Acid Sphingomyelinase Inhibitor, Imipramine, Reduces Hippocampal Neuronal Death after Traumatic Brain Injury

Lee, Si Hyun; Kho, A Ra; Lee, Song Hee; Hong, Dae Ki; Kang, Beom Seok; Park, Min Kyu; Lee, Chang Juhn; Yang, Hyun Wook; Woo, Seo Young; Park, Se Wan; Kim, Dong Yeon; Choi, Bo Young; Suh, Sang Won

doi:10.3390/ijms232314749

Cited by 7 publications

(5 citation statements)

References 70 publications

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“…The biomarkers studied, based on references to TBIs in the literature, were classified within three main injury phases as acute, sub-acute, and chronic (Figure 1), the corresponding detailed information for each biomarker, including the accessible biofluid Figure 1. Schematic timeline overview of the TBI biomarkers and their phases, acute (blue), subacute (orange), and chronic (green), during which each biomarker has been reported to either increase, persist, or decline post-injury [4,9,40,44,[46][47][48][49][50][51][52][53][54][55][56][57][58][59][60][61][62][63][64]. Biomarkers: N-Acetyl-L-aspartic acid (NAA), Glutathione (GSH), Neuron-Specific Enolase (NSE), Glial fibrillary acidic protein (GFAP), Ubiquitin carboxyl-terminal hydrolase isozyme L1 (UCHL1), Interleukin-6 (IL-6), Interleukin-18 (IL-18), and Neurofilament light chain (NFL).…”

Section: Resultsmentioning

confidence: 99%

Raman Spectroscopy Spectral Fingerprints of Biomarkers of Traumatic Brain Injury

Harris,

Stickland,

Lim

et al. 2023

Cells

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Traumatic brain injury (TBI) affects millions of people of all ages around the globe. TBI is notoriously hard to diagnose at the point of care, resulting in incorrect patient management, avoidable death and disability, long-term neurodegenerative complications, and increased costs. It is vital to develop timely, alternative diagnostics for TBI to assist triage and clinical decision-making, complementary to current techniques such as neuroimaging and cognitive assessment. These could deliver rapid, quantitative TBI detection, by obtaining information on biochemical changes from patient’s biofluids. If available, this would reduce mis-triage, save healthcare providers costs (both over- and under-triage are expensive) and improve outcomes by guiding early management. Herein, we utilize Raman spectroscopy-based detection to profile a panel of 18 raw (human, animal, and synthetically derived) TBI-indicative biomarkers (N-acetyl-aspartic acid (NAA), Ganglioside, Glutathione (GSH), Neuron Specific Enolase (NSE), Glial Fibrillary Acidic Protein (GFAP), Ubiquitin C-terminal Hydrolase L1 (UCHL1), Cholesterol, D-Serine, Sphingomyelin, Sulfatides, Cardiolipin, Interleukin-6 (IL-6), S100B, Galactocerebroside, Beta-D-(+)-Glucose, Myo-Inositol, Interleukin-18 (IL-18), Neurofilament Light Chain (NFL)) and their aqueous solution. The subsequently derived unique spectral reference library, exploiting four excitation lasers of 514, 633, 785, and 830 nm, will aid the development of rapid, non-destructive, and label-free spectroscopy-based neuro-diagnostic technologies. These biomolecules, released during cellular damage, provide additional means of diagnosing TBI and assessing the severity of injury. The spectroscopic temporal profiles of the studied biofluid neuro-markers are classed according to their acute, sub-acute, and chronic temporal injury phases and we have further generated detailed peak assignment tables for each brain-specific biomolecule within each injury phase. The intensity ratios of significant peaks, yielding the combined unique spectroscopic barcode for each brain-injury marker, are compared to assess variance between lasers, with the smallest variance found for UCHL1 (σ2 = 0.000164) and the highest for sulfatide (σ2 = 0.158). Overall, this work paves the way for defining and setting the most appropriate diagnostic time window for detection following brain injury. Further rapid and specific detection of these biomarkers, from easily accessible biofluids, would not only enable the triage of TBI, predict outcomes, indicate the progress of recovery, and save healthcare providers costs, but also cement the potential of Raman-based spectroscopy as a powerful tool for neurodiagnostics.

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Section: Resultsmentioning

confidence: 99%

Raman Spectroscopy Spectral Fingerprints of Biomarkers of Traumatic Brain Injury

Harris,

Stickland,

Lim

et al. 2023

Cells

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“…Genetically ablated Smpd1 −/− (aSMase) also reproduced similar results, indicating a major role of aSMase activation in the initiation of TBI neuropathology [ 87 ]. In another study modeling TBI in mice, inhibiting aSMase by intraperitoneal imipramine significantly reduced levels of Cer and aSMase activity in the brain tissue, neuronal death, and cognitive dysfunction [ 90 ]. In the context of these prior studies, these findings align well with other experimental models of Cer-regulated neuroinflammation-mediated neurodegeneration in TBI and suggests aSMase could be a potential therapeutic target in the acute phases of TBI, whereas nSMase for chronic phases of TBI.…”

Section: Discussionmentioning

confidence: 99%

Sphingolipid changes in mouse brain and plasma after mild traumatic brain injury at the acute phases

Mondal,

Del Mar,

Gary

et al. 2024

Lipids Health Dis

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Background Traumatic brain injury (TBI) causes neuroinflammation and can lead to long-term neurological dysfunction, even in cases of mild TBI (mTBI). Despite the substantial burden of this disease, the management of TBI is precluded by an incomplete understanding of its cellular mechanisms. Sphingolipids (SPL) and their metabolites have emerged as key orchestrators of biological processes related to tissue injury, neuroinflammation, and inflammation resolution. No study so far has investigated comprehensive sphingolipid profile changes immediately following TBI in animal models or human cases. In this study, sphingolipid metabolite composition was examined during the acute phases in brain tissue and plasma of mice following mTBI. Methods Wildtype mice were exposed to air-blast-mediated mTBI, with blast exposure set at 50-psi on the left cranium and 0-psi designated as Sham. Sphingolipid profile was analyzed in brain tissue and plasma during the acute phases of 1, 3, and 7 days post-TBI via liquid-chromatography-mass spectrometry. Simultaneously, gene expression of sphingolipid metabolic markers within brain tissue was analyzed using quantitative reverse transcription-polymerase chain reaction. Significance (P-values) was determined by non-parametric t-test (Mann–Whitney test) and by Tukey’s correction for multiple comparisons. Results In post-TBI brain tissue, there was a significant elevation of 1) acid sphingomyelinase (aSMase) at 1- and 3-days, 2) neutral sphingomyelinase (nSMase) at 7-days, 3) ceramide-1-phosphate levels at 1 day, and 4) monohexosylceramide (MHC) and sphingosine at 7-days. Among individual species, the study found an increase in C18:0 and a decrease in C24:1 ceramides (Cer) at 1 day; an increase in C20:0 MHC at 3 days; decrease in MHC C18:0 and increase in MHC C24:1, sphingomyelins (SM) C18:0, and C24:0 at 7 days. Moreover, many sphingolipid metabolic genes were elevated at 1 day, followed by a reduction at 3 days and an absence at 7-days post-TBI. In post-TBI plasma, there was 1) a significant reduction in Cer and MHC C22:0, and an increase in MHC C16:0 at 1 day; 2) a very significant increase in long-chain Cer C24:1 accompanied by significant decreases in Cer C24:0 and C22:0 in MHC and SM at 3 days; and 3) a significant increase of C22:0 in all classes of SPL (Cer, MHC and SM) as well as a decrease in Cer C24:1, MHC C24:1 and MHC C24:0 at 7 days. Conclusions Alterations in sphingolipid metabolite composition, particularly sphingomyelinases and short-chain ceramides, may contribute to the induction and regulation of neuroinflammatory events in the early stages of TBI, suggesting potential targets for novel diagnostic, prognostic, and therapeutic strategies in the future.

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“…Gene therapies Autophagy Endocrine Other NGF [172], BDNF [173], PEDF [135] and IGF-1 delivery via nanofibrous dural substitutes [197] Caspases [174], Rho-A [175], mTOR [176], chk2 [177], Rab [198] and transglutaminases [199] Caspases [174], Bcl-2 [200], imipramine [201], cyclosporin A [202] and statins [203] NgR [107], glutamate [163] and endothelin [204] AQP-4 [83], Ca 2+ channel inhibitors [164] and mPTP [165] Immunomodulation [166], gangliosides [49,167], HDAC inhibitors [205] and bexarotene [206] Mitochondria-endoplasmic reticulum contact sites [207] Antioxidants [168], ROS scavenger materials [170,171,208,209] and Uqcr11 overexpression [210] Chondroitinase ABC [169,170], decorin [106,171] and 4-methylumbelliferone [211] Neuronal differentiation [43,212] HSPs [213] Progesterone [214], erianin [215] Hydrogen sulphide…”

Section: Glial Scarmentioning

confidence: 99%

Neurotrauma—From Injury to Repair: Clinical Perspectives, Cellular Mechanisms and Promoting Regeneration of the Injured Brain and Spinal Cord

Stevens,

Belli,

Ahmed

2024

Biomedicines

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Traumatic injury to the brain and spinal cord (neurotrauma) is a common event across populations and often causes profound and irreversible disability. Pathophysiological responses to trauma exacerbate the damage of an index injury, propagating the loss of function that the central nervous system (CNS) cannot repair after the initial event is resolved. The way in which function is lost after injury is the consequence of a complex array of mechanisms that continue in the chronic phase post-injury to prevent effective neural repair. This review summarises the events after traumatic brain injury (TBI) and spinal cord injury (SCI), comprising a description of current clinical management strategies, a summary of known cellular and molecular mechanisms of secondary damage and their role in the prevention of repair. A discussion of current and emerging approaches to promote neuroregeneration after CNS injury is presented. The barriers to promoting repair after neurotrauma are across pathways and cell types and occur on a molecular and system level. This presents a challenge to traditional molecular pharmacological approaches to targeting single molecular pathways. It is suggested that novel approaches targeting multiple mechanisms or using combinatorial therapies may yield the sought-after recovery for future patients.

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Acid Sphingomyelinase Inhibitor, Imipramine, Reduces Hippocampal Neuronal Death after Traumatic Brain Injury

Cited by 7 publications

References 70 publications

Raman Spectroscopy Spectral Fingerprints of Biomarkers of Traumatic Brain Injury

Raman Spectroscopy Spectral Fingerprints of Biomarkers of Traumatic Brain Injury

Sphingolipid changes in mouse brain and plasma after mild traumatic brain injury at the acute phases

Neurotrauma—From Injury to Repair: Clinical Perspectives, Cellular Mechanisms and Promoting Regeneration of the Injured Brain and Spinal Cord

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