Invited ReviewNeuroinflammation after traumatic brain injury: Opportunities for therapeutic intervention
Highlight
► Neuroinflammation is a key secondary injury mechanism following traumatic brain injury, and selective inhibition of these pathways result in significant neuroprotection.
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.
Section snippets
The neuroinflammatory response to traumatic brain injury
Neuroinflammation is an important secondary injury mechanism that contributes to on-going neurodegeneration and neurological impairments associated with TBI. Post-traumatic neuroinflammation is characterized by glial cell activation, leukocyte recruitment, and upregulation of inflammatory mediators (Morganti-Kossmann et al., 2007). Although much research has focused on the detrimental effects of neuroinflammation on the injured brain, clear beneficial effects can be achieved if
Microglia – mediators of the innate immune response to CNS injury
Microglia are the primary innate immune cells in the CNS. Under normal physiological conditions these highly dynamic and motile cells are spread throughout the brain parenchyma and constantly survey their microenvironment for noxious agents and injurious processes (Nimmerjahn et al., 2005). They respond to extracellular signals and are responsible for clearing cellular debris and toxic substances by phagocytosis, thereby maintaining normal cellular homeostasis in the CNS (Hanisch and
Involvement of pro- and anti-inflammatory cytokines and chemokines in traumatic brain injury
The neuroinflammatory cascade activated in response to TBI is mediated by the release of pro- and anti-inflammatory cytokines and chemokines, and microglia are the primary source of these inflammatory mediators in the brain. Gene profiling studies in experimental models of TBI have shown that genes related to neuroinflammation are strongly up-regulated in the acute phase after injury (Kobori et al., 2002, Natale et al., 2003, Raghavendra Rao et al., 2003). Additional studies focused on
Chronic microglial activation and neurodegeneration after traumatic brain injury
Chronic microglial activation is considered to be the most damaging response of microglia to injury (Block et al., 2007). DAMPs released by injured neurons after TBI interact with TLRs and other PRRs on activated microglia and trigger a vicious self-perpetuating cycle of damaging events that lead to prolonged and dysregulated microglial activation that drives pathogenic processes and neurodegeneration (Block et al., 2007, Loane and Byrnes, 2010). Human and animal studies indicate that microglia
Challenges translating promising experimental neuroprotection strategies to the clinic
Neuroprotective treatments that limit secondary injury mechanisms and/or improve behavioral outcome have been well established in multiple animal models of TBI. However, translation of promising experimental neuroprotective treatments to human injury have been very disappointing, with none of the pharmacological treatments resulting in any consistent improvements in outcome in the clinic (Maas et al., 2010). Both conceptual issues and methodological differences between preclinical research and
Minocycline
Minocycline is a second generation tetracycline that is known to have neuroprotective properties that are independent of its anti-microbial activity (Yrjanheikki et al., 1998). Minocycline is a potent anti-inflammatory drug that suppresses the production of several pro-inflammatory cytokines (Choi et al., 2005, Seabrook et al., 2006), and inhibits microglial-mediated neurotoxicity (Tikka et al., 2001). It has been shown to have significant neuroprotective effects in spinal cord injury (SCI)
Cell cycle inhibitors
The cell cycle is upregulated in both mitotic (astrocytes and microglia) and post-mitotic (neurons, oligodendrocytes) cells of the brain after CNS injury, and post-traumatic cell cycle activation is associated with caspase-mediated neuronal cell death and glial cell proliferation (Di Giovanni et al., 2005). Cell cycle inhibitors have been extensively studied for their role in cancer treatment, and inhibitors such as flavopiridol, roscovitine and olomoucine, have been shown to exert powerful
Conclusions
Neuroinflammation and microglial activation are key secondary injury mechanisms that contribute to chronic neurodegeneration and loss of neurological function after TBI. However, the neuroinflammatory response to TBI possesses both beneficial and detrimental effects, and these likely differ in the acute and delayed phases after injury. The key to developing future neuroprotective treatments that target post-traumatic neuroinflammation and microglial activation is to minimize the detrimental and
Acknowledgment
This work is supported by a pilot award from the National Capital Area Rehabilitation Research Network (R24HD050845) (D.J.L.).
References (176)
- et al.
Longitudinal changes in patients with traumatic brain injury assessed with diffusion-tensor and volumetric imaging
Neuroimage
(2008) - et al.
Fenofibrate, a peroxisome proliferator-activated receptor alpha agonist, exerts neuroprotective effects in traumatic brain injury
Neurosci. Lett.
(2005) - et al.
Inhibition of geranylgeranylation mediates the effects of 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitors on microglia
J. Biol. Chem.
(2004) - et al.
Microglia and inflammation-mediated neurodegeneration: multiple triggers with a common mechanism
Prog. Neurobiol.
(2005) - et al.
Activation of microglia by aggregated beta-amyloid or lipopolysaccharide impairs MHC-II expression and renders them cytotoxic whereas IFN-gamma and IL-4 render them protective
Mol. Cell Neurosci.
(2005) - et al.
Transient neuroprotection by minocycline following traumatic brain injury is associated with attenuated microglial activation but no changes in cell apoptosis or neutrophil infiltration
Exp. Neurol.
(2007) - et al.
In-vivo measurement of activated microglia in dementia
Lancet
(2001) - 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)
Simvastatin reduces secondary brain injury caused by cortical contusion in rats: possible involvement of TLR4/NF-kappaB pathway
Exp. Neurol.
Effect of aging on the microglial response to peripheral nerve injury
Neurobiol. Aging
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.
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.
Astroglia: important mediators of traumatic brain injury
Prog. 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.
Effects of progesterone on the inflammatory response to brain injury in the rat
Brain Res.
Beta-Amyloid protein-dependent nitric oxide production from microglial cells and neurotoxicity
Brain Res.
Alzheimer’s pathology in human temporal cortex surgically excised after severe brain injury
Exp. Neurol.
Progesterone is neuroprotective after transient middle cerebral artery occlusion in male rats
Brain Res.
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-10 inhibits endotoxin-induced pro-inflammatory cytokines in microglial cell cultures
J. Neuroimmunol.
Tumor necrosis factor-alpha, interleukin-1beta, and interferon-gamma stimulate gamma-secretase-mediated cleavage of amyloid precursor protein through a JNK-dependent MAPK pathway
J. Biol. Chem.
Role of microglia in neurotrauma
Neurotherapeutics
Neuroprotection for traumatic brain injury: translational challenges and emerging therapeutic strategies
Trends Pharmacol. Sci.
Interleukin-4 mediates the neuroprotective effects of rosiglitazone in the aged brain
Neurobiol. Aging
Extracellular signal-regulated kinase-mediated IL-1-induced cortical neuron damage during traumatic brain injury
Neurosci. Lett.
Immune activation in brain aging and neurodegeneration: too much or too little?
Neuron
Moderate and severe traumatic brain injury in adults
Lancet Neurol.
Clinical trials in traumatic brain injury: past experience and current developments
Neurotherapeutics
The chemokine system in diverse forms of macrophage activation and polarization
Trends Immunol.
Reactive microglia in patients with senile dementia of the Alzheimer type are positive for the histocompatibility glycoprotein HLA-DR
Neurosci. Lett.
Administration of estradiol and progesterone modulate the activities of antioxidant enzyme and aminotransferases in naturally menopausal rats
Exp. Gerontol.
Modulation of immune response by head injury
Injury
Interleukin-1 and neuronal injury
Nat. Rev. Immunol.
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.
The mechanisms of action of PPARs
Annu. Rev. Med.
PPAR-gamma agonists as regulators of microglial activation and brain inflammation
Curr. Pharm. Des.
Microglia-mediated neurotoxicity: uncovering the molecular mechanisms
Nat. Rev.
Quantitative structural changes in white and gray matter 1 year following traumatic brain injury in rats
Acta Neuropathol.
Delayed mGluR5 activation limits neuroinflammation and neurodegeneration after traumatic brain injury
J. Neuroinflamm.
Functional axonal regeneration through astrocytic scar genetically modified to digest chondroitin sulfate proteoglycans
J. Neurosci.
Role of the cell cycle in the pathobiology of central nervous system trauma
Cell cycle (Georgetown Tex)
PPAR-gamma dependent and independent effects on macrophage-gene expression in lipid metabolism and inflammation
Nat. Med.
Atorvastatin induction of VEGF and BDNF promotes brain plasticity after stroke in mice
J. Cereb. Blood Flow Metab.
Neurological recovery-promoting, anti-inflammatory, and anti-oxidative effects afforded by fenofibrate, a PPAR alpha agonist, in traumatic brain injury
J. Neurotrauma
Cited by (522)
Generation of induced pluripotent stem cells from rat fibroblasts and optimization of its differentiation into mature functional neurons
2024, Journal of Neuroscience MethodsTrehalose: A promising new treatment for traumatic brain injury? A systematic review of animal evidence
2024, Interdisciplinary Neurosurgery: Advanced Techniques and Case ManagementInflammation, brain connectivity, and neuromodulation in post-traumatic headache
2024, Brain, Behavior, and Immunity - HealthNeurobehavioral and inflammatory responses following traumatic brain injury in male and female mice
2024, Behavioural Brain ResearchRole of regulatory non-coding RNAs in traumatic brain injury
2024, Neurochemistry International