Osteopontin expression in acute immune response mediates hippocampal synaptogenesis and adaptive outcome following cortical brain injury

Chan, Julie L.; Reeves, Thomas M.; Phillips, Linda R.

doi:10.1016/j.expneurol.2014.08.015

Cited by 48 publications

(57 citation statements)

References 123 publications

(148 reference statements)

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“…At the end of treatment intervals, flasks were photographed with phase microscopy to document cell morphology, then media was removed, flasks rinsed with Dulbecco’s PBS ( + Ca 2+ , Mg 2+ ) and cells scraped free (in Dulbecco’s PBS (‐Ca 2+ , Mg 2+ ) for protein extraction. As for tissue extracts, protein aliquots were separated by 4-12% SDS-PAGE and transferred to PVDF membrane (Reeves et al, 2010; Chan et al, 2014) prior to WB probe of IL1-β ( R&D Systems; 1:200) expression. Immunopositive bands were also visualized with Gene Snap ( Syngene ), relative optical density (ROD) measured with Gene Tools and results reported as percent of untreated control values run on the same blot.…”

Section: Methodsmentioning

confidence: 99%

Targeting Kv1.3 channels to reduce white matter pathology after traumatic brain injury

Reeves

Trimmer

Colley

et al. 2016

Experimental Neurology

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Axonal injury is present in essentially all clinically significant cases of traumatic brain injury (TBI). While no effective treatment has been identified to date, experimental TBI models have shown promising axonal protection using immunosuppressants FK506 and Cyclosporine-A, with treatment benefits attributed to calcineurin inhibition or protection of mitochondrial function. However, growing evidence suggests neuroprotective efficacy of these compounds may also involve direct modulation of ion channels, and in particular Kv1.3. The present study tested whether blockade of Kv1.3 channels, using Clofazimine (CFZ), would alleviate TBI-induced white matter pathology in rodents. Postinjury CFZ administration prevented suppression of compound action potential (CAP) amplitude in the corpus callosum of adult rats following midline fluid percussion TBI, with injury and treatment effects primarily expressed in unmyelinated CAPs. Kv1.3 protein levels in callosal tissue extracts were significantly reduced postinjury, but this loss was prevented by CFZ treatment. In parallel, CFZ also attenuated the injury-induced elevation in pro-inflammatory cytokine IL1-β. The effects of CFZ on glial function were further studied using mixed microglia/astrocyte cell cultures derived from P3-5 mouse corpus callosum. Cultures of callosal glia challenged with lipopolysaccharide exhibited a dramatic increase in IL1-β levels, accompanied by reactive morphological changes in microglia, both of which were attenuated by CFZ treatment. These results support a cell specific role for Kv1.3 signaling in white matter pathology after TBI, and suggest a treatment approach based on the blockade of these channels. This therapeutic strategy may be especially efficacious for normalizing neuro-glial interactions affecting unmyelinated axons after TBI.

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Section: Methodsmentioning

confidence: 99%

Targeting Kv1.3 channels to reduce white matter pathology after traumatic brain injury

Reeves

Trimmer

Colley

et al. 2016

Experimental Neurology

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“…While a few studies have examined the role of brain inflammation (Dietrich et al, 2004;Haber et al, 2013;Chan et al, 2014;Faden et al, 2015), the contribution of systemic inflammation to TBI pathology has not been fully examined. The present investigation into TBI-induced BBB permeability revealed the following three key findings: (1) loss of nAChRa7 exacerbates systemic inflammation and BBB permeability; (2) stimulation of nAChRa7 using a selective agonist or a positive allosteric modulator reduces BBB permeability after injury; and (3) blockade of nAChRa7 within the spleen exacerbates, while their activation reduces, BBB permeability.…”

Section: Discussionmentioning

confidence: 99%

Activation of Alpha 7 Cholinergic Nicotinic Receptors Reduce Blood–Brain Barrier Permeability following Experimental Traumatic Brain Injury

et al. 2016

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Traumatic brain injury (TBI)is a major human health concern that has the greatest impact on young men and women. The breakdown of the blood-brain barrier (BBB) is an important pathological consequence of TBI that initiates secondary processes, including infiltration of inflammatory cells, which can exacerbate brain inflammation and contribute to poor outcome. While the role of inflammation within the injured brain has been examined in some detail, the contribution of peripheral/systemic inflammation to TBI pathophysiology is largely unknown. Recent studies have implicated vagus nerve regulation of splenic cholinergic nicotinic acetylcholine receptor ␣7 (nAChRa7) signaling in the regulation of systemic inflammation. However, it is not known whether this mechanism plays a role in TBI-triggered inflammation and BBB breakdown. Following TBI, we observed that plasma TNF-␣ and IL-1␤ levels, as well as BBB permeability, were significantly increased in nAChRa7 null mice (Chrna7 Ϫ / Ϫ ) relative to wild-type mice. The administration of exogenous IL-1␤ and TNF-␣ to brain-injured animals worsened Evans Blue dye extravasation, suggesting that systemic inflammation contributes to TBI-triggered BBB permeability. Systemic administration of the nAChRa7 agonist PNU-282987 or the positive allosteric modulator PNU-120596 significantly attenuated TBI-triggered BBB compromise. Supporting a role for splenic nAChRa7 receptors, we demonstrate that splenic injection of the nicotinic receptor blocker ␣-bungarotoxin increased BBB permeability in brain-injured rats, while PNU-282987 injection decreased such permeability. These effects were not seen when ␣-bungarotoxin or PNU-282987 were administered to splenectomized, brain-injured rats. Together, these findings support the short-term use of nAChRa7-activating agents as a strategy to reduce TBI-triggered BBB permeability.

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“…Treatment with an MMP inhibitor reduced BBB disruption and brain water accumulation. In aggregate, MMP-9 appears to contribute to both neuronal cell loss following TBI and the facilitation of regenerative processes (Jourquin et al 2003;Reeves et al 2003;Chan et al 2014;Phillips et al 2014).…”

Section: Brain Injurymentioning

confidence: 99%

MMP‐9 in translation: from molecule to brain physiology, pathology, and therapy

Vafadari

Salamian

Kaczmarek

2016

Journal of Neurochemistry

292

257

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Matrix metalloproteinase-9 (MMP-9) is a member of the metzincin family of mostly extracellularly operating proteases. Despite the fact that all of these enzymes might be target promiscuous, with largely overlapping catalogs of potential substrates, MMP-9 has recently emerged as a major and apparently unique player in brain physiology and pathology. The specificity of MMP-9 may arise from its very local and time-restricted actions, even when released in the brain from cells of various types, including neurons, glia, and leukocytes. In fact, the quantity of MMP-9 is very low in the naive brain, but it is markedly activated at the levels of enzymatic activity, protein abundance, and gene expression following various physiological stimuli and pathological insults. Neuronal MMP-9 participates in synaptic plasticity by controlling the shape of dendritic spines and function of excitatory synapses, thus playing a pivotal role in learning, memory, and cortical plasticity. When improperly unleashed, MMP-9 contributes to a large variety of brain disorders, including epilepsy, schizophrenia, autism spectrum disorder, brain injury, stroke, neurodegeneration, pain, brain tumors, etc. The foremost mechanism of action of MMP-9 in brain disorders appears to be its involvement in immune/inflammation responses that are related to the enzyme's ability to process and activate various cytokines and chemokines, as well as its contribution to bloodbrain barrier disruption, facilitating the extravasation of leukocytes into brain parenchyma. However, another emerging possibility (i.e., the control of MMP-9 over synaptic plasticity) should not be neglected. The translational potential of MMP-9 has already been recognized in both the diagnosis and treatment domains. The most striking translational aspect may be the discovery of MMP-9 up-regulation in a mouse model of Fragile X syndrome, quickly followed by human studies and promising clinical trials that have sought to inhibit MMP-9. With regard to diagnosis, suggestions have been made to use MMP-9 alone or combined with tissue inhibitor of matrix metalloproteinase-1 or brain-derived neurotrophic factor as disease biomarkers.

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Osteopontin expression in acute immune response mediates hippocampal synaptogenesis and adaptive outcome following cortical brain injury

Cited by 48 publications

References 123 publications

Targeting Kv1.3 channels to reduce white matter pathology after traumatic brain injury

Targeting Kv1.3 channels to reduce white matter pathology after traumatic brain injury

Activation of Alpha 7 Cholinergic Nicotinic Receptors Reduce Blood–Brain Barrier Permeability following Experimental Traumatic Brain Injury

MMP‐9 in translation: from molecule to brain physiology, pathology, and therapy

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