Brain Phospholipid Precursors Administered Post-Injury Reduce Tissue Damage and Improve Neurological Outcome in Experimental Traumatic Brain Injury

Thau-Zuchman, Orli; Gomes, Rita N.; Dyall, Simon C.; Davies, Meirion; Priestley, John V.; Groenendijk, Martine; Wilde, Martijn C. de; Tremoleda, Jordi L.; Michael‐Titus, Adina T.

doi:10.1089/neu.2017.5579

Cited by 35 publications

(30 citation statements)

References 123 publications

(122 reference statements)

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“…Curiously, a similar increase in exploration of the open arm is not observed in the EPM test. Our findings are consistent with findings of decreased anxiety-like behavior in the EZM test at later time points after injury (Jones et al, 2008; Thau-Zuchman et al, 2019), as well as decreased anxiety in the OF test in rats exposed to lateral fluid percussion at 1 and 3 months post-injury (Jones et al, 2008). Interestingly, several studies have found decreased anxiety in the EPM as well, tested in mice following CCI at 20 days (Washington et al, 2012) and rats tested in a closed-head model at between 12 and 30 days (Pandey et al, 2009; Schwarzbold et al, 2010).…”

Section: Discussionsupporting

confidence: 91%

“…However, Amorós-Aguilar et al (2015) produced a mild CCI in rats and found no effects on behavior. A moderate to severe CCI can lead to no anxiety early after injury (Sierra-Mercado et al, 2015), increased anxiety at 45 days (Thau-Zuchman et al, 2019), or variable effects depending on the test used (Tucker et al, 2017). Washington et al (2012) explicitly tested this by using varying levels of injury severity.…”

Section: Introductionmentioning

confidence: 99%

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Long-Term Effects of Traumatic Brain Injury on Anxiety-Like Behaviors in Mice: Behavioral and Neural Correlates

Popovitz

Mysore

Adwanikar

2019

Front. Behav. Neurosci.

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Traumatic brain injury (TBI) has been frequently linked to affective disorders such as anxiety and depression. However, much remains to be understood about the underlying molecular and signaling mechanisms that mediate affective dysfunctions following injury. A lack of consensus in animal studies regarding what the affective sequelae of TBI are has been a major hurdle that has slowed progress, with studies reporting the full range of effects: increase, decrease, and no change in anxiety following injury. Here, we addressed this issue directly by investigating long-term anxiety outcomes in mice following a moderate to severe controlled cortical impact (CCI) injury using a battery of standard behavioral tests—the open field (OF), elevated zero maze (EZM), and elevated plus maze (EPM). Mice were tested on weeks 1, 3, 5 and 7 post-injury. Our results show that the effect of injury is time- and task-dependent. Early on—up to 3 weeks post-injury, there is an increase in anxiety-like behaviors in the elevated plus and zero mazes. However, after 5 weeks post-injury, anxiety-like behavior decreases, as measured in the OF and EZM. Immunostaining in the basolateral amygdala (BLA) for GAD, a marker for GABA, at the end of the behavioral testing showed the late decrease in anxiety behavior was correlated with upregulation of inhibition. The approach adopted in this study reveals a complex trajectory of affective outcomes following injury, and highlights the importance of comparing outcomes in different assays and time-points, to ensure that the affective consequences of injury are adequately assessed.

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Section: Discussionsupporting

confidence: 91%

Section: Introductionmentioning

confidence: 99%

Long-Term Effects of Traumatic Brain Injury on Anxiety-Like Behaviors in Mice: Behavioral and Neural Correlates

Popovitz

Mysore

Adwanikar

2019

Front. Behav. Neurosci.

View full text Add to dashboard Cite

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“…XFZYD leads to a lower content of uridine than the CCI group. TBI destabilizes cellular membranes, which creates a need for sustained biosynthesis of neuronal membrane phospholipids (Thau-Zuchman et al, 2019). Uridine serves as a substrate synthesizing phospholipids.…”

Section: Discussionmentioning

confidence: 99%

Metabolomics Deciphers Potential Targets of Xuefu Zhuyu Decoction Against Traumatic Brain Injury in Rat

et al. 2020

Front. Pharmacol.

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Xuefu Zhuyu decoction (XFZYD) performs multiple functions for traumatic brain injury (TBI) treatment. However, its clinical application is limited by the incomplete exploration of targets and inadequate discussion of mechanisms. We aimed to investigate the metabolic alterations of XFZYD in acute and chronic stages of TBI. Sprague-Dawley rats were randomly divided into the sham, controlled cortical impact (CCI) and XFZYD group. Behavioral and histopathological tests were used to evaluate the neuroprotective effects. Coagulation assays were performed to assess safety. Moreover, we analyzed the metabolomic profiling of hippocampal samples with different time intervals after CCI by high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). Differential metabolites were screened by multivariate data analysis. To further uncover the association between candidate metabolites and biological interaction networks, we applied bioinformatics analysis using MetaboAnalyst 4.0, STITCH 5.0 and TCMSP. The potential mechanism was verified by ELISA and Western blot. XFZYD ameliorated neurological deficiencies post-CCI without impairing blood coagulation in the rat's model. Seventeen and fourteen metabolites were filtered on d 3 and 21, respectively. Eleven of potential metabolites were common at these time points, involving two significant pathways (arginine and proline metabolism, phenylalanine, tyrosine and tryptophan biosynthesis). Gamma-aminobutyric acid (GABA) and the related pathways were specifically affected by XFZYD at the acute phase of TBI, while biosynthesis of amino acids was the major pathway influenced at the chronic phase. This study provides broad insights into the therapeutic effects of XFZYD in treating TBI through the whole phases.

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“…Recent studies suggest that blood and brain lipids are chronically disturbed in both mTBI and PTSD (Hauer et al, 2013;Emmerich et al, 2016). Further, we and others have shown that major phospholipid (PL) classes involved in providing both structural and functional support to the brain are chronically altered in both brain and blood of mouse models of severe and mTBI (Abdullah et al, 2014;Ojo et al, 2018;Thau-Zuchman et al, 2019), in the blood of soldiers with mTBI (Emmerich et al, 2016) and in CSF of civilians after severe TBI (Pasvogel et al, 2010). Many of the post-TBI changes in lipids that have been described involve alterations in blood and brain polyunsaturated fatty acids (PUFA)-containing PLs required for maintaining membrane integrity and synaptogenesis (Liu et al, 2015;Emmerich et al, 2017;Knobloch, 2017;Fiandaca et al, 2018).…”

Section: Introductionmentioning

confidence: 98%

Plasma Lipidomic Analyses in Cohorts With mTBI and/or PTSD Reveal Lipids Differentially Associated With Diagnosis and APOE ε4 Carrier Status

et al. 2020

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The differential diagnosis between mild Traumatic Brain Injury (mTBI) sequelae and Post-Traumatic Stress Disorder (PTSD) is challenging due to their symptomatic overlap and co-morbidity. As such, there is a need to develop biomarkers which can help with differential diagnosis of these two conditions. Studies from our group and others suggest that blood and brain lipids are chronically altered in both mTBI and PTSD. Therefore, examining blood lipids presents a minimally invasive and cost-effective approach to identify promising biomarkers of these conditions. Using liquid chromatography-mass spectrometry (LC-MS) we examined hundreds of lipid species in the blood of healthy active duty soldiers (n = 52) and soldiers with mTBI (n = 21), PTSD (n = 34) as well as co-morbid mTBI and PTSD (n = 13) to test whether lipid levels were differentially altered with each. We also examined if the apolipoprotein E (APOE) ε4 allele can affect the association between diagnosis and peripheral lipid levels in this cohort. We show that several lipid classes are altered with diagnosis and that there is an interaction between diagnosis and the ε4 carrier status on these lipids. Indeed, total lipid levels as well as both the degree of unsaturation and chain lengths are differentially altered with diagnosis and ε4 status, specifically long chain unsaturated triglycerides (TG) and both saturated and mono-unsaturated diglycerides (DG). Additionally, an examination of lipid species reveals distinct profiles in each diagnostic group stratified by ε4 status, mainly in TG, saturated DG species and polyunsaturated phosphatidylserines. In summary, we show that peripheral lipids are promising biomarker candidates to assist with the differential diagnosis of mTBI and PTSD. Further, ε4 carrier status alone and in interaction with diagnosis has a strong influence on peripheral lipid levels. Therefore, examining ε4 status along with peripheral lipid levels could help with differential diagnosis of mTBI and PTSD.

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Brain Phospholipid Precursors Administered Post-Injury Reduce Tissue Damage and Improve Neurological Outcome in Experimental Traumatic Brain Injury

Cited by 35 publications

References 123 publications

Long-Term Effects of Traumatic Brain Injury on Anxiety-Like Behaviors in Mice: Behavioral and Neural Correlates

Long-Term Effects of Traumatic Brain Injury on Anxiety-Like Behaviors in Mice: Behavioral and Neural Correlates

Metabolomics Deciphers Potential Targets of Xuefu Zhuyu Decoction Against Traumatic Brain Injury in Rat

Plasma Lipidomic Analyses in Cohorts With mTBI and/or PTSD Reveal Lipids Differentially Associated With Diagnosis and APOE ε4 Carrier Status

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