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Published in final edited form as: Neurochem Int. 2024 Feb 28;175:105701. doi: 10.1016/j.neuint.2024.105701

Glycerophospholipid dysregulation after traumatic brain injury

Chinmoy Sarkar 1,*, Marta M Lipinski 1,2
PMCID: PMC11040658  NIHMSID: NIHMS1974156  PMID: 38428503

Abstract

Brain tissue is highly enriched in lipids, the majority of which are glycerophospholipids (GPLs). Glycerophospholipids are the major constituents of cellular membranes and play an important role in maintaining integrity and function of cellular and subcellular structures. Any changes in glycerophospholipids homeostasis can adversely affect brain functions. Traumatic brain injury (TBI), an acquired injury caused by the impact of external forces to the brain, triggers activation of secondary biochemical events that include perturbation of lipid homeostasis. Several studies have demonstrated glycerophospholipid dysregulation in the brain and circulation after TBI. This includes spatial and temporal changes in abundance and distribution of glycerophospholipids in the injured brain. This is at least in part mediated by TBI-induced oxidative stress and by activation of lipid metabolism pathways involved in tissue repairing. In this review, we discuss current advances in understanding of the mechanisms and implications of glycerophospholipids dysregulation following TBI.

Introduction

Glycerophospholipids (GPLs) are amphipathic lipids that contain polar phosphate groups and hydrophobic fatty acyl chains attached to a glycerol backbone (Farooqui, Horrocks et al. 2000, Montealegre, Verardo et al. 2014). They are the primary building blocks of cellular membranes, which serve as a boundary for cellular and subcellular structures and maintain their integrity (Montealegre, Verardo et al. 2014, Wang and Tontonoz 2019). They also serve as docking platforms for different receptors and play an important role in cellular signal transduction pathways (Farooqui, Horrocks et al. 2000). Any perturbation of phospholipid composition and abundance can have deleterious impact on cellular function and survival. They are vulnerable to oxidative stress and metabolic dysfunctions. Phospholipid homeostasis is disrupted in different pathological conditions including traumatic brain injury (TBI) (Farooqui, Horrocks et al. 2000, Sarkar, Jones et al. 2020).

TBI is caused by the physical impact of external forces to the brain, which can be due to falls, motor vehicle accidents, assaults, combat situations or contact sport activities (Werner and Engelhard 2007, Xiong, Mahmood et al. 2013, Gardner and Zafonte 2016). It is one of the major causes of premature death for people of all ages. Those who survive the early impact of TBI may develop lifelong disabilities. Globally around 27 million people suffer from TBI or TBI related illness annually. In the US, this number is around 1.7 million (Injury and Spinal Cord Injury 2019). The pathophysiology of TBI is highly complex. Primary mechanical injury initiates a cascade of biochemical events leading to acute and progressive neurodegeneration and neuroinflammation (Werner and Engelhard 2007, Stoica and Faden 2010, Faden, Wu et al. 2016). These biochemical events include calcium imbalance, glutamate excitotoxicity, oxidative stress, ER stress, mitochondrial and lysosomal dysfunction. (Stoica and Faden 2010, Nguyen, Fiest et al. 2016, Vemuganti and Hall 2017). Recent studies also demonstrate that many types of phospholipids are dysregulated following TBI (Abdullah, Evans et al. 2014, Anthonymuthu, Kenny et al. 2019, Sarkar, Jones et al. 2020, Thomas, Dickens et al. 2022). Such changes in phospholipids homeostasis in response to TBI have been detected in the different regions of the injured brain as well as systemically in the blood. In this review, we discuss the mechanisms and implications of glycerophospholipids dysregulations after TBI.

Structural diversity of glycerophospholipids

Glycerophospholipid structure is built on a glycerol backbone which is attached to a polar head group at its sn-3 position through phosphodiester bond. Different types of polar head groups determine the polarity and degree of phospholipid’s hydrophilicity (Farooqui, Horrocks et al. 2000, Montealegre, Verardo et al. 2014, Wang and Tontonoz 2019). Based on their polar head groups phospholipids are generally divided into different classes – phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylserine (PS), phosphatidylinositol (PI), and phosphatidic acid (PA) (Farooqui, Horrocks et al. 2000, Wang and Tontonoz 2019). Among them, phosphatidylcholine (PC) is the most abundant in cellular membrane accounting for almost 40–50% of total membrane phospholipids (Wang and Tontonoz 2019).

The other two carbon atoms of the glycerol backbone are attached to fatty acyl chains of different carbon length and degree of saturation. This makes the phospholipid structure highly diverse and determines the level of hydrophobicity. Generally, polyunsaturated fatty acyl chains are attached to glycerol structure at the sn-2 position via an ester linkage. Fatty acyl chains at the sn-1 position are usually saturated or mononunsaturated, and are attached either via an ester bond in diacyl-glycerophospholipids or through an ether bond in ether phospholipids (Farooqui, Horrocks et al. 2000, Wang and Tontonoz 2019). Ether phospholipids can be further divided into two types – alkenyl and alkyl, based on the presence or absence of unsaturation next to the ether bond (Dean and Lodhi 2018). Alkenyl ether phospholipids containing vinyl ether bond are also called plasmalogens and are highly abundant in the brain (Farooqui, Horrocks et al. 2000, Dean and Lodhi 2018).

Glycerophospholipid metabolism

Glycerophospholipid synthesis is a multi-steps process which overlaps with other lipid biosynthesis pathways. The biochemical steps of diacyl-glycerophospholipid synthesis are carried out in the smooth endoplasmic reticulum (Farooqui, Horrocks et al. 2000, Vance 2015). Diacyl-glycerophospholipids are synthesized by the condensation of diacyl-glycerol (DAG) phosphate or phosphatidate with CDP-choline/phosphatidyl ethanolamine through the Kennedy pathway (Kennedy and Weiss 1956, Farooqui, Horrocks et al. 2000, Vance 2015). DAG phosphate also serves as a precursor for triglyceride synthesis. DAG phosphate or phosphatidate is synthesized from L-glycerol-3-phosphate, which is generated by the reduction of dihydroxyacetone phosphate by dihydroxyacetone phosphate dehydrogenase or by phosphorylation of glycerol by glycerol kinase. L-glycerol-3-phosphate is then esterified with fatty acids by fatty acyl transferases to form DAG phosphate. Ether glycerophospholipids synthesis is initiated in peroxisomes and completed within ER. Peroxisomal steps generate the ether phospholipids precursor, 1-O-alkylglycerol (OAG) from dihydroxyacetone phosphate, in a reaction mediated by the peroxisomal enzymes glyceronephosphate-O-acyl transferase, alkylglyceronephosphate synthase and fatty acyl reductase 1 . OAG is then transported and converted into fully formed ether phospholipids in the ER (Dean and Lodhi 2018).

Phospholipids are hydrolyzed by phospholipases. There are different types of phospholipases which act at different positions of the phospholipid structures. Phospholipases A1 (PLA1) and A2 (PLA2) cleave the fatty-acyl ester bonds at sn-1 and sn-2 positions, respectively (Farooqui, Horrocks et al. 2000, Kudo and Murakami 2002, Ghosh, Tucker et al. 2006, Burke and Dennis 2009, Burke and Dennis 2009). Both bonds can be also hydrolyzed by phospholipase B. PLA2 species can be further subdivided based on their localization and regulation into calcium dependent cytosolic PLA2 (cPLA2), calcium independent cytosolic PLA2 (iPLA2) and secretory PLA2 (sPLA2) (Sarkar and Lipinski 2023). Polar head groups attached to the phospholipid structures are removed by phosphodiesterases, also called phospholipases C and D. While phospholipase C cleaves the phosphodiester bond between the phosphate polar head group and the glycerol moiety, phospholipase D hydrolyzes the phosphodiester bond between polar head group and the phosphate attached to the glycerol structure of the phospholipids (Farooqui, Horrocks et al. 2000, Kudo and Murakami 2002, Ghosh, Tucker et al. 2006, Sarkar and Lipinski 2023).

Impact of TBI on brain glycerophospholipid abundance

Multiple studies have shown that TBI strongly affects brain glycerophospholipids homeostasis (Table 1). Reduced abundance of different glycerophospholipids has been reported in the experimental rodent TBI models at both acute and chronic stages after injury. Spatial and temporal changes in brain phospholipids abundance was detected in the mouse brain using liquid chromatography-mass spectrometry (LC-MS) after controlled cortical impact (CCI)-induced TBI (Abdullah, Evans et al. 2014). . This included decreased levels of diacyl- and ether-PC and PE in the mouse cortices and cerebellum at 3 months post injury. However, in the hippocampi of the injured mice abundance of these lipids increased. Recently, cell-type specific changes in phospholipid abundance in the mouse brain after TBI has been reported (Agrawal, Larrea et al. 2023). At acute stages after injury (1–3 days) Robust changes in microglial lipid composition in both cortex and hippocampus were detected in the acute stages of TBI (1–3 days post injury). These include pronounced TBI-induced accumulation of cholesteryl esters, di- and tri-glycerides. Levels of some of the same lipid species also increased in astrocytes and neurons following injury. The authors hypothesized that these changes in glial lipid composition might be indicative of their TBI-induced activation and proliferation. Accumulation of PC and PE was observed in the isolated neurons and increased PC levels in the astrocytes of injured mice. These changes in cellular lipid composition were associated with alteration in lipid metabolism after injury, including upregulation of lipid receptors and transporters (scavenge receptor for free fatty acids – CD36, lipoprotein receptors and transporters – Ldlr and Lrp1) and enzymes involved in lipogenic pathways (Fatty acid synthase, Sterol regulatory protein binding 1 and acetyl-CoA carboxylase 1). These data suggest that cellular lipid remodeling pathways may be activated, potentially contributing to tissue repair.

Table 1.

Studies depicting phospholipid dysregulation after experimental TBI:

Species TBI model Time point Tissue regions/body fluid analyzed Major findings Ref
Mouse CCI 3 M Cortex, hippocampus and cerebellum Region specific PLs dysregulation Abdullah, Evans et al. 2014
Mouse CCI 1–3 days Brain Cell type specific changes in PLs Agrawal, Larrea et al. 2023
Rat FPI 1–7 days Brain Region specific PLs dysregulation Guo, Zhou et al. 2017
Mouse CCI 1 h Isolated cortical lysosome Increase in lysophospholipids Sarkar, Jones et al. 2020
Rat CCI 1–3 h Cortex and whiter matter Region specific PLs dysregulation McDonald, Jones et al. 2018
Rat (17 day old) CCI 4 h and 1 d Pericontusional cortex and plasma Inverse correlation of brain and plasma cardiolipin Anthonymuthu, Kenny et al. 2019
Rat CCI 3 h Crude brain mitochondrial fractions Cardiolipin oxidation Ji, Kline et al. 2012
APOE4 and APOE3 expressing transgenic mice BOP Induced TBI 24 h Hippocampus Changes in PIP2 level Cao, Gaamouch et al. 2017
Transgenic mice expressing human tau Repetitive mild TBI 24 h, 3 M, 6 M, 9 M and 12 M Cortex and hippocampus Time dependent region specific PLs dysregulation Ojo, Algamal et al. 2018
PS1/APP mice Closed head injury (mild TBI) 24 h, 3 M, 6 M, 9 M and 12 M Cortex and hippocampus Time dependent region specific PLs dysregulation Ojo, Algamal et al. 2019
Rat CCI 3 and 7 days Serum Increase in PUFA containing DAG after TBI Hogan, Phan et al. 2018
Mouse CCI 1, 3, 7, 14 and 28 days Plasma Increase in ether PLs after TBI Morel, Hegdekar et al. 2021
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CCI – Controlled cortical impact, FPI – Fluid percussion injury; BOP – Blast overexposure induced TBI; PL – Phospholipids; DAG – Diacylglycerol; PUFA – Polyunsaturated fatty acid. PIP2 – Phosphoinositol bisphosphate.

Several studies have detected an increase in lipid degradation products including lysophospholipids in the injured brain. Guo et al used mass spectrometry imaging (MSI) to demonstrate increased levels of docosahexaenoic acid (DHA)-containing lysophospholipids with concomitant reduction in DHA-containing glycerophospholipids in the rat brain during acute phase of injury (1 day after TBI) (Guo, Zhou et al. 2017). These changes returned to the basal level within 3–7 days after the injury. Increase in lysophospholipids in the rat brain after TBI has also been detected in other studies (McDonald, Jones et al. 2018, Anthonymuthu, Kenny et al. 2019). This included widespread increase in lysophosphatidic acid and its precursors – phosphatidic acid, lysophosphatidylcholine, lysophosphatidylethanolamine and diacylglycerol within 3 h after CCI-induced TBI. Increase in lysophosphatidic acid was associated with neuronal death and axonal damage after TBI. Accumulation of lysophospholipids following TBI is at least in part mediated by the activation of phospholipases at the injury site. We previously reported increased levels of lysophosphatidylcholine (lyso-PC) and lysophosphatidylethanolamine (lyso-PE) in lysosomes isolated from the mouse brain after CCI. Our data demonstrated that lysosomal lysophospholipid accumulation was due to the activation of cytosolic phospholipase A2, which translocated to the lysosomes and mediated hydrolysis of lysosomal membrane phospholipids (Sarkar, Jones et al. 2020). This led to lysosomal membrane permeabilization, inhibition of autophagy, and consequent neuronal cell death. These data demonstrate the molecular mechanisms of how phospholipid changes may contribute to the secondary injury and TBI outcomes. Additionally, our study indicates that in addition to brain region and cell-type specificity, in order to understand the role of phospholipids, changes in their abundance have to be considered in an organelle-specific manner.

TBI also causes dysregulation in cardiolipin homeostasis (Anthonymuthu, Kenny et al. 2019). An inverse distribution pattern of cardiolipin was detected in the brain and plasma of injured rats: while brain cardiolipin level decreased after injury, its abundance increased in plasma. Since cellular cardiolipin is primarily localized to the mitochondrial inner membrane, this could indicate leakage of cardiolipin from the mitochondria of the damaged brain cells into circulation. Therefore, plasma cardiolipin level could potentially be used as a biomarker for TBI. Decrease in brain cardiolipin levels has also been reported by others (Ji, Kline et al. 2012, Falabella, Vernon et al. 2021). Ji et al showed reduced abundance of cardiolipin in both in vivo mouse TBI model and in vitro neuronal stretch injury model and demonstrated that this was due to injury-induced oxidation of cardiolipin (Ji, Kline et al. 2012). The authors proposed that accumulation of oxidized cardiolipin following injury is an indication of mitochondrial damage and subsequent activation of apoptotic pathways and showed that inhibition of cardiolipin oxidation using mitochondria specific antioxidant, XJB-5-131, is beneficial in restricting neuronal loss and improving functional recovery after TBI.

TBI-induced phospholipid changes and neurodegeneration

TBI is considered a major risk factor for Alzheimer’s disease (AD) and other dementias (Breunig, Guillot-Sestier et al. 2013, Smith, Johnson et al. 2013, Kokiko-Cochran, Ransohoff et al. 2016, Edwards, Zhao et al. 2020). However, the mechanisms of how prior TBI may contribute to development of neurodegenerative disease later in life remains poorly understood. Predisposition to AD and other dementias is strongly influenced by lipid metabolism genes, such as apolipoprotein E (APOE). APOE proteins play an important role in lipid metabolism and transport. Among its 3 isoforms (APOE2, 3 and 4), the APOE4 allele increases the risk of developing AD among its carriers (Armstrong 2019, Knopman, Amieva et al. 2021). APOE4 is also associated with worse TBI outcomes with increased mortality, prolonged coma, and more severe functional impairment (Sorbi, Nacmias et al. 1995, Teasdale, Nicoll et al. 1997, Lawrence, Comper et al. 2015). Impact of APOE alleles on phospholipids dysregulation after TBI was investigated by Cao et al using blast overexposure (BOP) injury model in transgenic mice expressing either human APOE3 or APOE4 (Cao, Gaamouch et al. 2017). Elevated levels of phosphatidylinositol bis-phosphate (PIP2) in the hippocampus of APOE3 but not in APOE4 mice was detected following repetitive BOP. This was due to differential expression of synaptojanin 1 (synj1), the rate limiting enzyme of brain PIP2 pathway, in APOE3 versus APOE4 mice. Increased PIP2 levels inversely correlated with the extent of tau-phosphorylation in these mice after injury. This suggests that APOE4 can adversely influence TBI-induced phospholipid changes to promote development of AD phenotypes. Interestingly, unlike other injury models, this study did not detect any significant changes in other phospholipids in either APOE3 or APOE4 mice after BOP suggesting that the extent and specificity of phospholipid dysregulation depends on the severity and nature of injury.

TBI-induced phospholipid dysregulation has also been investigated in other AD mouse models. Increased level of several phospholipids in both cortex and hippocampus of transgenic mice expressing human tau was detected within 24 h after repetitive mild TBI (Ojo, Algamal et al. 2018). TBI-induced changes in lysophospholipids persisted in their cortices and hippocampi up to 3 and 9 months after injury, respectively, suggesting that phospholipid abundance in these mice were differently regulated over time in different brain regions. However, it is not clear whether this was tau dependent, as no non-transgenic wildtype (WT) control mice were included in this study. A separate study from the same group demonstrated increased abundance of different phospholipids (PC, PE, PI, lyso-PC) in WT mouse hippocampi and cortices following repetitive mild TBI at both acute and chronic phases after injury (Ojo, Algamal et al. 2019). Most of these changes were absent in AD model PS1/APP mice exposed to the same injury paradigm. However, they detected higher levels of lyso-PC and sphingomyelin in the hippocampi of PS1/APP mice as compared to WT after repetitive mild TBI. Lyso-PC has proinflammatory functions and its chronic accumulation in the hippocampi of PS1/APP mice could indicate that they are more prone to develop chronic neuroinflammation in response to TBI.

TBI-induced changes in plasma phospholipids

Lower overall levels of phospholipids, including PC, PE, PI, lyso-PC and lyso-PE, have been reported in the plasma of military personnel with mild TBI with or without post-traumatic stress disorder (PTSD) by Emmerich et al (Emmerich, Abdullah et al. 2016). Decrease in the phospholipid levels was more pronounced in the plasma of army personnel with TBI or both TBI and post-traumatic stress disorder (PTSD) than those with PTSD alone. Furthermore, plasma ether phospholipid levels decreased more in those with TBI and PTSD than those with either TBI or PTSD alone. This suggests that PTSD aggravates TBI-induced changes in plasma ether phospholipids. Interestingly, changes in plasma phospholipids were less severe among APOE4 carriers. This could be due to APOE4 mediated alterations in lipid transport and regulation. It is possible that these differential changes in plasma phospholipids could be used as biomarkers for TBI and PTSD in APOE2/3 and APOE4 carriers.

Studies in rodent models also indicate potential utility of plasma phospholipid changes as TBI biomarkers. In a lipidomic study using rat TBI-model, PUFA-containing diacylglycerol has been identified as a potential biomarker for TBI (Hogan, Phan et al. 2018). Elevated levels of PUFA, PUFA-containing DAGs and slight increase in phosphatidylserine (PS) species, and decreased levels of arachidonic acid containing PEs, sphingomyelin and ceramide were reported in male rat serum following CCI. Our group also demonstrated dysregulation of plasma ether phospholipids in mice after CCI-induced moderate TBI (Morel, Hegdekar et al. 2021). We detected elevated levels of different ether-phospholipids in the plasma at day 1 after injury, probably due to their release from the damaged brain tissue into the plasma. This suggests that plasma ether-phospholipids level could be used as a biomarker for TBI in the acute phase. Recently, Thomas et al identified possible lipid biomarkers for TBI severity and outcomes (Thomas, Dickens et al. 2022). They performed comprehensive analysis of serum metabolomes of 716 acute TBI patients (24 h post injury) and compared them to a non-TBI reference group comprised of 229 patients with non-trauma related neurological disorders, orthopedic injuries and acute medical illness. They identified several phospholipids, including ether-PC, Lyso-PC and sphingomeylins, whose levels were associated with the injury severity of TBI. Interestingly, they observed highest increase in these lipids in mild-TBI patients; with levels gradually decreased with the increasing severity of injury. This might be due to differential systemic response to restore brain lipid homeostasis in response to TBI of different severity. They also demonstrated that higher levels of these lipids were associated with favorable injury outcomes. Recently, worse functional recovery among mild TBI patients with reduced plasma lysophospholipids (1-linoleoyl-GPC, 1-linoleoyl-GPE, and 1-linolenoyl-GPC) levels at 24 h after injury has also been reported (Gusdon, Savarraj et al. 2023). This might be due to lower availability of lysophospholipids for the synthesis of new phospholipids during tissue repair after injury. These suggest that plasma lysophospholipids levels after injury could be used as a predictor for TBI outcome.

Restoration of phospholipid balance as TBI treatment

Both patient and rodent model data indicate that TBI-induced changes in brain glycerophospholipid abundance and metabolism can contribute to TBI pathology and poor functional outcomes. This suggests that restoring phospholipid balance could be beneficial. Effects of phospholipids restoration have been investigated in a mouse TBI model using a lipid enriched multinutrient mixture named as Fortasyn Connect (FC) that contains polyunsaturated omega-3 fatty acids, choline, uridine and vitamins to promote phospholipids synthesis (Thau-Zuchman, Gomes et al. 2019). FC treatment has been demonstrated to attenuate injury induced decrease in PC and PE level in the cerebellum, restore myelin structure in the injured brain, improve functional recovery, reduce gliosis and promote neurogenesis in mice after TBI. Treatment of mice using anti-lysophosphatidic acid (a phospholipid breakdown product) antibody has been shown to improve functional recovery and attenuate neuroinflammation after TBI (Crack, Zhang et al. 2014, Eisenried, Meidahl et al. 2017). Similarly, our studies using inhibitor of cPLA2 demonstrated that attenuation of lyso-phospholipid accumulation could decrease cell death and improve outcomes in CCI mouse model (Sarkar, Jones et al. 2020, Sarkar and Lipinski 2023).

Perspective

Glycerophospholipids dysregulation after TBI has been well documented in several studies (Table 1). Their differential levels in both brain and blood in response to injury of varying severity is an indicative of both tissue damage and subsequent repair response (Fig. 1). TBI-induced changes in glycerophospholipids are most likely due to both pathological factors such as oxidative stress and activation of phospholipases, as well as to activation of reparative lipid metabolism pathways. However, the full set of mechanisms contributing to glycerophospholipid dysregulation following TBI is yet to be elucidated. Particularly, the mechanisms of cell type specific differential regulation of phospholipids after TBI are not clear. Determining them would be extremely important in understanding the role and functions of phospholipids in neuronal death and neuroinflammation after TBI. This will open up new avenues for novel treatment options to restrict neuronal loss and neuroinflammation and improve functional recovery after TBI.

Figure 1.

Figure 1.

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Schematic diagram representing cellular mechanisms of phospholipid dysregulation after TBI. PL – Phospholipids; LPL – Lyso-PLs; PLA2 – Phospholipase A2; ROS – Reactive oxygen species. This figure was created with Biorender.com.

Highlights:

  • Traumatic brain injury (TBI) perturbs brain and systemic glycerophospholipid homeostasis.

  • TBI-induced glycerophospholipid dysregulation contributes to neurodegeneration.

  • Brain phospholipids restoration is beneficial in restoring functional recovery after TBI.

Declaration of competing interest

This work was supported by NIH R21 (R21NS117867) grant to CS and NIH R01 (R01 NS115876) to MML.

Footnotes

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Data availability

No experimental data was used for this article.

References

  1. Abdullah L, Evans JE, Ferguson S, Mouzon B, Montague H, Reed J, Crynen G, Emmerich T, Crocker M, Pelot R, Mullan M and Crawford F (2014). “Lipidomic analyses identify injury-specific phospholipid changes 3 mo after traumatic brain injury.” FASEB J 28(12): 5311–5321. [DOI] [PubMed] [Google Scholar]
  2. Agrawal RR, Larrea D, Xu Y, Shi L, Zirpoli H, Cummins LG, Emmanuele V, Song D, Yun TD, Macaluso FP, Min W, Kernie SG, Deckelbaum RJ and Area-Gomez E (2023). “Alzheimer’s-Associated Upregulation of Mitochondria-Associated ER Membranes After Traumatic Brain Injury.” Cell Mol Neurobiol 43(5): 2219–2241. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Anthonymuthu TS, Kenny EM, Hier ZE, Clark RSB, Kochanek PM, Kagan VE and Bayir H (2019). “Detection of brain specific cardiolipins in plasma after experimental pediatric head injury.” Exp Neurol 316: 63–73. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Armstrong AR (2019). “Risk factors for Alzheimer’s disease.” Folia Neuropathol 57(2): 87–105. [DOI] [PubMed] [Google Scholar]
  5. Breunig JJ, Guillot-Sestier MV and Town T (2013). “Brain injury, neuroinflammation and Alzheimer’s disease.” Front Aging Neurosci 5: 26. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Burke JE and Dennis EA (2009). “Phospholipase A2 biochemistry.” Cardiovasc Drugs Ther 23(1): 49–59. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Burke JE and Dennis EA (2009). “Phospholipase A2 structure/function, mechanism, and signaling.” J Lipid Res 50 Suppl: S237–242. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Cao J, Gaamouch FE, Meabon JS, Meeker KD, Zhu L, Zhong MB, Bendik J, Elder G, Jing P, Xia J, Luo W, Cook DG and Cai D (2017). “ApoE4-associated phospholipid dysregulation contributes to development of Tau hyper-phosphorylation after traumatic brain injury.” Sci Rep 7(1): 11372. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Crack PJ, Zhang M, Morganti-Kossmann MC, Morris AJ, Wojciak JM, Fleming JK, Karve I, Wright D, Sashindranath M, Goldshmit Y, Conquest A, Daglas M, Johnston LA, Medcalf RL, Sabbadini RA and Pebay A (2014). “Anti-lysophosphatidic acid antibodies improve traumatic brain injury outcomes.” J Neuroinflammation 11: 37. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Dean JM and Lodhi IJ (2018). “Structural and functional roles of ether lipids.” Protein Cell 9(2): 196–206. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Edwards G 3rd, Zhao J, Dash PK, Soto C and Moreno-Gonzalez I (2020). “Traumatic Brain Injury Induces Tau Aggregation and Spreading.” J Neurotrauma 37(1): 80–92. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Eisenried A, Meidahl ACN, Klukinov M, Tzabazis AZ, Sabbadini RA, Clark JD and Yeomans DC (2017). “Nervous system delivery of antilysophosphatidic acid antibody by nasal application attenuates mechanical allodynia after traumatic brain injury in rats.” Pain 158(11): 2181–2188. [DOI] [PubMed] [Google Scholar]
  13. Emmerich T, Abdullah L, Crynen G, Dretsch M, Evans J, Ait-Ghezala G, Reed J, Montague H, Chaytow H, Mathura V, Martin J, Pelot R, Ferguson S, Bishop A, Phillips J, Mullan M and Crawford F (2016). “Plasma Lipidomic Profiling in a Military Population of Mild Traumatic Brain Injury and Post-Traumatic Stress Disorder with Apolipoprotein E varepsilon4-Dependent Effect.” J Neurotrauma 33(14): 1331–1348. [DOI] [PubMed] [Google Scholar]
  14. Faden AI, Wu J, Stoica BA and Loane DJ (2016). “Progressive inflammation-mediated neurodegeneration after traumatic brain or spinal cord injury.” Br J Pharmacol 173(4): 681–691. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Falabella M, Vernon HJ, Hanna MG, Claypool SM and Pitceathly RDS (2021). “Cardiolipin, Mitochondria, and Neurological Disease.” Trends Endocrinol Metab 32(4): 224–237. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Farooqui AA, Horrocks LA and Farooqui T (2000). “Glycerophospholipids in brain: their metabolism, incorporation into membranes, functions, and involvement in neurological disorders.” Chem Phys Lipids 106(1): 1–29. [DOI] [PubMed] [Google Scholar]
  17. Gardner AJ and Zafonte R (2016). “Neuroepidemiology of traumatic brain injury.” Handb Clin Neurol 138: 207–223. [DOI] [PubMed] [Google Scholar]
  18. Ghosh M, Tucker DE, Burchett SA and Leslie CC (2006). “Properties of the Group IV phospholipase A2 family.” Prog Lipid Res 45(6): 487–510. [DOI] [PubMed] [Google Scholar]
  19. Guo S, Zhou D, Zhang M, Li T, Liu Y, Xu Y, Chen T and Li Z (2017). “Monitoring changes of docosahexaenoic acid-containing lipids during the recovery process of traumatic brain injury in rat using mass spectrometry imaging.” Sci Rep 7(1): 5054. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Gusdon AM, Savarraj JP, Redell JB, Paz A, Hinds S, Burkett A, Torres G, Ren X, Badjatia N, Hergenroeder GW, Moore AN, Choi HA and Dash PK (2023). “Lysophospholipids Are Associated With Outcomes in Hospitalized Patients With Mild Traumatic Brain Injury.” J Neurotrauma. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Hogan SR, Phan JH, Alvarado-Velez M, Wang MD, Bellamkonda RV, Fernandez FM and LaPlaca MC (2018). “Discovery of Lipidome Alterations Following Traumatic Brain Injury via High-Resolution Metabolomics.” J Proteome Res 17(6): 2131–2143. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Injury GBDTB and Spinal Cord Injury C (2019). “Global, regional, and national burden of traumatic brain injury and spinal cord injury, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016.” Lancet Neurol 18(1): 56–87. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Ji J, Kline AE, Amoscato A, Samhan-Arias AK, Sparvero LJ, Tyurin VA, Tyurina YY, Fink B, Manole MD, Puccio AM, Okonkwo DO, Cheng JP, Alexander H, Clark RS, Kochanek PM, Wipf P, Kagan VE and Bayir H (2012). “Lipidomics identifies cardiolipin oxidation as a mitochondrial target for redox therapy of brain injury.” Nat Neurosci 15(10): 1407–1413. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Kennedy EP and Weiss SB (1956). “The function of cytidine coenzymes in the biosynthesis of phospholipides.” J Biol Chem 222(1): 193–214. [PubMed] [Google Scholar]
  25. Knopman DS, Amieva H, Petersen RC, Chetelat G, Holtzman DM, Hyman BT, Nixon RA and Jones DT (2021). “Alzheimer disease.” Nat Rev Dis Primers 7(1): 33. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Kokiko-Cochran O, Ransohoff L, Veenstra M, Lee S, Saber M, Sikora M, Teknipp R, Xu G, Bemiller S, Wilson G, Crish S, Bhaskar K, Lee YS, Ransohoff RM and Lamb BT (2016). “Altered Neuroinflammation and Behavior after Traumatic Brain Injury in a Mouse Model of Alzheimer’s Disease.” J Neurotrauma 33(7): 625–640. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Kudo I and Murakami M (2002). “Phospholipase A2 enzymes.” Prostaglandins Other Lipid Mediat 68–69: 3–58. [DOI] [PubMed] [Google Scholar]
  28. Lawrence DW, Comper P, Hutchison MG and Sharma B (2015). “The role of apolipoprotein E episilon (epsilon)-4 allele on outcome following traumatic brain injury: A systematic review.” Brain Inj 29(9): 1018–1031. [DOI] [PubMed] [Google Scholar]
  29. McDonald WS, Jones EE, Wojciak JM, Drake RR, Sabbadini RA and Harris NG (2018). “Matrix-Assisted Laser Desorption Ionization Mapping of Lysophosphatidic Acid Changes after Traumatic Brain Injury and the Relationship to Cellular Pathology.” Am J Pathol 188(8): 1779–1793. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Montealegre C, Verardo V, Luisa Marina M and Caboni MF (2014). “Analysis of glycerophospho- and sphingolipids by CE.” Electrophoresis 35(6): 779–792. [DOI] [PubMed] [Google Scholar]
  31. Morel Y, Hegdekar N, Sarkar C, Lipinski MM, Kane MA and Jones JW (2021). “Structure-specific, accurate quantitation of plasmalogen glycerophosphoethanolamine.” Anal Chim Acta 1186: 339088. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Nguyen R, Fiest KM, McChesney J, Kwon CS, Jette N, Frolkis AD, Atta C, Mah S, Dhaliwal H, Reid A, Pringsheim T, Dykeman J and Gallagher C (2016). “The International Incidence of Traumatic Brain Injury: A Systematic Review and Meta-Analysis.” Can J Neurol Sci 43(6): 774–785. [DOI] [PubMed] [Google Scholar]
  33. Ojo JO, Algamal M, Leary P, Abdullah L, Mouzon B, Evans JE, Mullan M and Crawford F (2018). “Disruption in Brain Phospholipid Content in a Humanized Tau Transgenic Model Following Repetitive Mild Traumatic Brain Injury.” Front Neurosci 12: 893. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Ojo JO, Algamal M, Leary P, Abdullah L, Mouzon B, Evans JE, Mullan M and Crawford F (2019). “Converging and Differential Brain Phospholipid Dysregulation in the Pathogenesis of Repetitive Mild Traumatic Brain Injury and Alzheimer’s Disease.” Front Neurosci 13: 103. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Sarkar C, Jones JW, Hegdekar N, Thayer JA, Kumar A, Faden AI, Kane MA and Lipinski MM (2020). “PLA2G4A/cPLA2-mediated lysosomal membrane damage leads to inhibition of autophagy and neurodegeneration after brain trauma.” Autophagy 16(3): 466–485. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Sarkar C and Lipinski MM (2023). Role and function of cPLA2 in CNS trauma and age-associated neurodegenerative diseases. Phospholipases in Physiology and Pathology. Chakraborti S, Elsevier. 7:Phospholipases in Nonmalignant Human Diseases: 103–117. [Google Scholar]
  37. Smith DH, Johnson VE and Stewart W (2013). “Chronic neuropathologies of single and repetitive TBI: substrates of dementia?” Nat Rev Neurol 9(4): 211–221. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Sorbi S, Nacmias B, Piacentini S, Repice A, Latorraca S, Forleo P and Amaducci L (1995). “ApoE as a prognostic factor for post-traumatic coma.” Nat Med 1(9): 852. [DOI] [PubMed] [Google Scholar]
  39. Stoica BA and Faden AI (2010). “Cell death mechanisms and modulation in traumatic brain injury.” Neurotherapeutics 7(1): 3–12. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Teasdale GM, Nicoll JA, Murray G and Fiddes M (1997). “Association of apolipoprotein E polymorphism with outcome after head injury.” Lancet 350(9084): 1069–1071. [DOI] [PubMed] [Google Scholar]
  41. Thau-Zuchman O, Gomes RN, Dyall SC, Davies M, Priestley JV, Groenendijk M, De Wilde MC, Tremoleda JL and Michael-Titus AT (2019). “Brain Phospholipid Precursors Administered Post-Injury Reduce Tissue Damage and Improve Neurological Outcome in Experimental Traumatic Brain Injury.” J Neurotrauma 36(1): 25–42. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Thomas I, Dickens AM, Posti JP, Czeiter E, Duberg D, Sinioja T, Krakstrom M, Retel Helmrich IRA, Wang KKW, Maas AIR, Steyerberg EW, Menon DK, Tenovuo O, Hyotylainen T, Buki A, Oresic M, C.-T. Participants and Investigators (2022). “Serum metabolome associated with severity of acute traumatic brain injury.” Nat Commun 13(1): 2545. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Vance JE (2015). “Phospholipid synthesis and transport in mammalian cells.” Traffic 16(1): 1–18. [DOI] [PubMed] [Google Scholar]
  44. Vemuganti R and Hall ED (2017). “Cellular and molecular mechanisms of neuroprotection and plasticity after traumatic brain injury.” Neurochem Int 111: 1–2. [DOI] [PubMed] [Google Scholar]
  45. Wang B and Tontonoz P (2019). “Phospholipid Remodeling in Physiology and Disease.” Annu Rev Physiol 81: 165–188. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Werner C and Engelhard K (2007). “Pathophysiology of traumatic brain injury.” Br J Anaesth 99(1): 4–9. [DOI] [PubMed] [Google Scholar]
  47. Xiong Y, Mahmood A and Chopp M (2013). “Animal models of traumatic brain injury.” Nat Rev Neurosci 14(2): 128–142. [DOI] [PMC free article] [PubMed] [Google Scholar]

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