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  1. Article: Treatment With Nilvadipine Mitigates Inflammatory Pathology and Improves Spatial Memory in Aged hTau Mice After Repetitive Mild TBI.

    Morin, Alexander / Mouzon, Benoit / Ferguson, Scott / Paris, Daniel / Saltiel, Nicole / Lungmus, Carlyn / Mullan, Mike / Crawford, Fiona

    Frontiers in aging neuroscience

    2018  Volume 10, Page(s) 292

    Abstract: Mild traumatic brain injury (mTBI) is the most common form of brain trauma worldwide. The effects of mTBI are not well-studied within the elderly population, yet older adults constitute a significant portion of all mTBI patients. Few preclinical studies ... ...

    Abstract Mild traumatic brain injury (mTBI) is the most common form of brain trauma worldwide. The effects of mTBI are not well-studied within the elderly population, yet older adults constitute a significant portion of all mTBI patients. Few preclinical studies have focused on the effects of mTBI, or mTBI treatments, in the aged brain, and none have explored repetitive mTBI (r-mTBI). In this study, we have administered our well-characterized 5-injury model (5 r-mTBI) to hTau mice aged 24 months to explore the neurobehavioral and neuropathological outcomes, and the effects of treatment with the dihydropyridine, Nilvadipine. Our previous studies have shown that Nilvadipine inhibits spleen tyrosine kinase (Syk), is effective at reducing inflammation, tau hyperphosphorylation, and amyloid production, and it has recently been investigated in a European Phase III clinical trial for Alzheimer's disease (AD). In our 24-month-old r-mTBI mice, we observed increased neuroinflammation and a trend toward impaired cognitive performance compared to sham controls. Treatment with Nilvadipine mitigated the TBI-induced inflammatory response in aged r-mTBI animals and significantly improved spatial memory. To our knowledge, this is the only preclinical study focusing on the treatment of r-mTBI in aged, and these results suggest a therapeutic potential of Nilvadipine for consequences of mTBI.
    Language English
    Publishing date 2018-10-11
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2558898-9
    ISSN 1663-4365
    ISSN 1663-4365
    DOI 10.3389/fnagi.2018.00292
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: APOE Genotype Specific Effects on the Early Neurodegenerative Sequelae Following Chronic Repeated Mild Traumatic Brain Injury.

    Muza, Phillip / Bachmeier, Corbin / Mouzon, Benoit / Algamal, Moustafa / Rafi, Naomi G / Lungmus, Carlyn / Abdullah, Laila / Evans, James E / Ferguson, Scott / Mullan, Michael / Crawford, Fiona / Ojo, Joseph O

    Neuroscience

    2019  Volume 404, Page(s) 297–313

    Abstract: Repeated mild traumatic brain injury (r-mTBI) can potentially manifest into chronic traumatic encephalopathy (CTE). The apolipoprotein E (APOE4) genotype, a well-recognized potent genetic risk factor in age-related neurodegenerative diseases such as ... ...

    Abstract Repeated mild traumatic brain injury (r-mTBI) can potentially manifest into chronic traumatic encephalopathy (CTE). The apolipoprotein E (APOE4) genotype, a well-recognized potent genetic risk factor in age-related neurodegenerative diseases such as Alzheimer's disease, has been linked to worse outcome after TBI in individuals who carry this allele. The underlying molecular modifications triggered by APOE genotype following r-mTBI remain elusive. We addressed the influence of APOE genotype on TBI dependent tau pathology in middle-aged mice. Using a previously established experimental mTBI protocol in a new repetitive injury paradigm, we report the pathological changes that occurred following one-month of repetitive injuries in APOE3/4 gene targeted mice. Firstly, pathological assessment demonstrated evidence of microgliosis and astrogliosis in the corpus callosum of injured animals, but there was no APOE dependent genotype effect on injury. However, in the parietal cortex Iba1-immunoreactivity was significantly increased in injured versus sham APOE3 mice, but not in APOE4 mice. No effects were observed in soluble amyloid levels with injury or interaction with genotype. APOE4 mice showed significant increases in the tau conformational marker MC1, neurofilament H, brain phospholipids, and endothelial specific oxidized low density lipoprotein receptor in cortical homogenates obtained from injured mice compared to sham counterparts. This pilot work suggests APOE3 and APOE4 specific effects following injury in a mouse model of r-mTBI. These changes may underlie the molecular changes that trigger the vulnerability and increased risk of developing neurodegenerative diseases in aged individuals exposed to repetitive mTBI.
    MeSH term(s) Animals ; Apolipoprotein E3/genetics ; Apolipoprotein E3/metabolism ; Apolipoprotein E4/genetics ; Apolipoprotein E4/metabolism ; Brain Concussion/genetics ; Brain Concussion/metabolism ; Brain Concussion/pathology ; Chronic Disease ; Female ; Genotype ; Male ; Mice ; Mice, Transgenic ; Neurodegenerative Diseases/genetics ; Neurodegenerative Diseases/metabolism ; Neurodegenerative Diseases/pathology
    Chemical Substances Apolipoprotein E3 ; Apolipoprotein E4
    Language English
    Publishing date 2019-02-01
    Publishing country United States
    Document type Journal Article
    ZDB-ID 196739-3
    ISSN 1873-7544 ; 0306-4522
    ISSN (online) 1873-7544
    ISSN 0306-4522
    DOI 10.1016/j.neuroscience.2019.01.049
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 1215: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (1.OG)
    ab Jg. 2022: Lesesaal (EG)

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  3. Article: Chronic Hippocampal Abnormalities and Blunted HPA Axis in an Animal Model of Repeated Unpredictable Stress.

    Algamal, Moustafa / Ojo, Joseph O / Lungmus, Carlyn P / Muza, Phillip / Cammarata, Constance / Owens, Margaret J / Mouzon, Benoit C / Diamond, David M / Mullan, Michael / Crawford, Fiona

    Frontiers in behavioral neuroscience

    2018  Volume 12, Page(s) 150

    Abstract: Incidence of post-traumatic stress disorder (PTSD) ranges from 3 to 30% in individuals exposed to traumatic events, with the highest prevalence in groups exposed to combat, torture, or rape. To date, only a few FDA approved drugs are available to treat ... ...

    Abstract Incidence of post-traumatic stress disorder (PTSD) ranges from 3 to 30% in individuals exposed to traumatic events, with the highest prevalence in groups exposed to combat, torture, or rape. To date, only a few FDA approved drugs are available to treat PTSD, which only offer symptomatic relief and variable efficacy. There is, therefore, an urgent need to explore new concepts regarding the biological responses causing PTSD. Animal models are an appropriate platform for conducting such studies. Herein, we examined the chronic behavioral and neurobiological effects of repeated unpredictable stress (RUS) in a mouse model. 12 weeks-old C57BL/6J male mice were exposed to a 21-day RUS paradigm consisting of exposures to a predator odor (TMT) whilst under restraint, unstable social housing, inescapable footshocks and social isolation. Validity of the model was assessed by comprehensive examination of behavioral outcomes at an acute timepoint, 3 and 6 months post-RUS; and molecular profiling was also conducted on brain and plasma samples at the acute and 6 months timepoints. Stressed mice demonstrated recall of traumatic memories, passive stress coping behavior, acute anxiety, and weight gain deficits when compared to control mice. Immunoblotting of amygdala lysates showed a dysregulation in the p75NTR/ProBDNF, and glutamatergic signaling in stressed mice at the acute timepoint. At 6 months after RUS, stressed mice had lower plasma corticosterone, reduced hippocampal CA1 volume and reduced brain-derived neurotrophic factor levels. In addition, glucocorticoid regulatory protein FKBP5 was downregulated in the hypothalamus of stressed mice at the same timepoint, together implicating an impaired hypothalamus-pituitary-adrenal-axis. Our model demonstrates chronic behavioral and neurobiological outcomes consistent with those reported in human PTSD cases and thus presents a platform through which to understand the neurobiology of stress and explore new therapeutic interventions.
    Language English
    Publishing date 2018-07-20
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2452960-6
    ISSN 1662-5153
    ISSN 1662-5153
    DOI 10.3389/fnbeh.2018.00150
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Impact of age on acute post-TBI neuropathology in mice expressing humanized tau: a Chronic Effects of Neurotrauma Consortium Study.

    Mouzon, Benoit / Saltiel, Nicole / Ferguson, Scott / Ojo, Joseph / Lungmus, Carlyn / Lynch, Cillian / Algamal, Moustafa / Morin, Alexander / Carper, Benjamin / Bieler, Gayle / Mufson, Elliott J / Stewart, William / Mullan, Michael / Crawford, Fiona

    Brain injury

    2018  Volume 32, Issue 10, Page(s) 1285–1294

    Abstract: Objectives: We hypothesized that polypathology is more severe in older than younger mice during the acute phase following repetitive mild traumatic brain injury (r-mTBI).: Methods: Young and aged male and female mice transgenic for human tau (hTau) ... ...

    Abstract Objectives: We hypothesized that polypathology is more severe in older than younger mice during the acute phase following repetitive mild traumatic brain injury (r-mTBI).
    Methods: Young and aged male and female mice transgenic for human tau (hTau) were exposed to r-mTBI or a sham procedure. Twenty-four hours post-last injury, mouse brain tissue was immunostained for alterations in astrogliosis, microgliosis, tau pathology, and axonal injury.
    Results: Quantitative analysis revealed a greater percent distribution of glial fibrillary acid protein and Iba-1 reactivity in the brains of all mice exposed to r-mTBI compared to sham controls. With respect to axonal injury, the number of amyloid precursor protein-positive profiles was increased in young vs aged mice post r-mTBI. An increase in tau immunoreactivity was found in young and aged injured male hTau mice.
    Conclusions: We report the first evidence in our model that r-mTBI precipitates a complex sequelae of events in aged vs young hTau mice at an acute time point, typified by an increase in phosphorylated tau and astroglisosis, and a diminished microgliosis response and axonal injury in aged mice. These findings suggest differential age-dependent effects in TBI pathobiology.
    MeSH term(s) Age Factors ; Amyloid beta-Protein Precursor/metabolism ; Animals ; Brain Concussion/genetics ; Brain Concussion/metabolism ; Calcium-Binding Proteins/metabolism ; Disease Models, Animal ; Female ; Gene Expression Regulation/genetics ; Glial Fibrillary Acidic Protein/metabolism ; Humans ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Microfilament Proteins/metabolism ; tau Proteins/genetics ; tau Proteins/metabolism
    Chemical Substances Aif1 protein, mouse ; Amyloid beta-Protein Precursor ; Calcium-Binding Proteins ; Glial Fibrillary Acidic Protein ; Microfilament Proteins ; tau Proteins
    Language English
    Publishing date 2018-06-21
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 639115-1
    ISSN 1362-301X ; 0269-9052
    ISSN (online) 1362-301X
    ISSN 0269-9052
    DOI 10.1080/02699052.2018.1486457
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 2242: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (1.OG)
    ab Jg. 2022: Lesesaal (EG)

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  5. Article ; Online: Author Correction: Oleoylethanolamide treatment reduces neurobehavioral deficits and brain pathology in a mouse model of Gulf War Illness.

    Joshi, Utsav / Evans, James E / Joseph, Ross / Emmerich, Tanja / Saltiel, Nicole / Lungmus, Carlyn / Oberlin, Sarah / Langlois, Heather / Ojo, Joseph / Mouzon, Benoit / Paris, Daniel / Mullan, Michael / Jin, Chao / Klimas, Nancy / Sullivan, Kimberly / Crawford, Fiona / Abdullah, Laila

    Scientific reports

    2019  Volume 9, Issue 1, Page(s) 11011

    Abstract: A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper. ...

    Abstract A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper.
    Language English
    Publishing date 2019-07-24
    Publishing country England
    Document type Published Erratum
    ZDB-ID 2615211-3
    ISSN 2045-2322 ; 2045-2322
    ISSN (online) 2045-2322
    ISSN 2045-2322
    DOI 10.1038/s41598-019-46255-z
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article: Negative Impact of Female Sex on Outcomes from Repetitive Mild Traumatic Brain Injury in hTau Mice Is Age Dependent: A Chronic Effects of Neurotrauma Consortium Study.

    Ferguson, Scott A / Mouzon, Benoit C / Lynch, Cillian / Lungmus, Carlyn / Morin, Alexander / Crynen, Gogce / Carper, Benjamin / Bieler, Gayle / Mufson, Elliott J / Stewart, William / Mullan, Michael / Crawford, Fiona

    Frontiers in aging neuroscience

    2017  Volume 9, Page(s) 416

    Abstract: Traumatic brain injury (TBI) is a serious public health concern which strikes someone every 15 s on average in the US. Even mild TBI, which comprise as many as 75% of all TBI cases, carries long term consequences. The effects of age and sex on long term ... ...

    Abstract Traumatic brain injury (TBI) is a serious public health concern which strikes someone every 15 s on average in the US. Even mild TBI, which comprise as many as 75% of all TBI cases, carries long term consequences. The effects of age and sex on long term outcome from TBI is not fully understood, but due to the increased risk for neurodegenerative diseases after TBI it is important to understand how these factors influence the outcome from TBI. This study examined the neurobehavioral and neuropathological effects of age and sex on the outcome 15 days following repetitive mild traumatic brain injury (r-mTBI) in mice transgenic for human tau (hTau). These mice express the six human isoforms of tau but do not express endogenous murine tau and they develop tau pathology and memory impairment in an age-dependent manner. After 5 mild impacts, aged female mice showed motor impairments that were absent in aged male mice, as well as younger animals. Conversely, aged female sham mice outperformed all other groups of aged mice in a Barnes maze spatial memory test. Pathologically, increases in IBA-1 and GFAP staining typically seen in this model of r-mTBI showed the expected increases with both injury and age, but phosphorylated tau stained with CP13 in the hippocampus (reduced in female sham mice compared to males) and PHF1 in the cortex (reduced in female TBI mice compared to male TBI mice) showed the only histological signs of sex-dependent differences in these mice.
    Language English
    Publishing date 2017-12-22
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2558898-9
    ISSN 1663-4365
    ISSN 1663-4365
    DOI 10.3389/fnagi.2017.00416
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article ; Online: Oleoylethanolamide treatment reduces neurobehavioral deficits and brain pathology in a mouse model of Gulf War Illness.

    Joshi, Utsav / Evans, James E / Joseph, Ross / Emmerich, Tanja / Saltiel, Nicole / Lungmus, Carlyn / Oberlin, Sarah / Langlois, Heather / Ojo, Joseph / Mouzon, Benoit / Paris, Daniel / Mullan, Michael / Jin, Chao / Klimas, Nancy / Sullivan, Kimberly / Crawford, Fiona / Abdullah, Laila

    Scientific reports

    2018  Volume 8, Issue 1, Page(s) 12921

    Abstract: There are nearly 250,000 Gulf War (GW) veterans who suffer from Gulf War Illness (GWI), a multi-symptom condition that remains untreatable. The main objective was to determine if targeting peroxisomal function could be of therapeutic value in GWI. We ... ...

    Abstract There are nearly 250,000 Gulf War (GW) veterans who suffer from Gulf War Illness (GWI), a multi-symptom condition that remains untreatable. The main objective was to determine if targeting peroxisomal function could be of therapeutic value in GWI. We performed a pilot study that showed accumulation of very long chain fatty acids (VLCFA), which are metabolized in peroxisomes, in plasma from veterans with GWI. We then examined if targeting peroxisomal β-oxidation with oleoylethanolamide (OEA) restores these lipids to the normal levels and mitigates neuroinflammation and neurobehavioral deficits in a well-established mouse model of GWI. In GWI mice, treatment with OEA corresponded with cognitive benefits and reduced fatigue and disinhibition-like behavior in GWI mice. Biochemical and molecular analysis of the brain tissue showed reduced astroglia and microglia staining, decreased levels of chemokines and cytokines, and decreased NFκB phosphorylation. Treatment with OEA reduced accumulation of peroxisome specific VLCFA in the brains of GWI mice. These studies further support the translational value of targeting peroxisomes. We expect that OEA may be a potential therapy for treating neurobehavioral symptoms and the underlying lipid dysfunction and neuroinflammation associated with GWI. Oleoylethanolamide is available as a dietary supplement, making it appealing for human translational studies.
    MeSH term(s) Animals ; Astrocytes/drug effects ; Astrocytes/metabolism ; Brain/drug effects ; Brain/metabolism ; Brain/physiology ; Endocannabinoids/therapeutic use ; Humans ; Mice ; Microglia/drug effects ; Microglia/metabolism ; Oleic Acids/therapeutic use ; Persian Gulf Syndrome/drug therapy ; Persian Gulf Syndrome/metabolism ; Promoter Regions, Genetic/genetics ; Sequence Analysis, DNA
    Chemical Substances Endocannabinoids ; Oleic Acids ; oleoylethanolamide (1HI5J9N8E6)
    Language English
    Publishing date 2018-08-27
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2615211-3
    ISSN 2045-2322 ; 2045-2322
    ISSN (online) 2045-2322
    ISSN 2045-2322
    DOI 10.1038/s41598-018-31242-7
    Database MEDical Literature Analysis and Retrieval System OnLINE

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