Brain, behavior, and immunity
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Brain Behav. Immun. · Nov 2017
Treatment with an interleukin-1 receptor antagonist mitigates neuroinflammation and brain damage after polytrauma.
Traumatic brain injury (TBI) and long bone fracture are common in polytrauma. This injury combination in mice results in elevated levels of the pro-inflammatory cytokine interleukin-1β (IL-1β) and exacerbated neuropathology when compared to isolated-TBI. Here we examined the effect of treatment with an IL-1 receptor antagonist (IL-1ra) in mice given a TBI and a concomitant tibial fracture (i.e., polytrauma). ⋯ At 48h post-injury, markers for activated microglia and astrocytes, as well as neutrophils and edema, were decreased in polytrauma mice treated with IL-1ra compared to polytrauma mice treated with vehicle. At 14weeks post-injury, MRI analysis demonstrated that IL-1ra treatment after polytrauma reduced volumetric loss in the injured cortex and mitigated track-weighted MRI markers for axonal injury. As IL-1ra (Anakinra) is approved for human use, it may represent a promising therapy in polytrauma cases involving TBI and fracture.
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There is a growing emphasis on the relationship between the microorganisms inhabiting the gut (gastrointestinal microbiota) and human health. The emergence of a microbiota-gut-brain axis to describe the complex networks and relationship between the gastrointestinal microbiota and host reflects the major influence this environment may have in brain health and disorders of the central nervous system (CNS). Bidirectional communication between the microbiota and the CNS occurs through autonomic, neuroendocrine, enteric, and immune system pathways. ⋯ Perturbations of the gut microbial community have already been implicated in multiple host diseases such as obesity, diabetes, and inflammation, while recent evidence suggests a potential role of the microbiota-gut-brain axis in neuropsychiatric disorders, such as depression and anxiety. Here, we review the current literature related to the influence of the gut microbial community on central nervous system function, with a specific focus on anxiety and depressive symptoms. The role of stress and stress-mediated changes in autonomic, neuroendocrine, immune, and neurotransmitter systems are examined, followed by a discussion of the role of the microbiota in novel gastrointestinal-based treatment options for the prevention and treatment of brain-based disorders such as anxiety and depression.
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Brain Behav. Immun. · Nov 2017
ReviewThe bidirectional gut-brain-microbiota axis as a potential nexus between traumatic brain injury, inflammation, and disease.
As head injuries and their sequelae have become an increasingly salient matter of public health, experts in the field have made great progress elucidating the biological processes occurring within the brain at the moment of injury and throughout the recovery thereafter. Given the extraordinary rate at which our collective knowledge of neurotrauma has grown, new insights may be revealed by examining the existing literature across disciplines with a new perspective. This article will aim to expand the scope of this rapidly evolving field of research beyond the confines of the central nervous system (CNS). ⋯ Despite this void, the proposed mechanisms emanating from a damaged gut are closely implicated in the inflammatory processes known to promote neuropathology in the brain following TBI, which suggests the gut-brain axis may be a therapeutic target to reduce the risk of Chronic Traumatic Encephalopathy and other neurodegenerative diseases following TBI. To better appreciate how various peripheral influences are implicated in the health of the CNS following TBI, this paper will also review the secondary biological injury mechanisms and the dynamic pathophysiological response to neurotrauma. Together, this review article will attempt to connect the dots to reveal novel insights into the bidirectional influence of the gut-brain axis and propose a conceptual model relevant to the recovery from TBI and subsequent risk for future neurological conditions.
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Brain Behav. Immun. · Nov 2017
Deletion of the P2X4 receptor is neuroprotective acutely, but induces a depressive phenotype during recovery from ischemic stroke.
Acute ischemic injury leads to severe neuronal loss. One of the key mechanisms responsible for this effect is inflammation, which is characterized by the activation of myeloid cells, including resident microglia and infiltrating monocytes/macrophages. P2X4 receptors (P2X4Rs) present on these immune cells modulate the inflammatory response. For example, excessive release of adenosine triphosphate during acute ischemic stroke triggers stimulation of P2X4Rs, leading to myeloid cell activation and proliferation and further exacerbating post-ischemic inflammation. In contrast, during recovery P2X4Rs activation on microglia leads to the release of brain-derived neurotrophic factor (BDNF), which alleviate depression, maintain synaptic plasticity and hasten post-stroke behavioral recovery. Therefore, we hypothesized that deletion of the P2X4R specifically from myeloid cells would have differential effects on acute versus chronic recovery following stroke. ⋯ P2X4R deletion protects against stroke acutely but predisposes to depression-like behavior chronically after stroke. Thus, a time-sensitive approach should be considered when targeting P2X4Rs after stroke.