Lipoxins and resolvins have anti-inflammatory and pro-resolving actions and accumulating evidence indicates that these lipid mediators also attenuate pain-like behavior in a number of experimental models of inflammation and tissue injury-induced pain. The present study was undertaken to assess if spinal administration of lipoxin A4 (LXA4) or 17 (R)-resolvin D1 (17(R)-RvD1) attenuates mechanical hypersensitivity in the carrageenan model of peripheral inflammation in the rat. Given the emerging role of spinal cytokines in the generation and maintenance of inflammatory pain we measured cytokine levels in the cerebrospinal fluid (CSF) after LXA4 or 17(R)-RvD1 administration, and the ability of these lipid metabolites to prevent stimuli-induced release of cytokines from cultured primary spinal astrocytes. We found that intrathecal bolus injection of LXA4 and17(R)-RvD1 attenuated inflammation-induced mechanical hypersensitivity without reducing the local inflammation. Furthermore, both LXA4 and 17(R)-RvD1 reduced carrageenan-induced tumor necrosis factor (TNF) release in the CSF, while only 17(R)-RvD1attenuated LPS and IFN-γ-induced TNF release in astrocyte cell culture. In conclusion, this study demonstrates that lipoxins and resolvins potently suppress inflammation-induced mechanical hypersensitivity, possibly by attenuating cytokine release from spinal astrocytes. The inhibitory effect of lipoxins and resolvins on spinal nociceptive processing puts them in an intriguing position in the search for novel pain therapeutics.

Supplemental Digital Content is Available in the Text.Glial inhibitors only reverse mechanical hypersensitivity in male mice subjected to arthritis. No obvious arthritis-related transcriptional difference was identified between male and female spinal microglia.

Immune-related events in the periphery can remotely affect brain function, contributing to neurodegenerative processes and cognitive decline. In mice, peripheral surgery induces a systemic inflammatory response associated with changes in hippocampal synaptic plasticity and transient cognitive decline, however, the underlying mechanisms remain unknown. Here we investigated the effect of peripheral surgery on neuronal-glial function within hippocampal neuronal circuits of relevance to cognitive processing in male mice at 6, 24, and 72 h postsurgery. At 6 h we detect the proinflammatory cytokine IL-6 in the hippocampus, followed up by alterations in the mRNA and protein expression of astrocytic and neuronal proteins necessary for optimal energy supply to the brain and for the reuptake and recycling of glutamate in the synapse. Similarly, at 24 h postsurgery the mRNA expression of structural proteins (GFAP and AQP4) was compromised. At this time point, functional analysis in astrocytes revealed a decrease in resting calcium signaling. Examination of neuronal activity by whole-cell patch-clamp shows elevated levels of glutamatergic transmission and changes in AMPA receptor subunit composition at 72 h postsurgery. Finally, lactate, an essential energy substrate produced by astrocytes and critical for memory formation, decreases at 6 and 72 h after surgery. Based on temporal parallels with our previous studies, we propose that the previously reported cognitive decline observed at 72 h postsurgery in mice might be the consequence of temporal hippocampal metabolic, structural, and functional changes in astrocytes that lead to a disruption of the neuroglial metabolic coupling and consequently to a neuronal dysfunction. A growing body of evidence suggests that surgical trauma launches a systemic inflammatory response that reaches the brain and associates with immune activation and cognitive decline. Understanding the mechanisms by which immune-related events in the periphery can influence brain processes is essential for the development of therapies to prevent or treat postoperative cognitive dysfunction and other forms of cognitive decline related to immune-to-brain communication, such as Alzheimer's and Parkinson's diseases. Here we describe the temporal orchestration of a series of metabolic, structural, and functional changes after aseptic trauma in mice related to astrocytes and later in neurons that emphasize the role of astrocytes as key intermediaries between peripheral immune events, neuronal processing, and potentially cognition.

This study shows that inflammation during active RA has long-term consequences on molecular remodelling and contractile function of the heart, which further supports that rheumatology patients should be followed for development of heart failure.

After contusion spinal cord injury (SCI), astrocytes become reactive and form a glial scar. While this reduces spreading of the damage by containing the area of injury, it inhibits regeneration. One strategy to improve the recovery after SCI is therefore to reduce the inhibitory effect of the scar, once the acute phase of the injury has passed. The pleiotropic cytokine interleukin-6 (IL-6) is secreted immediately after injury and regulates scar formation; however, little is known about the role of IL-6 in the sub-acute phases of SCI. Interestingly, IL-6 also promotes axon regeneration, and therefore its induction in reactive astrocytes may improve regeneration after SCI. We found that IL-6 is expressed by astrocytes and neurons one week post-injury and then declines. Using primary cultures of rat astrocytes we delineated the molecular mechanisms that regulate IL-6 expression and secretion. IL-6 expression requires activation of p38 and depends on NF-κB transcriptional activity. Activation of these pathways in astrocytes occurs when the PI3K-mTOR-AKT pathway is inhibited. Furthermore, we found that an increase in cytosolic calcium concentration was necessary for IL-6 secretion. To induce IL-6 secretion in astrocytes, we used torin2 and rapamycin to block the PI3K-mTOR pathway and increase cytosolic calcium, respectively. Treating injured animals with torin2 and rapamycin for two weeks, starting two weeks after injury when the scar has been formed, lead to a modest effect on mechanical hypersensitivity, limited to the period of treatment. These data, taken together, suggest that treatment with torin2 and rapamycin induces IL-6 secretion by astrocytes and may contribute to the reduction of mechanical hypersensitivity after SCI.

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Background: There are multiple promising treatment strategies for central nervous system trauma and disease. However, to develop clinically potent and safe treatments, models of human-specific conditions are needed to complement in vitro and in vivo animal model-based studies. Methods: We established human brain stem and spinal cord (cross-and longitudinal sections) organotypic cultures (hOCs) from first trimester tissues after informed consent by donor and ethical approval by the Regional Human Ethics Committee, Stockholm (lately referred to as Swedish Ethical Review Authority), and The National Board of Health and Welfare, Sweden. We evaluated the stability of hOCs with a semi-quantitative hOC score, immunohistochemistry, flow cytometry, Ca 2+ signaling, and electrophysiological analysis. We also applied experimental allogeneic human neural cell therapy after injury in the ex vivo spinal cord slices. Results: The spinal cord hOCs presented relatively stable features during 7-21 days in vitro (DIV) (except a slightly increased cell proliferation and activated glial response). After contusion injury performed at 7 DIV, a significant reduction of the hOC score, increase of the activated caspase-3 + cell population, and activated microglial populations at 14 days postinjury compared to sham controls were observed. Such elevation in the activated caspase-3 + population and activated microglial population was not observed after allogeneic human neural cell therapy. Conclusions: We conclude that human spinal cord slice cultures have potential for future structural and functional studies of human spinal cord development, injury, and treatment strategies.