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Experimental neurology [journal]
- Scaling in Neurotrauma: How do we apply animal experiments to people? [REVIEW]
- Exp Neurol 2014 Jul 14.
Scaling is an essential component for translating the clinical outcomes of a neurotrauma model to the human equivalent. This article reviews the principles of biomechanical scaling for traumatic brain injuries, and a number of different approaches to scaling the dose (inputs) and response (outputs) of an animal model to humans are highlighted. A particular focus on blast injury scaling is given as an ongoing area of research, and discussion on the implications of scaling on the current blast TBI literature is provided. The risk of using neurotrauma models without considering an appropriate scaling method is that injuries may be induced with non-realistic loading conditions, and the injury mechanisms produced in the laboratory may not be consistent with those in the clinical setting.
- Non-mammalian model systems for studying neuro-immune interactions after spinal cord injury. [REVIEW]
- Exp Neurol 2014 Aug.:130-140.
Mammals exhibit poor recovery after injury to the spinal cord, where the loss of neurons and neuronal connections can be functionally devastating. In contrast, it has long been appreciated that many non-mammalian vertebrate species exhibit significant spontaneous functional recovery after spinal cord injury (SCI). Identifying the biological responses that support an organism's inability or ability to recover function after SCI is an important scientific and medical question. While recent advances have been made in understanding the responses to SCI in mammals, we remain without an effective clinical therapy for SCI. A comparative biological approach to understanding responses to SCI in non-mammalian vertebrates will yield important insights into mechanisms that promote recovery after SCI. Presently, mechanistic studies aimed at elucidating responses, both intrinsic and extrinsic to neurons, that result in different regenerative capacities after SCI across vertebrates are just in their early stages. There are several inhibitory mechanisms proposed to impede recovery from SCI in mammals, including reactive gliosis and scarring, myelin associated proteins, and a suboptimal immune response. One hypothesis to explain the robust regenerative capacity of several non-mammalian vertebrates is a lack of some or all of these inhibitory signals. This review presents the current knowledge of immune responses to SCI in several non-mammalian species that achieve anatomical and functional recovery after SCI. This subject is of growing interest, as studies increasingly show both beneficial and detrimental roles of the immune response following SCI in mammals. A long-term goal of biomedical research in all experimental models of SCI is to understand how to promote functional recovery after SCI in humans. Therefore, understanding immune responses to SCI in non-mammalian vertebrates that achieve functional recovery spontaneously may identify novel strategies to modulate immune responses in less regenerative species and promote recovery after SCI.
- The paradox of chronic neuroinflammation, systemic immune suppression, autoimmunity after traumatic chronic spinal cord injury. [REVIEW]
- Exp Neurol 2014 Aug.:121-129.
During the transition from acute to chronic stages of recovery after spinal cord injury (SCI), there is an evolving state of immunologic dysfunction that exacerbates the problems associated with the more clinically obvious neurologic deficits. Since injury directly affects cells embedded within the "immune privileged/specialized" milieu of the spinal cord, maladaptive or inefficient responses are likely to occur. Collectively, these responses qualify as part of the continuum of "SCI disease" and are important therapeutic targets to improve neural repair and neurological outcome. Generic immune suppressive therapies have been largely unsuccessful, mostly because inflammation and immunity exert both beneficial (plasticity enhancing) and detrimental (e.g. glia- and neurodegenerative; secondary damage) effects and these functions change over time. Moreover, "compartimentalized" investigations, limited to only intraspinal inflammation and associated cellular or molecular changes in the spinal cord, neglect the reality that the structure and function of the CNS are influenced by systemic immune challenges and that the immune system is 'hardwired' into the nervous system. Here, we consider this interplay during the progression from acute to chronic SCI. Specifically, we survey impaired/non-resolving intraspinal inflammation and the paradox of systemic inflammatory responses in the context of ongoing chronic immune suppression and autoimmunity. The concepts of systemic inflammatory response syndrome (SIRS), compensatory anti-inflammatory response syndrome (CARS) and "neurogenic" spinal cord injury-induced immune depression syndrome (SCI-IDS) are discussed as determinants of impaired "host-defense" and trauma-induced autoimmunity.
- Is neuroinflammation in the injured spinal cord different than in the brain? Examining intrinsic differences between the brain and spinal cord. [REVIEW]
- Exp Neurol 2014 Aug.:112-120.
The field of neuroimmunology is rapidly advancing. There is a growing appreciation for heterogeneity, both in inflammatory composition and region-specific inflammatory responses. This understanding underscores the importance of developing targeted immunomodulatory therapies for treating neurological disorders. Concerning neurotrauma, there is a dearth of publications directly comparing inflammatory responses in the brain and spinal cord after injury. The question therefore remains as to whether inflammatory cells responding to spinal cord vs. brain injury adopt similar functions and are therefore amenable to common therapies. In this review, we address this question while revisiting and modernizing the conclusions from publications that have directly compared inflammation across brain and spinal cord injuries. By examining molecular differences, anatomical variations, and inflammatory cell phenotypes between the injured brain and spinal cord, we provide insight into how neuroinflammation relates to neurotrauma and into fundamental differences between the brain and spinal cord.
- The systemic response to CNS injury. [REVIEW]
- Exp Neurol 2014 Aug.:105-111.
Inflammation within the brain or spinal cord has the capacity to damage neurons and is known to contribute to long-term disability in a spectrum of central nervous system (CNS) pathologies. However, there is a more profound increase in the recruitment of potentially damaging populations of leukocytes to the spinal cord than to the brain after equivalent injuries. Increased levels of inflammatory cytokines and chemokines in the spinal cord underpin this dissimilarity after injury, which also appears to be very sensitive to processes that operate within organs distant from the primary injury site such as the liver, lung and spleen. Indeed, CNS injury per se can generate profound changes in gene expression and the cellularity of these organs, which, as a consequence, gives rise to secondary organ damage. Our understanding of the local inflammatory processes that can damage neurons is becoming clearer, but our understanding of how the peripheral immune system coordinates the response to CNS injury and how any concomitant infections or injury might impact on the outcome of CNS injury is not so well developed. It is clear that the orientation of the response to peripheral challenges, be it a pro- or anti-inflammatory effect, appears to be dependent on the nature and timing of events. Here, the importance of the inter-relationship between inflammation in the CNS and the consequent inflammatory response in peripheral tissues is highlighted.
- Immune modulatory therapies for spinal cord injury - Past, present and future. [REVIEW]
- Exp Neurol 2014 Aug.:91-104.
Historically, the immune response after spinal cord injury was considered largely detrimental owing to the release of neurotoxic factors. While there is validity to this view, there is much greater heterogeneity of immune cells than was previously realized. Associated with this heterogeneity of immune cell subtypes, there is diversity of functions of immune cells that is still poorly understood after spinal cord injury. Modulating the immune system requires improved understanding of the major players: those immune cell subtypes that are more detrimental than beneficial and those that are important in repair. In this review we will discuss the early findings that supported the use of various anti-inflammatory medications as well as the evolving concept that not all immune subtypes are detrimental and some might even be beneficial. In the last section we will highlight the need to characterize better the role of immune cell subsets in the hopes of developing potential therapeutic targets for the future.
- Lymphocytes and autoimmunity after spinal cord injury. [REVIEW]
- Exp Neurol 2014 Aug.:78-90.
Over the past 15years an immense amount of data has accumulated regarding the infiltration and activation of lymphocytes in the traumatized spinal cord. Although the impact of the intraspinal accumulation of lymphocytes is still unclear, modulation of the adaptive immune response via active and passive vaccination is being evaluated for its preclinical efficacy in improving the outcome for spinal-injured individuals. The complexity of the interaction between the nervous and the immune systems is highlighted in the contradictions that appear in response to these modulations. Current evidence regarding augmentation and inhibition of the adaptive immune response to spinal cord injury is reviewed with an aim toward reconciling conflicting data and providing consensus issues that may be exploited in future therapies. Opportunities such an approach may provide are highlighted as well as the obstacles that must be overcome before such approaches can be translated into clinical trials.
- Cytokine pathways regulating glial and leukocyte function after spinal cord and peripheral nerve injury. [REVIEW]
- Exp Neurol 2014 Aug.:62-77.
Injury to the nervous system causes the almost immediate release of cytokines by glial cells and neurons. These cytokines orchestrate a complex array of responses leading to microgliosis, immune cell recruitment, astrogliosis, scarring, and the clearance of cellular debris, all steps that affect neuronal survival and repair. This review will focus on cytokines released after spinal cord and peripheral nerve injury and the primary signalling pathways triggered by these inflammatory mediators. Notably, the following cytokine families will be covered: IL-1, TNF, IL-6-like, TGF-β, and IL-10. Whether interfering with cytokine signalling could lead to novel therapies will also be discussed. Finally, the review will address whether manipulating the above-mentioned cytokine families and signalling pathways could exert distinct effects in the injured spinal cord versus peripheral nerve.
- Neuroinflammatory contributions to pain after SCI: Roles for central glial mechanisms and nociceptor-mediated host defense. [REVIEW]
- Exp Neurol 2014 Aug.:48-61.
Neuropathic pain after spinal cord injury (SCI) is common, often intractable, and can be severely debilitating. A number of mechanisms have been proposed for this pain, which are discussed briefly, along with methods for revealing SCI pain in animal models, such as the recently applied conditioned place preference test. During the last decade, studies of animal models have shown that both central neuroinflammation and behavioral hypersensitivity (indirect reflex measures of pain) persist chronically after SCI. Interventions that reduce neuroinflammation have been found to ameliorate pain-related behavior, such as treatment with agents that inhibit the activation states of microglia and/or astroglia (including IL-10, minocycline, etanercept, propentofylline, ibudilast, licofelone, SP600125, carbenoxolone). Reversal of pain-related behavior has also been shown with disruption by an inhibitor (CR8) and/or genetic deletion of cell cycle-related proteins, deletion of a truncated receptor (trkB.T1) for brain-derived neurotrophic factor (BDNF), or reduction by antisense knockdown or an inhibitor (AMG9810) of the activity of channels (TRPV1 or Nav1.8) important for electrical activity in primary nociceptors. Nociceptor activity is known to drive central neuroinflammation in peripheral injury models, and nociceptors appear to be an integral component of host defense. Thus, emerging results suggest that spinal and systemic effects of SCI can activate nociceptor-mediated host defense responses that interact via neuroinflammatory signaling with complex central consequences of SCI to drive chronic pain. This broader view of SCI-induced neuroinflammation suggests new targets, and additional complications, for efforts to develop effective treatments for neuropathic SCI pain.
- Complement and spinal cord injury: Traditional and non-traditional aspects of complement cascade function in the injured spinal cord microenvironment. [REVIEW]
- Exp Neurol 2014 Aug.:35-47.
The pathology associated with spinal cord injury (SCI) is caused not only by primary mechanical trauma, but also by secondary responses of the injured CNS. The inflammatory response to SCI is robust and plays an important but complex role in the progression of many secondary injury-associated pathways. Although recent studies have begun to dissect the beneficial and detrimental roles for inflammatory cells and proteins after SCI, many of these neuroimmune interactions are debated, not well understood, or completely unexplored. In this regard, the complement cascade is a key component of the inflammatory response to SCI, but is largely underappreciated, and our understanding of its diverse interactions and effects in this pathological environment is limited. In this review, we discuss complement in the context of SCI, first in relation to traditional functions for complement cascade activation, and then in relation to novel roles for complement proteins in a variety of models.