The influence of chronic ibuprofen treatment on proteins expressed in the mouse hippocampus

Matsuura, Kenji; Otani, Mieko; Takano, Masaoki; Kadoyama, Keiichi; Matsuyama, Shogo

doi:10.1016/j.ejphar.2015.01.047

Cited by 8 publications

(5 citation statements)

References 37 publications

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“…Therefore, it is possible that the beneficial effects of ibuprofen treatment may be independent of COX-2. Consistent with our results, proteomic analysis of the hippocampus of mice treated with ibuprofen for 6 months also identified the down-regulations of GFAP (Matsuura, et al, 2015), although further studies are needed to determine whether ibuprofen directly influences GFAP levels or indirectly modify them by blocking prostaglandin-mediated neuroinflammation. Thus, astrocytes are predicted to play a critical role in regulating cognitive functions during aging.…”

Section: Discussionsupporting

confidence: 87%

Subacute ibuprofen treatment rescues the synaptic and cognitive deficits in advanced-aged mice

Rogers

Liu

Zhao

et al. 2017

Neurobiology of Aging

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Aging is accompanied by increased neuroinflammation, synaptic dysfunction and cognitive deficits both in rodents and humans, yet the onset and progression of these deficits throughout the life span remain unknown. These aging-related deficits affect the quality of life and present challenges to our aging society. Here, we defined age-dependent and progressive impairments of synaptic and cognitive functions and showed that reducing astrocyte-related neuroinflammation through anti-inflammatory drug treatment in aged mice reverses these events. By comparing young (3 months), middle-aged (18 months), aged (24 months) and advanced-aged wild-type mice (30 months), we found that the levels of an astrocytic marker, GFAP, progressively increased after 18 months of age, which preceded the decreases of the synaptic marker PSD-95. Hippocampal long-term potentiation (LTP) was also suppressed in an age-dependent manner, where significant deficits were observed after 24 months of age. Fear conditioning tests demonstrated that associative memory in the context and cued conditions was decreased starting at the ages of 18 and 30 months, respectively. When the mice were tested on hidden platform water maze, spatial learning memory was significantly impaired after 24 months of age. Importantly, subacute treatment with the anti-inflammatory drug ibuprofen suppressed astrocyte activation, and restored synaptic plasticity and memory function in advanced-aged mice. These results support the critical contribution of aging-related inflammatory responses to hippocampal-dependent cognitive function and synaptic plasticity, in particular during advanced aging. Our findings provide strong evidence that suppression of neuroinflammation could be a promising treatment strategy to preserve cognition during aging.

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Section: Discussionsupporting

confidence: 87%

Subacute ibuprofen treatment rescues the synaptic and cognitive deficits in advanced-aged mice

Rogers

Liu

Zhao

et al. 2017

Neurobiology of Aging

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“…This suggests that ibuprofen can affect NMDA receptors at the protein level and can affect some proteins in opposite directions, depending on the brain region. In the mouse hippocampus, chronic ibuprofen (6 months) affected the expression of 28 different proteins and seven phosphoproteins, both up- and down-regulation was seen, depending on the protein (Matsuura et al, 2015). Affected proteins that are involved in signal transduction, such as G protein and synapsin-2 phosphoprotein, were down-regulated (Matsuura et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

“…In the mouse hippocampus, chronic ibuprofen (6 months) affected the expression of 28 different proteins and seven phosphoproteins, both up- and down-regulation was seen, depending on the protein (Matsuura et al, 2015). Affected proteins that are involved in signal transduction, such as G protein and synapsin-2 phosphoprotein, were down-regulated (Matsuura et al, 2015). The mechanism by which ibuprofen can alter mRNA and protein expression, however, is not yet known.…”

Section: Discussionmentioning

confidence: 99%

Effects of ibuprofen on cognition and NMDA receptor subunit expression across aging

et al. 2017

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Age-related declines in long- and short-term memory show relationships to decreases in N-methyl-D-aspartate (NMDA) receptor expression, which may involve inflammation. This study was designed to determine effects of an anti-inflammatory drug, ibuprofen, on cognitive function and NMDA receptor expression across aging. Male C57BL/6 mice (ages 5, 14, 20, and 26 months) were fed ibuprofen (375 ppm) in NIH31 diet or diet alone for 6 weeks prior to testing. Behavioral testing using the Morris water maze showed that older mice performed significantly worse than younger in spatial long-term memory, reversal, and short-term memory tasks. Ibuprofen enhanced overall performance in the short-term memory task, but this appeared to be more related to improved executive function than memory. Ibuprofen induced significant decreases over all ages in the mRNA densities for GluN2B subunit, all GluN1 splice variants, and GluN1-1 splice forms in the frontal cortex and in protein expression of GluN2A, GluN2B and GluN1 C2′ cassettes in the hippocampus. GluN1-3 splice form mRNA and C2′ cassette protein were significantly increased across ages in frontal lobes of ibuprofen-treated mice. Ibuprofen did not alter expression of pro-inflammatory cytokines IL-1β and TNFα, but did reduce the area of reactive astrocyte immunostaining in frontal cortex of aged mice. Enhancement in executive function showed a relationship to increased GluN1-3 mRNA and decreased gliosis. These findings suggest that inflammation may play a role in executive function declines in aged animals, but other effects of ibuprofen on NMDA receptors appeared to be unrelated to aging or inflammation.

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“…Interestingly, in a rat model for AD, low frequency electromagnetic fields partially improved cognitive and pathologic symptoms correlating with up-regulation of EFhd2 in the hippocampus [14]. On the other hand, the antiinflammatory drug Ibuprofen led to down-regulation of EFhd2 in the hippocampus of mice [15]. However, to date the most systematic and largest study (n = 48 brains) that has linked EFhd2 expression directly to human dementia, was described in Borger et al 2014, which revealed a significant down-regulation of EFhd2 both at the mRNA and protein level in the cortex of AD brain and other dementias including various different types of frontotemporal lobar degeneration (FTLD) including FTDP-17 and FTLD-tau with Pick bodies (Pick disease), which are all classified as tauopathies [6].…”

Section: Expression Of Efhd2 In the Nervous System And Links To Neuromentioning

confidence: 99%

Physiological and pathophysiological functions of Swiprosin-1/EFhd2 in the nervous system

Mielenz

Gunn‐Moore

2016

Biochemical Journal

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Synaptic dysfunction and dysregulation of Ca 2+ are linked to neurodegenerative processes and behavioural disorders. Our understanding of causes and factors involved in behavioural disorders and neurodegeneration, especially Alzheimer's disease, a tau-related disease, is on the one hand limited and on the other hand controversial. Here, we reviewed recent data about the links between the Ca 2+ -binding, EF-hand containing cytoskeletal protein Swiprosin-1/EFhd2 (EFhd2) and neurodegeneration. Specifically, we have summarized the functional biochemical data obtained in vitro with use of recombinant EFhd2 protein, and integrated them with in vivo data in order to interpret the emerging role of EFhd2 in synaptic plasticity and in the pathophysiology of neurodegenerative disorders, particularly involving the tauopathies. We have also discussed its functions in actin remodeling through cofilin and small GTPases, thereby, linking EFhd2, synapses and the actin cytoskeleton. Expression data and functional experiments in mouse and in man have led to the hypothesis that downregulation of EFhd2, especially in the cortex, is involved to dementia. KeywordsActin; Cofilin; Alzheimer's disease; axonal transport; GTPase; Swiprosin-1/EFhd2; tauopathy Expression of EFhd2 in the nervous system and links to neurodegenerative diseasesMany genes and proteins have been identified in one tissue type only to be found that they have equally important signaling roles in others. Indeed, activated B cells involved in T cell dependent immune reactions within germinal centers, express many hitherto thought to be neuron-specific genes and reveal long extensions reminiscent of neurites [1] Our own work has extended our knowledge of where EFhd2 is expressed in the mammalian brain and how it changes expression in dementias [6,7]. Specifically, Brachs et al. generated an EFhd2 knockout (KO)/lacZ reporter gene knockin mouse (EFhd2KO) by blastocyst injection of commercially available ES cells in which the efhd2 gene had been replaced with an in frame lacZ reporter cassette through homologous recombination [8] EFhd2KO mice reveal a dose-dependent increase of lacZ compared to heterozygous mice carrying only one mutated allele (EFhd2HT), concomitant with a dose-dependent decrease of EFhd2 expression. This indicated that efhd2 expression is haplo-insufficient, at least in this system, and that for full efhd2 expression, both alleles need to be active [7]. This mouse strain next allowed for the detailed characterization of EFhd2 expression in the mouse brain by detecting the presence of β-galactosidase activity, which was confirmed by the use of specific EFhd2 antibodies [9] and immunostaining of sections of the brain. EFhd2 expression was observed in the pyramidal layers of the cortex, the dentate gyrus, and the CA1-CA2 regions of the hippocampus [7]. These findings confirmed previous in situ hybridizations described in the Allen brain atlas which had indicated strong efhd2 mRNA expression in neuronal rich areas of the brain. White matter regions s...

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The influence of chronic ibuprofen treatment on proteins expressed in the mouse hippocampus

Cited by 8 publications

References 37 publications

Subacute ibuprofen treatment rescues the synaptic and cognitive deficits in advanced-aged mice

Subacute ibuprofen treatment rescues the synaptic and cognitive deficits in advanced-aged mice

Effects of ibuprofen on cognition and NMDA receptor subunit expression across aging

Physiological and pathophysiological functions of Swiprosin-1/EFhd2 in the nervous system

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