Systemic Elevation of n-3 Polyunsaturated Fatty Acids (n-3-PUFA) Is Associated with Protection against Visual, Motor, and Emotional Deficits in Mice following Closed-Head Mild Traumatic Brain Injury

Mondal, Kalyani; Takahashi, Haruka; Cole, J. W.; Mar, Nobel A. Del; Li, Chunyan; Stephenson, Daniel J.; Allegood, Jeremy C.; Cowart, L. Ashley; Chalfant, Charles E.; Reiner, Anton; Mandal, Nawajes A.

doi:10.1007/s12035-021-02501-y

Cited by 9 publications

(12 citation statements)

References 61 publications

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“…Among the up-regulated proteins (including BDNF, as expected), a number of them have been reported to show neuroprotective functions in the brain. In particular, it has been reported that metalloproteinase inhibitor 1 (TIMP) and agrin (ARGN) have neuroprotective and recovery functions in animal TBI models [ 51 , 52 ]. Through proteomic analysis of the secretome expressed by BDNF-eMSCs, it was confirmed that other effective molecules could act alongside BDNF in the treatment of TBI.…”

Section: Discussionmentioning

confidence: 99%

Engineered Mesenchymal Stem Cells Over-Expressing BDNF Protect the Brain from Traumatic Brain Injury-Induced Neuronal Death, Neurological Deficits, and Cognitive Impairments

et al. 2023

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Traumatic brain injury (TBI) causes transitory or permanent neurological and cognitive impairments, which can intensify over time due to secondary neuronal death. However, no therapy currently exists that can effectively treat brain injury following TBI. Here, we evaluate the therapeutic potential of irradiated engineered human mesenchymal stem cells over-expressing brain-derived neurotrophic factor (BDNF), which we denote by BDNF-eMSCs, in protecting the brain against neuronal death, neurological deficits, and cognitive impairment in TBI rats. BDNF-eMSCs were administered directly into the left lateral ventricle of the brain in rats that received TBI damage. A single administration of BDNF-eMSCs reduced TBI-induced neuronal death and glial activation in the hippocampus, while repeated administration of BDNF-eMSCs reduced not only glial activation and delayed neuronal loss but also enhanced hippocampal neurogenesis in TBI rats. In addition, BDNF-eMSCs reduced the lesion area in the damaged brain of the rats. Behaviorally, BDNF-eMSC treatment improved the neurological and cognitive functions of the TBI rats. The results presented in this study demonstrate that BDNF-eMSCs can attenuate TBI-induced brain damage through the suppression of neuronal death and increased neurogenesis, thus enhancing functional recovery after TBI, indicating the significant therapeutic potential of BDNF-eMSCs in the treatment of TBI.

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Section: Discussionmentioning

confidence: 99%

Engineered Mesenchymal Stem Cells Over-Expressing BDNF Protect the Brain from Traumatic Brain Injury-Induced Neuronal Death, Neurological Deficits, and Cognitive Impairments

et al. 2023

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“…PUFA are involved in the crosstalk between brain lipid metabolism and post‐traumatic neuroinflammation. In mice expressing the C. elegans transgene, fat1 + , which endogenously produces ϖ‐3 PUFA, there are reduced numbers of Iba1+ microglia/macrophages within the cortical lesion and reduced expression of pro‐inflammatory mediators in TBI tissue (e.g., Cxcl1 , Tnfa , Il6 ; Mondal et al, 2021). Furthermore, nutritional supplementation of ϖ‐3 PUFA in injured wild‐type mice reduced microglia/macrophage activation and improved long‐term neurological recovery to similar levels observed in injured fat1 + transgenic mice (Desai et al, 2021).…”

Section: Tbi Disrupts Microglial Lipid Metabolism and Increases Keton...mentioning

confidence: 99%

Fundamental Neurochemistry Review: Microglial immunometabolism in traumatic brain injury

Strogulski,

Portela,

Polster

et al. 2023

Journal of Neurochemistry

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Traumatic brain injury (TBI) is a devastating neurological disorder caused by a physical impact to the brain that promotes diffuse damage and chronic neurodegeneration. Key mechanisms believed to support secondary brain injury include mitochondrial dysfunction and chronic neuroinflammation. Microglia and brain‐infiltrating macrophages are responsible for neuroinflammatory cytokine and reactive oxygen species (ROS) production after TBI. Their production is associated with loss of homeostatic microglial functions such as immunosurveillance, phagocytosis, and immune resolution. Beyond providing energy support, mitochondrial metabolic pathways reprogram the pro‐ and anti‐inflammatory machinery in immune cells, providing a critical immunometabolic axis capable of regulating immunologic response to noxious stimuli. In the brain, the capacity to adapt to different environmental stimuli derives, in part, from microglia's ability to recognize and respond to changes in extracellular and intracellular metabolite levels. This capacity is met by an equally plastic metabolism, capable of altering immune function. Microglial pro‐inflammatory activation is associated with decreased mitochondrial respiration, whereas anti‐inflammatory microglial polarization is supported by increased oxidative metabolism. These metabolic adaptations contribute to neuroimmune responses, placing mitochondria as a central regulator of post‐traumatic neuroinflammation. Although it is established that profound neurometabolic changes occur following TBI, key questions related to metabolic shifts in microglia remain unresolved. These include (a) the nature of microglial mitochondrial dysfunction after TBI, (b) the hierarchical positions of different metabolic pathways such as glycolysis, pentose phosphate pathway, glutaminolysis, and lipid oxidation during secondary injury and recovery, and (c) how immunometabolism alters microglial phenotypes, culminating in chronic non‐resolving neuroinflammation. In this basic neurochemistry review article, we describe the contributions of immunometabolism to TBI, detail primary evidence of mitochondrial dysfunction and metabolic impairments in microglia and macrophages, discuss how major metabolic pathways contribute to post‐traumatic neuroinflammation, and set out future directions toward advancing immunometabolic phenotyping in TBI.image

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“…Total RNA from HREC and BV2 cell pellets was extracted using the Ambion RNA mini extraction kit following the manufacturer's protocol (Ambion TRIzol ® Plus RNA purification kit: Life Technologies, Carlsbad, CA, USA); cDNA synthesis was carried out by SuperScript™ IV First-Strand Synthesis SuperMix (Invitrogen, Carlsbad, CA, USA). Quantitative RT-PCR was performed according to our previously published procedure [4,7]. The sequence of the primers for human gene expression (for HREC) and rodent gene expression (for BV2) are provided in Supplementary Tables S1 and S2.…”

Section: Quantitative Rt-pcrmentioning

confidence: 99%

“…The enzymatic activities of acidic and neutral sphingomyelinase (aSMase and nSMase, respectively) were measured in HREC and BV2 using the Amplex Red Sphingomyelinase Assay Kit (Invitrogen, Carlsbad, CA, USA) following previously published protocols [4,32].…”

Section: Sphingomyelinase Assaysmentioning

confidence: 99%

“…Sphingolipids (SPLs) are a diverse and ubiquitous family of lipids that function as structural components of the cellular membranes and have signaling roles in various cellular processes, including cell growth, cell adhesion, inflammation, and apoptosis [1][2][3][4]. Biochemically, all SPLs contain an amino-alcohol backbone and a covalently bound fatty acid forming the base structure of an SPL, the Ceramide (Cer).…”

Section: Introductionmentioning

confidence: 99%

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A Comprehensive Profiling of Cellular Sphingolipids in Mammalian Endothelial and Microglial Cells Cultured in Normal and High-Glucose Conditions

Mondal

Grambergs

Gangaraju

et al. 2022

Cells

Self Cite

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Sphingolipids (SPLs) play a diverse role in maintaining cellular homeostasis. Dysregulated SPL metabolism is associated with pathological changes in stressed and diseased cells. This study investigates differences in SPL metabolism between cultured human primary retinal endothelial (HREC) and murine microglial cells (BV2) in normal conditions (normal glucose, NG, 5 mM) and under high-glucose (HG, 25 mM)-induced stress by sphingolipidomics, immunohistochemistry, biochemical, and molecular assays. Measurable differences were observed in SPL profiles between HREC and BV2 cells. High-glucose treatment caused a >2.5-fold increase in the levels of Lactosyl-ceramide (LacCer) in HREC, but in BV2 cells, it induced Hexosyl-Ceramides (HexCer) by threefold and a significant increase in Sphingosine-1-phosphate (S1P) compared to NG. Altered SPL profiles coincided with changes in transcript levels of inflammatory and vascular permeability mediators in HREC and inflammatory mediators in BV2 cells. Differences in SPL profiles and differential responses to HG stress between endothelial and microglial cells suggest that SPL metabolism and signaling differ in mammalian cell types and, therefore, their pathological association with those cell types.

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Systemic Elevation of n-3 Polyunsaturated Fatty Acids (n-3-PUFA) Is Associated with Protection against Visual, Motor, and Emotional Deficits in Mice following Closed-Head Mild Traumatic Brain Injury

Cited by 9 publications

References 61 publications

Engineered Mesenchymal Stem Cells Over-Expressing BDNF Protect the Brain from Traumatic Brain Injury-Induced Neuronal Death, Neurological Deficits, and Cognitive Impairments

Engineered Mesenchymal Stem Cells Over-Expressing BDNF Protect the Brain from Traumatic Brain Injury-Induced Neuronal Death, Neurological Deficits, and Cognitive Impairments

Fundamental Neurochemistry Review: Microglial immunometabolism in traumatic brain injury

A Comprehensive Profiling of Cellular Sphingolipids in Mammalian Endothelial and Microglial Cells Cultured in Normal and High-Glucose Conditions

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