Abstract
Sphingosine 1‐phosphate receptors (S1
PR
) are G protein‐coupled and compose a family with five subtypes, S1P1R–S1P5R. The drug Gilenya
®
(Novartis, Basel, Switzerland) (Fingolimod;
FTY
720) ...targets S1
PR
s and was the first oral therapy for patients with relapsing‐remitting multiple sclerosis (
MS
). The phosphorylated form of
FTY
720 (
pFTY
720) binds S1
PR
s causing initial agonism, then subsequent receptor internalization and functional antagonism. Internalization of S1P1R attenuates sphingosine 1‐phosphate (S1P)‐mediated egress of lymphocytes from lymph nodes, limiting aberrant immune function in
MS
.
pFTY
720 also exerts direct actions on neurons and glial cells which express S1
PR
s. In this study, we investigated the regulation of pro‐inflammatory chemokine release by S1
PR
s in enriched astrocytes and microglial cultures. Astrocytes and microglia were stimulated with lipopolysaccharide (
LPS
) and increases in C‐X‐C motif chemokine 5 (
CXCL
5), also known as
LIX
(lipopolysaccharide‐induced
CXC
chemokine) expression were quantified. Results showed that
pFTY
720 attenuated
LPS
‐induced
CXCL
5 (
LIX
) protein release from astrocytes, as did the S1P1R selective agonist,
SEW
2871. In addition,
pFTY
720 blocked messenger ribonucleic acid (
mRNA
) transcription of the chemokines, (i)
CXCL
5/
LIX
, (ii) C‐X‐C motif chemokine 10 (
CXCL
10) also known as interferon gamma‐induced protein 10 (
IP
10) and (iii) chemokine (C‐C motif) ligand 2 (
CCL
2) also known as monocyte chemoattractant protein 1 (
MCP
1). Interestingly, inhibition of sphingosine kinase attenuated
LPS
‐induced increases in
mRNA
levels of all three chemokines, suggesting that
LPS
‐
TLR
4 (Toll‐like receptor 4) signalling may enhance chemokine expression via S1P‐S1
PR
transactivation. Lastly, these observations were not limited to astrocytes since we also found that
pFTY
720 attenuated
LPS
‐induced release of
CXCL
5 from microglia. These data highlight a role for S1
PR
signalling in regulating the levels of chemokines in glial cells and support the notion that
pFTY
720 efficacy in multiple sclerosis may involve the direct modulation of astrocytes and microglia.
image
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
An essential aspect of normal brain function is the bidirectional interaction and communication between neurons and neighbouring glial cells. To this end, the brain has evolved ligand–receptor ...partnerships that facilitate crosstalk between different cell types. The chemokine, fractalkine (FKN), is expressed on neuronal cells, and its receptor, CX
3
CR1, is predominantly expressed on microglia. This review focuses on several important functional roles for FKN/CX
3
CR1 in both health and disease of the central nervous system. It has been posited that FKN is involved in microglial infiltration of the brain during development. Microglia, in turn, are implicated in the developmental synaptic pruning that occurs during brain maturation. The abundance of FKN on mature hippocampal neurons suggests a homeostatic non-inflammatory role in mechanisms of learning and memory. There is substantial evidence describing a role for FKN in hippocampal synaptic plasticity. FKN, on the one hand, appears to prevent excess microglial activation in the absence of injury while promoting activation of microglia and astrocytes during inflammatory episodes. Thus, FKN appears to be neuroprotective in some settings, whereas it contributes to neuronal damage in others. Many progressive neuroinflammatory disorders that are associated with increased microglial activation, such as Alzheimer's disease, show disruption of the FKN/CX
3
CR1 communication system. Thus, targeting CX
3
CR1 receptor hyperactivation with specific antagonists in such neuroinflammatory conditions may eventually lead to novel neurotherapeutics.
Hippocampal memory-associated synaptic plasticity is driven by a cascade of transcription and new protein synthesis. In vitro electrophysiological studies on acute hippocampal slices have elucidated ...much of what we know about this molecular cascade. Curiously, these slices require a period of “equilibration” for the recovery of electrophysiological properties such as LTP, implying ongoing time-dependent molecular events necessary for full expression of plasticity. Using standard immunofluorescence combined with confocal imaging and a novel data analysis approach, we implicate the transcription factor NF-κB in this plasticity-related molecular adaptation during equilibration. Marked differences in basal NF-κB activity in distinct cell types of the hippocampus were observed, with the amount of active NF-κB increasing throughout the 2-h equilibration period in all cell types. Moreover, distinct hippocampal neuronal subfields exhibit very different responses to the GABA
A
receptor blocker picrotoxin, the presence of which is required to achieve LTP in the dentate gyrus. These findings have implications for the use of acute hippocampal slices to study the effects of compounds that signal through NF-κB on synaptic plasticity. Further investigation into the cellular processes that occur during this molecular adaptation may increase our understanding of plasticity-related events common to both LTP and memory formation.
A learning event initiates a cascade of altered gene expression leading to synaptic remodelling within the hippocampal dentate gyrus, a structure vital to memory formation. To illuminate this ...transcriptional program of synaptic plasticity we used microarrays to quantify mRNA from the rat dentate gyrus at increasing times following passive avoidance learning. Approximately, 500 known genes were transcriptionally regulated across the 24 h post-training period. The 0-2 h period saw up-regulation of genes involved in transcription while genes with a role in synaptic/cytoskeletal structure increased 0-6 h, consistent with structural rearrangements known to occur at these times. The most striking feature was the profound down-regulation, across all functional groups, 12 h post-training. Bioinformatics analysis identified the likely transcription factors controlling gene expression in each post-training period. The role of NFκB, implicated in the early post-training period was subsequently confirmed with activation and nuclear translocation seen in dentate granule neurons following training. mRNA changes for four genes, LRP3 (0 h), alpha actin (3 h), SNAP25 and NSF (6-12 h), were validated at message and/or protein level and shown to be learning specific. Thus, the memory-associated transcriptional cascade supports the cardinal periods of synaptic loosening, reorganisation and selection thought to underpin the process of long-term memory consolidation in the hippocampus.
Full text
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
37.
Calcium homeostasis and exercise Henderson, S A; Graham, H K; Mollan, R A ...
International orthopaedics,
01/1989, Volume:
13, Issue:
1
Journal Article
Peer reviewed
Calcium homeostasis is altered by strenuous physical exercise. The mechanism is unclear. Our study was designed to investigate this relationship, particularly any associated changes in the calcium ...regulating hormones. Six subjects carried out a strenuous exercise programme for 10 min on a bicycle ergometer. Blood samples were analysed for ionized calcium, total calcium, calcitonin and pH. Plasma parathormone was assayed using a new and very sensitive N-terminal assay. Serum ionized calcium was significantly elevated by exercise at 50% of maximum aerobic capacity (VO2 max). The rise persisted until the late recovery phase, when it fell significantly below resting levels. Plasma parathormone levels were initially depressed by moderate exercise (50% VO2 max.) but were significantly elevated during and immediately after severe exercise. Our results suggest that exercise stimulates the hormonal, osteolytic influences acting on the skeleton, with increases in plasma parathormone and mobilisation of calcium stores. These changes may provide a supply of raw material allowing the osteogenic mechanical forces initiated by exercise to produce a positive skeletal balance. In view of the possible relevance of these findings to the understanding and management of osteoporosis we feel that this area merits further study.
Hippocampal memory-associated synaptic plasticity is driven by a cascade of transcription and new protein synthesis. In vitro electrophysiological studies on acute hippocampal slices have elucidated ...much of what we know about this molecular cascade. Curiously, these slices require a period of "equilibration" for the recovery of electrophysiological properties such as LTP, implying ongoing time-dependent molecular events necessary for full expression of plasticity. Using standard immunofluorescence combined with confocal imaging and a novel data analysis approach, we implicate the transcription factor NF-kappaB in this plasticity-related molecular adaptation during equilibration. Marked differences in basal NF-kappaB activity in distinct cell types of the hippocampus were observed, with the amount of active NF-kappaB increasing throughout the 2-h equilibration period in all cell types. Moreover, distinct hippocampal neuronal subfields exhibit very different responses to the GABA(A) receptor blocker picrotoxin, the presence of which is required to achieve LTP in the dentate gyrus. These findings have implications for the use of acute hippocampal slices to study the effects of compounds that signal through NF-kappaB on synaptic plasticity. Further investigation into the cellular processes that occur during this molecular adaptation may increase our understanding of plasticity-related events common to both LTP and memory formation.
Information storage is a fundamental capacity of neuronal circuits that underpins all higher cognitive functions including long-term memory formation, working memory, behavioural control and ...language. The storage of information requires alterations in strength and pattern of synaptic connections in key brain structures such as the hippocampus. It is now clear that such memory-associated synaptic plasticity is driven by a cascade of gene transcription and new protein synthesis. Here, we review how the use of high-throughput microarray platforms and bioinformatic in silico analyses is now revealing an extensive, integrated transcriptional programme underpinning synaptic plasticity that confirms roles for the previously well-characterised transcription factors NF-kB and CREB but also implicates more novel players such as SRF, NFAT and HIF-1. The transcriptional programme likely sees recruitment of tens of transcription factors and hundreds of genes, orchestrated through the three core periods of synapse destabilisation, new synapse construction and selective synapse retention. We discuss the nature of the contributions of NF-kB, CREB, SRF and NFAT to cognitionassociated synaptic plasticity and present new data to support a biphasic role of HIF-1 during the early memory consolidation period.
To determine the prevalence of invasive bacterial infections (IBIs) and adverse events in afebrile infants with acute otitis media (AOM).
We conducted a 33-site cross-sectional study of afebrile ...infants ≤90 days of age with AOM seen in emergency departments from 2007 to 2017. Eligible infants were identified using emergency department diagnosis codes and confirmed by chart review. IBIs (bacteremia and meningitis) were determined by the growth of pathogenic bacteria in blood or cerebrospinal fluid (CSF) culture. Adverse events were defined as substantial complications resulting from or potentially associated with AOM. We used generalized linear mixed-effects models to identify factors associated with IBI diagnostic testing, controlling for site-level clustering effect.
Of 5270 infants screened, 1637 met study criteria. None of the 278 (0%; 95% confidence interval CI: 0%-1.4%) infants with blood cultures had bacteremia; 0 of 102 (0%; 95% CI: 0%-3.6%) with CSF cultures had bacterial meningitis; 2 of 645 (0.3%; 95% CI: 0.1%-1.1%) infants with 30-day follow-up had adverse events, including lymphadenitis (1) and culture-negative sepsis (1). Diagnostic testing for IBI varied across sites and by age; overall, 278 (17.0%) had blood cultures, and 102 (6.2%) had CSF cultures obtained. Compared with infants 0 to 28 days old, older infants were less likely to have blood cultures (
< .001) or CSF cultures (
< .001) obtained.
Afebrile infants with clinician-diagnosed AOM have a low prevalence of IBIs and adverse events; therefore, outpatient management without diagnostic testing may be reasonable.
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