Chapter 22 - Neuroprotection for traumatic brain injury
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
References (250)
- et al.
Longitudinal changes in patients with traumatic brain injury assessed with diffusion-tensor and volumetric imaging
Neuroimage
(2008) - et al.
Microglia and inflammation-mediated neurodegeneration: multiple triggers with a common mechanism
Prog Neurobiol
(2005) - et al.
Intracellular progesterone receptors are differentially regulated by sex steroid hormones in the hypothalamus and the cerebral cortex of the rabbit
J Steroid Biochem Mol Biol
(1994) - et al.
Interleukin-1 and tumor necrosis factor-alpha synergistically mediate neurotoxicity: involvement of nitric oxide and of N-methyl-D-aspartate receptors
Brain Behav Immun
(1995) - et al.
Lovastatin improves histological and functional outcomes and reduces inflammation after experimental traumatic brain injury
Life Sci
(2007) - et al.
Simvastatin reduces secondary brain injury caused by cortical contusion in rats: possible involvement of TLR4/NF-kappaB pathway
Exp Neurol
(2009) - et al.
Effect of aging on the microglial response to peripheral nerve injury
Neurobiol Aging
(2006) - et al.
IL-10 levels in cerebrospinal fluid and serum of patients with severe traumatic brain injury: relationship to IL-6 TNF-alpha TGF-beta1 and blood–brain barrier function
J Neuroimmunol
(1999) - et al.
Use of statins in CNS disorders
J Neurol Sci
(2001) - et al.
Apoptosis-inducing factor (AIF): a ubiquitous mitochondrial oxidoreductase involved in apoptosis
FEBS Lett
(2000)
Dual face apoptotic machinery: from initiator of apoptosis to guardian of necroptosis
Immunity
Neuroprotective effects of novel small peptides in vitro and after brain injury
Neuropharmacology
Experimental brain injury induces expression of interleukin-1 beta mRNA in the rat brain
Brain Res Mol Brain Res
Experimental brain injury induces differential expression of tumor necrosis factor-alpha mRNA in the CNS
Brain Res Mol Brain Res
Effects of progesterone on experimental spinal cord injury
Brain Res
Antagonists of excitatory amino acids and endogenous opioid peptides in the treatment of experimental central nervous system injury
Ann Emerg Med
Long-term intracerebral inflammatory response after traumatic brain injury
Forensic Sci Int
Basis of progesterone protection in spinal cord neurodegeneration
J Steroid Biochem Mol Biol
Preinjury alcohol exposure attenuates the neuroinflammatory response to traumatic brain injury
J Surg Res
Caspase inhibition selectively reduces the apoptotic component of oxygen-glucose deprivation-induced cortical neuronal cell death
Mol Cell Neurosci
Peripheral administration of a novel diketopiperazine NNZ 2591 prevents brain injury and improves somatosensory-motor function following hypoxia-ischemia in adult rats
Neuropharmacology
Progesterone is neuroprotective after transient middle cerebral artery occlusion in male rats
Brain Res
CR8 a selective and potent CDK inhibitor provides neuroprotection in experimental traumatic brain injury
Neurotherapeutics
Interleukin-10 improves outcome and alters proinflammatory cytokine expression after experimental traumatic brain injury
Exp Neurol
Altered expression of novel genes in the cerebral cortex following experimental brain injury
Brain Res Mol Brain Res
Interleukin-1 and neuronal injury
Nat Rev Immunol
High-dose atorvastatin after stroke or transient ischemic attack
N Engl J Med
Iduna protects the brain from glutamate excitotoxicity and stroke by interfering with poly(ADP-ribose) polymer-induced cell death
Nat Med
Clinical characteristics and pathophysiological mechanisms of focal and diffuse traumatic brain injury
J Cell Mol Med
The type 1 interleukin-1 receptor is essential for the efficient activation of microglia and the induction of multiple proinflammatory mediators in response to brain injury
J Neurosci
Caspase inhibitors attenuate 1-methyl-4-phenylpyridinium toxicity in primary cultures of mesencephalic dopaminergic neurons
J Neurosci
Microglia-mediated neurotoxicity: uncovering the molecular mechanisms
Nat Rev Neurosci
Quantitative structural changes in white and gray matter 1 year following traumatic brain injury in rats
Acta Neuropathol
Key note lecture: toward a mechanistic taxonomy for cell death programs
Stroke
Programmed cell death mechanisms in neurological disease
Curr Mol Med
Cell death in the nervous system
Nature
Delayed mGluR5 activation limits neuroinflammation and neurodegeneration after traumatic brain injury
J Neuroinflammation
Functional axonal regeneration through astrocytic scar genetically modified to digest chondroitin sulfate proteoglycans
J Neurosci
AIF and cyclophilin A cooperate in apoptosis-associated chromatinolysis
Oncogene
Role of the cell cycle in the pathobiology of central nervous system trauma
Cell Cycle
Pathophysiological response to experimental diffuse brain trauma differs as a function of developmental age
Dev Neurosci
Atorvastatin induction of VEGF and BDNF promotes brain plasticity after stroke in mice
J Cereb Blood Flow Metab
Alcohol use at time of injury and survival following traumatic brain injury: results from the National Trauma Data Bank
J Stud Alcohol Drugs
“Simple but not simpler”: toward a unified picture of energy requirements in cell death
FASEB J
Caspase-3 mediated neuronal death after traumatic brain injury in rats
J Neurochem
boc-Aspartyl(OMe)-fluoromethylketone attenuates mitochondrial release of cytochrome c and delays brain tissue loss after traumatic brain injury in rats
J Cereb Blood Flow Metab
Heterogeneity of microglial activation in the innate immune response in the brain
J Neuroimmune Pharmacol
Expression profiles for macrophage alternative activation genes in AD and in mouse models of AD
J Neuroinflammation
Microglia in the aging brain
J Neuropathol Exp Neurol
Experimental brain injury induces regionally distinct apoptosis during the acute and delayed post-traumatic period
J Neurosci
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