many of the neurological deficits observed after TBI (McIntosh et al., 1996), and their delayed nature suggests that there is a window for therapeutic intervention (pharmacological or other) to prevent progressive tissue damage and improve functional recovery after injury.

Secondary injury mechanisms include a wide variety of processes such as depolarizations and 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 generate a host of toxic and pro-inflammatory molecules such as prostaglandins, oxidative metabolites, chemokines and pro-inflammatory 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, secondary hemorrhage and herniation and additional neuronal cell death via necrotic and apoptotic mechanisms (McIntosh et al., 1996). Although each secondary injury mechanism is often considered to be a distinct event, many are highly interactive and may occur in parallel.

Considerable research efforts have sought to elucidate secondary injury mechanisms in order to develop neuroprotective treatments. Although preclinical studies have suggested many promising pharmacological treatments, more than 30 phase III prospective clinical trials have failed to show significance for their primary endpoint (Maas et al., 2010). Most of these trials targeted single secondary injury mechanisms, but given the multifactorial nature of the secondary injury process targeting a single factor will unlikely result in significant improvements in outcome. The complexity and diversity of secondary injury mechanisms have led to calls to target multiple delayed secondary injury mechanisms, either by combining agents that have complementary effects or by using multipotential drugs that modulate multiple injury mechanisms (Loane and Faden, 2010, Margulies and Hicks, 2009, Vink and Nimmo, 2009). This recognition has led to the recent emphasis on multipotential drug treatments, several of which are now in clinical trials for human head injury (Vink and Nimmo, 2009). Historically neuroprotection treatments for TBI have been dominated by a neuronocentric view, in which modification of neuronal based injury mechanisms is the primary or even exclusive focus of the neuroprotective strategy. However, it is well established that neuroinflammation represents a key pathological response to brain injury, and the important role that non-neuronal cells, such as endothelial cells, astrocytes, microglia, oligodendrocytes, play in secondary injury-mediated responses is becoming increasingly recognized (Floyd and Lyeth, 2007, Loane and Byrnes, 2010, Simard et al., 2010, Ziebell and Morganti-Kossmann, 2010).

In this review we will discuss neuroinflammation as a key secondary injury mechanism in TBI before focusing on the complex and varied responses of microglia in terms of their detrimental and beneficial effects after injury. In addition, we will describe emerging experimental anti-inflammatory and multipotential drug treatment strategies that show considerable promise for the treatment of human TBI, and we will discuss some of the challenges facing basic and clinical researchers in translating novel drug treatment strategies from the bench to the bedside.