scholarly journals 3,6’-dithiopomalidomide reduces neural loss, inflammation, behavioral deficits in brain injury and microglial activation

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Chih-Tung Lin ◽  
Daniela Lecca ◽  
Ling-Yu Yang ◽  
Weiming Luo ◽  
Michael T Scerba ◽  
...  
Keyword(s):  
Cell Death ◽  
Brain Injury ◽  
Microglial Activation ◽  
Therapeutic Window ◽  
Post Injury ◽  
Behavioral Deficits ◽  
Immunomodulatory Agents ◽  
Associated Proteins ◽  
Behavioral Impairments ◽  
Pro Inflammatory Cytokines

Traumatic brain injury (TBI) causes mortality and disability worldwide. It can initiate acute cell death followed by secondary injury induced by microglial activation, oxidative stress, inflammation and autophagy in brain tissue, resulting in cognitive and behavioral deficits. We evaluated a new pomalidomide (Pom) analog, 3,6’-dithioPom (DP), and Pom as immunomodulatory agents to mitigate TBI-induced cell death, neuroinflammation, astrogliosis and behavioral impairments in rats challenged with controlled cortical impact TBI. Both agents significantly reduced the injury contusion volume and degenerating neuron number evaluated histochemically and by MRI at 24 hr and 7 days, with a therapeutic window of 5 hr post-injury. TBI-induced upregulated markers of microglial activation, astrogliosis and the expression of pro-inflammatory cytokines, iNOS, COX-2, and autophagy-associated proteins were suppressed, leading to an amelioration of behavioral deficits with DP providing greater efficacy. Complementary animal and cellular studies demonstrated DP and Pom mediated reductions in markers of neuroinflammation and α-synuclein-induced toxicity.

scholarly journals 3,6′-Dithiopomalidomide Ameliorates Hippocampal Neurodegeneration, Microgliosis and Astrogliosis and Improves Cognitive Behaviors in Rats with a Moderate Traumatic Brain Injury

2021 ◽  
Vol 22 (15) ◽  
pp. 8276
Author(s):  
Pen-Sen Huang ◽  
Ping-Yen Tsai ◽  
Ling-Yu Yang ◽  
Daniela Lecca ◽  
Weiming Luo ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Short Term Memory ◽  
Post Injury ◽  
Behavioral Deficits ◽  
Cognitive Behaviors ◽  
Moderate Traumatic Brain Injury ◽  
Short And Long Term ◽  
Behavioral Impairments ◽  
Hippocampal Neurodegeneration

Traumatic brain injury (TBI) is a leading cause of disability and mortality worldwide. It can instigate immediate cell death, followed by a time-dependent secondary injury that results from disproportionate microglial and astrocyte activation, excessive inflammation and oxidative stress in brain tissue, culminating in both short- and long-term cognitive dysfunction and behavioral deficits. Within the brain, the hippocampus is particularly vulnerable to a TBI. We studied a new pomalidomide (Pom) analog, namely, 3,6′-dithioPom (DP), and Pom as immunomodulatory imide drugs (IMiD) for mitigating TBI-induced hippocampal neurodegeneration, microgliosis, astrogliosis and behavioral impairments in a controlled cortical impact (CCI) model of TBI in rats. Both agents were administered as a single intravenous dose (0.5 mg/kg) at 5 h post injury so that the efficacies could be compared. Pom and DP significantly reduced the contusion volume evaluated at 24 h and 7 days post injury. Both agents ameliorated short-term memory deficits and anxiety behavior at 7 days after a TBI. The number of degenerating neurons in the CA1 and dentate gyrus (DG) regions of the hippocampus after a TBI was reduced by Pom and DP. DP, but not Pom, significantly attenuated the TBI-induced microgliosis and DP was more efficacious than Pom at attenuating the TBI-induced astrogliosis in CA1 and DG at 7D after a TBI. In summary, a single intravenous injection of Pom or DP, given 5 h post TBI, significantly reduced hippocampal neurodegeneration and prevented cognitive deficits with a concomitant attenuation of the neuroinflammation in the hippocampus.

scholarly journals miR-212-5p attenuates ferroptotic neuronal death after traumatic brain injury by targeting Ptgs2

2019 ◽  
Vol 12 (1) ◽  
Author(s):  
Xiao Xiao ◽  
Youjing Jiang ◽  
Weibo Liang ◽  
Yanyun Wang ◽  
Shuqiang Cao ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Cell Death ◽  
Brain Injury ◽  
Neuronal Death ◽  
Sham Group ◽  
Ferrous Ion ◽  
Post Injury ◽  
Regulated Cell Death ◽  
Prostaglandin Endoperoxide Synthase ◽  
Improved Learning

Abstract Ferroptosis, a newly discovered form of iron-dependent regulated cell death, has been implicated in traumatic brain injury (TBI). MiR-212-5p has previously been reported to be downregulated in extracellular vesicles following TBI. To investigate whether miR-212-5p is involved in the ferroptotic neuronal death in TBI mice, we first examined the accumulation of malondialdehyde (MDA) and ferrous ion, and the expression of ferroptosis-related molecules at 6 h, 12 h, 24 h, 48 h and 72 h following controlled cortical impact (CCI) in mice. There was a significant upregulation in the expression of Gpx4 and Acsl4 at 6 h, Slc7a11 from 12 h to 72 h, and Nox2 and Sat1 from 6 h to 72 h post injury. Similarly, an upregulation in the expression of Gpx4 at 6 h, Nox2 from 6 h to 72 h, xCT from 12 h to 72 h, and Sat1 at 72 h after CCI was observed at the protein level. Interestingly, MDA and ferrous ion were increased whereas miR-212-5p was decreased in the CCI group compared to the sham group. Furthermore, we found that overexpression of miR-212-5p attenuated ferroptosis while downregulation of miR-212-5p promoted ferroptotic cell death partially by targeting prostaglandin-endoperoxide synthase-2 (Ptgs2) in HT-22 and Neuro-2a cell lines. In addition, administration of miR-212-5p in CCI mice significantly improved learning and spatial memory. Collectively, these findings indicate that miR-212-5p may protect against ferroptotic neuronal death in CCI mice partially by targeting Ptgs2.

scholarly journals Increased Vulnerability of NFH-LacZ Transgenic Mouse to Traumatic Brain Injury-Induced Behavioral Deficits and Cortical Damage

1999 ◽  
Vol 19 (7) ◽  
pp. 762-770 ◽  
Author(s):  
Michio Nakamura ◽  
Kathryn E. Saatman ◽  
James E. Galvin ◽  
Uwe Scherbel ◽  
Ramesh Raghupathi ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Motor Dysfunction ◽  
Tissue Loss ◽  
Post Injury ◽  
Behavioral Deficits ◽  
Beam Balance ◽  
Brain Injured ◽  
Neuromotor Function ◽  
Histopathologic Analysis

The authors evaluated the neurobehavioral and neuropathologic sequelae after traumatic brain injury (TBI) in transgenic (TG) mice expressing truncated high molecular weight neurofilament (NF) protein fused to beta-galactosidase (NFH-LacZ), which develop Lewy body-like NF-rich inclusions throughout the CNS. TG mice and their wild-type (WT) littermates were subjected to controlled cortical impact brain injury (TG, n=19; WT, n=17) or served as uninjured controls (TG, n =11; WT, n =11). During a 3-week period, mice were evaluated with an array of neuromotor function tests including neuroscore, beam balance, and both fast and slow acceleration rotarod. Brain-injured WT and TG mice showed significant motor dysfunction until 15 days and 21 days post-injury, respectively ( P < .025). Compared with brain-injured WT mice, brain-injured TG mice had significantly greater motor dysfunction as assessed by neuroscore ( P < .01) up to and including 15 days post-injury. Similarly, brain-injured TG mice performed significantly worse than brain-injured WT mice on slow acceleration rotarod at 2, 8, and 15 days post-injury ( P < .05), and beam balance over 2 weeks post-injury ( P < .01). Histopathologic analysis showed significantly greater tissue loss in the injured hemisphere in TG mice at 4 weeks post-injury ( P < .01). Together these data show that NFH-LacZ TG mice are more behaviorally and histologically vulnerable to TBI than WT mice, suggesting that the presence of NF-rich inclusions may exacerbate neuromotor dysfunction and cell death after TBI.

scholarly journals B-Cell Lymphoma 2 (Bcl-2) and Regulation of Apoptosis after Traumatic Brain Injury: A Clinical Perspective

Medicina ◽  
2020 ◽  
Vol 56 (6) ◽  
pp. 300
Author(s):  
Hansen Deng ◽  
John K. Yue ◽  
Benjamin E. Zusman ◽  
Enyinna L. Nwachuku ◽  
Hussam Abou-Al-Shaar ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Cell Death ◽  
Brain Injury ◽  
B Cell ◽  
Head Trauma ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Terminal Deoxynucleotidyl Transferase ◽  
Post Injury ◽  
Pubmed Database

Background and Objectives: The injury burden after head trauma is exacerbated by secondary sequelae, which leads to further neuronal loss. B-cell lymphoma 2 (Bcl-2) is an anti-apoptotic protein and a key modulator of the programmed cell death (PCD) pathways. The current study evaluates the clinical evidence on Bcl-2 and neurological recovery in patients after traumatic brain injury (TBI). Materials and Methods: All studies in English were queried from the National Library of Medicine PubMed database using the following search terms: (B-cell lymphoma 2/Bcl-2/Bcl2) AND (brain injury/head injury/head trauma/traumatic brain injury) AND (human/patient/subject). There were 10 investigations conducted on Bcl-2 and apoptosis in TBI patients, of which 5 analyzed the pericontutional brain tissue obtained from surgical decompression, 4 studied Bcl-2 expression as a biomarker in the cerebrospinal fluid (CSF), and 1 was a prospective randomized trial. Results: Immunohistochemistry (IHC) in 94 adults with severe TBI showed upregulation of Bcl-2 in the pericontusional tissue. Bcl-2 was detected in 36–75% of TBI patients, while it was generally absent in the non-TBI controls, with Bcl-2 expression increased 2.9- to 17-fold in TBI patients. Terminal deoxynucleotidyl transferase-mediated biotinylated dUTP nick-end labeling (TUNEL) positivity for cell death was detected in 33–73% of TBI patients. CSF analysis in 113 TBI subjects (90 adults, 23 pediatric patients) showed upregulation of Bcl-2 that peaked on post-injury day 3 and subsequently declined after day 5. Increased Bcl-2 in the peritraumatic tissue, rising CSF Bcl-2 levels, and the variant allele of rs17759659 are associated with improved mortality and better outcomes on the Glasgow Outcome Score (GOS). Conclusions: Bcl-2 is upregulated in the pericontusional brain and CSF in the acute period after TBI. Bcl-2 has a neuroprotective role as a pro-survival protein in experimental models, and increased expression in patients can contribute to improvement in clinical outcomes. Its utility as a biomarker and therapeutic target to block neuronal apoptosis after TBI warrants further evaluation.

scholarly journals Impaired visual working memory and reduced connectivity in undergraduates with a history of mild traumatic brain injury

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Hector Arciniega ◽  
Jorja Shires ◽  
Sarah Furlong ◽  
Alexandrea Kilgore-Gomez ◽  
Adelle Cerreta ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Working Memory ◽  
Brain Injury ◽  
Mild Traumatic Brain Injury ◽  
Resting State Fmri ◽  
Underlying Mechanism ◽  
Post Injury ◽  
Behavioral Deficits ◽  
Specific Outcome ◽  
History Of

AbstractMild traumatic brain injury (mTBI), or concussion, accounts for 85% of all TBIs. Yet survivors anticipate full cognitive recovery within several months of injury, if not sooner, dependent upon the specific outcome/measure. Recovery is variable and deficits in executive function, e.g., working memory (WM) can persist years post-mTBI. We tested whether cognitive deficits persist in otherwise healthy undergraduates, as a conservative indicator for mTBI survivors at large. We collected WM performance (change detection, n-back tasks) using various stimuli (shapes, locations, letters; aurally presented numbers and letters), and wide-ranging cognitive assessments (e.g., RBANS). We replicated the observation of a general visual WM deficit, with preserved auditory WM. Surprisingly, visual WM deficits were equivalent in participants with a history of mTBI (mean 4.3 years post-injury) and in undergraduates with recent sports-related mTBI (mean 17 days post-injury). In seeking the underlying mechanism of these behavioral deficits, we collected resting state fMRI (rsfMRI) and EEG (rsEEG). RsfMRI revealed significantly reduced connectivity within WM-relevant networks (default mode, central executive, dorsal attention, salience), whereas rsEEG identified no differences (modularity, global efficiency, local efficiency). In summary, otherwise healthy current undergraduates with a history of mTBI present behavioral deficits with evidence of persistent disconnection long after full recovery is expected.

scholarly journals Author response: 3,6’-dithiopomalidomide reduces neural loss, inflammation, behavioral deficits in brain injury and microglial activation

2020 ◽  
Author(s):  
Chih-Tung Lin ◽  
Daniela Lecca ◽  
Ling-Yu Yang ◽  
Weiming Luo ◽  
Michael T Scerba ◽  
...  
Keyword(s):  
Brain Injury ◽  
Microglial Activation ◽  
Author Response ◽  
Behavioral Deficits

scholarly journals SUN-216 Investigating the Role of the Liver X Receptor in Potentiating Mitotane Therapy in Adrenocortical Carcinoma

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Kate Warde ◽  
Erik Shoenmakers ◽  
Maeve Leonard ◽  
Rebecca Maunsells ◽  
Constanze Hantel ◽  
...  
Keyword(s):  
Cell Death ◽  
Cell Lines ◽  
Lipid Droplet ◽  
Adrenocortical Carcinoma ◽  
Free Cholesterol ◽  
Hormone Sensitive Lipase ◽  
Therapeutic Window ◽  
Cholesterol Esters ◽  
Associated Proteins ◽  
H295r Cells

Abstract Introduction: Adrenocortical Carcinoma is a rare aggressive cancer which carries a poor prognosis. Adjuvant mitotane improves survival but is limited by a narrow therapeutic window and severe adverse effects. Liver X receptors (LXRs), part of the nuclear receptor superfamily are highly expressed in adrenal tissue and mediate transcellular and intracellular cholesterol homeostasis. We hypothesise that LXRα inhibition increases toxic lipid accumulation in adrenocortical cancer cells and potentiates the adrenolytic effect of mitotane. Methodology: ATCC-H295R and MUC1 ACC cells and were pre-treated with the LXRα inverse agonist SR9243 5µM and antagonist GSK2033 5µM followed by mitotane treatment (20, 40, 50μΜ) for 6 hours. Cholesterol-methyl-β-cyclodextrin treatment was carried out 1hr prior to mitotane. H295R cells were transfected with a LXR⍺ dominant negative construct using lipofectamine. Cell death was assessed using annexin/PI staining and proliferation using MTT assay. Free cholesterol (FC) levels were assayed using filipin staining and lipid droplets via BODIPY® and analysed on the Amnis ImageStream® imaging cytometer. Downstream targets ABCA1 and ABCG1 were evaluated by qRT-PCR. Lipid droplet associated proteins PLIN 1-4 and hormone sensitive lipase (HSL) expression were evaluated using western blotting. Results: Downstream reduction of ABCA1 and ABCG1 expression confirmed LXRα blockade. Mitotane effectively induced dose-dependent H295R apoptotic cell death which was potentiated pharmacologically and genetically by LXR⍺ inhibition. In line with these findings, cholesterol-methyl-β-cyclodextrin treatment increased cell death in H295R and MUC1 cells. In addition to inducing cell death, LXR⍺ inhibition decreased proliferation of both cell lines. An increase in FC and a decrease in cholesterol esters was observed following mitotane treatment in H295R cells. This was accompanied by decreased lipid droplet numbers confirmed by lower expression of lipid droplet associated proteins, PLIN1-3. These effects were potentiated when mitotane was combined with LXRα inhibition. We demonstrate increased HSL activity, which was associated with higher SOAT-1 expression and increasing toxic FC accumulation. Investigation of lipid droplet content BODIPY® of both cell lines showed H295R cells preferentially store cholesterol esters and MUC1 cells store triacylglycerides.Conclusion: We propose a mechanism for enhancing mitotane’s efficacy as an adrenolytic through increased free cholesterol via LXR⍺inhibition. Targeting the LXRα, its putative ligands, or associated lipid mediators may present a novel therapeutic approach in the setting of primary and metastatic ACC.

scholarly journals Repetitive Traumatic Brain Injury Causes Neuroinflammation before Tau Pathology in Adolescent P301S Mice

2021 ◽  
Vol 22 (2) ◽  
pp. 907
Author(s):  
Saef Izzy ◽  
Alexander Brown-Whalen ◽  
Taha Yahya ◽  
Aliyah Sarro-Schwartz ◽  
Gina Jin ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Behavioral Outcomes ◽  
Closed Head Injury ◽  
Tau Pathology ◽  
Post Injury ◽  
Behavioral Deficits ◽  
Tau Mutation ◽  
Injury Causes

Repetitive closed head injury (rCHI) is commonly encountered in young athletes engaged in contact and collision sports. Traumatic brain injury (TBI) including rCHI has been reported to be an important risk factor for several tauopathies in studies of adult humans and animals. However, the link between rCHI and the progression of tau pathology in adolescents remains to be elucidated. We evaluated whether rCHI can trigger the initial acceleration of pathological tau in adolescent mice and impact the long-term outcomes post-injury. To this end, we subjected adolescent transgenic mice expressing the P301S tau mutation to mild rCHI and assessed tau hyperphosphorylation, tangle formation, markers of neuroinflammation, and behavioral deficits at 40 days post rCHI. We report that rCHI did not accelerate tau pathology and did not worsen behavioral outcomes compared to control mice. However, rCHI induced cortical and hippocampal microgliosis and corpus callosum astrocytosis in P301S mice by 40 days post-injury. In contrast, we did not find significant microgliosis or astrocytosis after rCHI in age-matched WT mice or sham-injured P301S mice. Our data suggest that neuroinflammation precedes the development of Tau pathology in this rCHI model of adolescent repetitive mild TBI.

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