Abstracts from The 39 th Annual Symposium of the National Neurotrauma Society, including the AANS/CNS Joint Section on Neurotrauma and Critical Care
2022; Mary Ann Liebert, Inc.; Volume: 39; Issue: 11-12 Linguagem: Inglês
10.1089/neu.2022.29126.abstracts
ISSN1557-9042
Tópico(s)Traumatic Brain Injury Research
ResumoJournal of NeurotraumaVol. 39, No. 11-12 AbstractsFree AccessAbstracts from The 39th Annual Symposium of the National Neurotrauma Society, including the AANS/CNS Joint Section on Neurotrauma and Critical CareJune 26–29, 2022 Atlanta, Georgia, USAPublished Online:3 Jun 2022https://doi.org/10.1089/neu.2022.29126.abstractsAboutSectionsPDF/EPUB Permissions & CitationsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail Data Blitz Oral PresentationsDBA‐01 SLEEP FRAGMENTATION FOLLOWING TRAUMATIC BRAIN INJURY EXACERBATES SUB‐ACUTE BEHAVIORAL DEFICITS AND TRANSCRIPTIONAL CHANGES AT CHRONIC TIME POINTSMr. Sam Houle1,2, Mrs. Zoe Tapp‐Poole1,2, Mr. Christopher Cotter1,2, Mr. Zachary Zimomra2, Ms. Sienna Robertson1, Ms. Yvanna Reyes1, Ms. Shannon Dobres1, Mr. Sakeef Ahsan1, Ms. Jessica Mitsch1, Dr. Rachel Rowe4, Dr. Jonathan Lifshitz3, Dr. John Sheridan1,2, Dr. Jonathan Godbout1,2, Dr. Olga Kokiko‐Cochran1,21Department of Neuroscience, The Ohio State University, Columbus OH, United States, 2Institute for Behavioral Medicine Research, The Ohio State University, Columbus OH, United States, 3College of Medicine, University of Arizona, Phoenix AZ, United States, 4Department of Integrative Physiology, University of Colorado, Boulder, Boulder CO, United StatesStressful experiences elicit an immune response that is initially adaptive. However, persistent stress shifts the immune response to be detrimental. Stress‐immune interactions may worsen long‐term outcome in traumatic brain injury (TBI) survivors, who often experience impaired stress response. Here, we leverage sleep fragmentation (SF) as a common physiological consequence of stress to study post‐TBI neuroinflammation. We hypothesize that post‐injury SF exacerbates TBI‐induced sleep‐wake disturbances, neuroinflammation, and cognitive impairments. Adult male and female mice received either a moderate lateral fluid percussion TBI or a sham injury. Mice were exposed to SF 5am‐10am beginning one hour prior to light cycle or remained in control housing for 14 days post‐injury (DPI). At 14DPI all mice were allowed to recover until 30DPI. Sleep‐wake activity was acquired for all mice using custom piezo‐electric sensors for 30DPI.TBI increased sleep for 4 hours following injury. Unexpectedly, all mice exposed to SF slept more than control mice through 7DPI. However, post‐TBI SF exacerbated spatial learning and memory deficits in the Morris water maze 14DPI. By the last week of recovery SF mice slept comparably to control animals. Nonetheless, post‐TBI SF increased transcription of cortical inflammation (Spi1, Abca1, Itga7), neurodegeneration (Abca1, Atg2b), and immunometabolic (Abca1, Lpl) genes compared to other groups. Canonical pathway analysis revealed that post‐TBI SF upregulated the complement cascade, and nitric oxide and reactive oxygen species production in macrophages. Together, these results indicate that post‐injury stress impairs the ability of the brain to adequately respond to and recover from injury.Keywords: Sleep, Microglia, Cognition/Learning/Memory, Inflammation/Immune FunctionDBA‐02 SMOOTH MUSCLE EXCITATION AND REMODELING OF COLONIC INTERSTITIAL CELLS OF CAJAL AFTER SPINAL CORD INJURYMs. Claire Werner1, Lisa Willing1, Dr. Gregory Holmes11Penn State University College of Medicine, Hershey PA, United StatesSpinal cord injury (SCI) frequently provokes reduced colonic transit; termed neurogenic bowel. Intrinsic to the colon, the enteric nervous system (ENS) drives smooth muscle slow‐wave activity largely through Interstitial Cells of Cajal (ICC). These electrically coupled pacemaker cells generate electrical activity by phasic Ca2+ release and are further influenced by excitatory (ACh) and inhibitory (NO, ATP) neural inputs from the ENS. Neurogenic bowel treatment often involves pro‐motility drugs targeting the ENS and ICC's, which are often clinically ineffective.This study aims to expand current understanding of neurogenic bowel neurobiology in acute and chronic SCI rats by accessing colonic ICC's plasticity and neuromuscular responsiveness to promotility drugs. Experimentally, male and female rats received surgical control or T3 SCI (n = 41). Following euthanasia, distal colon smooth muscle was harvested for immunohistochemical and electrophysiological analysis. The ICC's were fluorescently labeled with c‐Kit antibody. Upon quantification, we identified a significant increase in pacemaker myenteric plexus ICC's (p = 0.05) and their projection length (p = 0.009) following chronic SCI. Additionally, a significant interaction effect was observed between animal timepoint and surgical group for cell count (p = 0.001). Smooth muscle electrophysiology revealed that during application of cholinergic agonist (Bethanechol), cells depolarized in a dose dependent manner in control and SCI rats (p < 0.0001). Inversely, neuronally‐mediated colonic junction potentials did not respond upon electrical field stimulation in a dose dependent manner after SCI. The current data illustrates a potential compensatory ICC response due to loss of functional inputs, alluding to why pro‐motility ENS and ICC pharmacodynamics have poor patient satisfaction.Support: NINDS‐105987Keywords: Imaging, ElectrophysiologyDBA‐03 EPISODIC MEMORY IMPAIRMENT FOLLOWING MILD TRAUMATIC BRAIN INJURYMr. Gabriel Nah1, Ms. Mira Antonopoulos1, Dr. Andrea Hohmann1, Dr. Nicholas Port1, Dr. Jonathon Crystal11Indiana University, Bloomington IN, United StatesMild traumatic brain injury (mTBI) is the most common type of traumatic brain injury, and it leads to temporary memory impairment as well as an excitotoxic response in the brain, particularly the hippocampus. While many animal models of mTBI exist, it is difficult to fully replicate the injury seen in humans, and the effects of mTBI on the microenvironments of the brain are unclear. Additionally, no treatments specifically for mTBI currently exist. Notably, the Wayne State modified weight drop rat model of mTBI accurately recapitulates the elements of a sport‐related injury, as well as the excitotoxic response in the hippocampus. Yet, this model has not previously been evaluated using a complex memory task. In this study, rats were trained in an odor‐based item‐in‐context task which dissociates episodic and non‐episodic memory (Panoz‐Brown et al., Current Biology, 2016). The animals then underwent either a weight drop or sham treatment using the Wayne State model. After the manipulation, animals continued the item‐in‐context task. Episodic memory suffered a 11% drop in performance (p < 0.01) in the injured rats, but not in the sham rats. Non‐episodic memory was not impaired in either group. Additionally, immunohistochemical analysis of the hippocampus documented morphological changes in astrocytes and microglia in injured rats compared to sham rats. These findings are the first to document episodic memory impairment in an animal model of mTBI.Keywords: Astrocyte, Microglia, Cognition/Learning/Memory, Imaging, Concussion/mTBI, Inflammation/Immune FunctionDBA‐04 ASSESSMENT OF MAGNETIC RESONANCE IMAGING CHANGES IN RESPONSE TO DAILY GUT MICROBIAL THERAPY IN A PIGLET TBI MODELMrs. Madison Fagan1,2,3, Ms. Christina B. Welch1,3, Dr. Kelly M. Scheulin1,2,3, Ms. Sydney E. Sneed1,3, Ms. Julie H. Jeon4, Mrs. Morgane Golan1,2,3, Dr. T. Dean Pringle1, Dr. Todd R. Callaway1, Dr. Hea J. Park4, Dr. Jeferson M. Lourenco1, Dr. Kylee J. Duberstein1,2,3, Dr. Franklin D. West1,2,31Department of Animal and Dairy Science, University Of Georgia, Athens GA, United States, 2Neuroscience Program, Biomedical and Health Sciences Institute, University of Georgia, Athens GA, United States , 3Regenerative Bioscience Center, University of Georgia, Athens GA, United States , 4Department of Foods and Nutrition, College of Family and Consumer Sciences, University of Georgia, Athens GA, United StatesPediatric traumatic brain injury (TBI) is a leading cause of death and disability in children. Due to the bidirectional communication between the brain and gut microbial population, the introduction of key gut bacteria may mitigate critical TBI‐induced secondary injury cascades, thus lessening neural damage. The objective of this study was to determine the ability of gut microbial transplantation (GMT) to reduce injury severity in a piglet TBI model. A moderate/severe TBI was induced by controlled cortical impact in 4‐week‐old male crossbred piglets (treated: GMT, n = 6; control: CON, n = 6). Sham animals (S, n = 6) underwent craniectomy only. TBI animals were administered a 25 mL oral gavage of GMT or saline, 2‐hours post‐injury and every 24 hours for 7 days. An MRI was collected 1‐day (1D) and 7‐days (7D) post‐injury. Sequences included T2 FSE for lesion volume and midline shift (MLS) analysis, and SWAN for intracranial hemorrhage (ICH) volume measurement. No differences were noted between lesion volume, ICH volume, or MLS between GMT and CON pigs at 1D. GMT animals exhibited smaller lesion volumes (P = 0.005) and reduced ICH volumes (P = 0.031) at 7D relative to 1D. At 7D, MLS did not significantly differ between GMT and S animals. No significant differences were observed in lesion and ICH volume between 1D and 7D in CON animals. CON animals showed the most pronounced level of MLS at 7D, which differed from CON 1D (P = 0.004). These results indicate that daily GMT significantly decreased neural injury severity after a moderate/severe pediatric TBI.Keywords: Pediatric, Secondary Injury, Imaging, Therapeutics/Drug DiscoveryDBA‐05 ENDOCANNABINOIDS 2‐ARACHIDONOYLGLYCEROL AS AN IMMUNE MODULATOR OF NEUROVASCULAR RECOVERY AFTER TRAUMATIC BRAIN INJURYDr. Meenakshi Ahluwalia1, Dr. Manish Kumar1, Dr. Molly Braun1,2, Ms. Hannah McMichael1, Mr. Nicholas Moore1, Dr. Evila L. Salles3, Dr. David C. Hess4, Dr. John R. Vender1, Dr. Fernando L. Vale1, Dr. Babak Baban3, Dr. Krishnan M. Dhandapani1, Dr. Kumar Vaibhav1,31Department of Neurosurgery, Medical College of Georgia, Augusta University, Augusta GA, United States, 2Department of Psychiatry and Behavioral Sciences at University of Washington, School of Medicine, Seattle WA, United States, 3Department of Oral Biology and Diagnostic Science, Dental College of Georgia, Augusta University, Augusta GA, United States, 4Department of Neurology, Medical College of Georgia, Augusta University, Augusta GA, United StatesInflammation is an important mediator of secondary pathological events after traumatic brain injury (TBI). Endocannabinoids, endogenously produced arachidonate based lipids, are endogenous anti‐inflammatory compounds and bind to two cannabinoid receptors‐CB1R and CB2R, yet the molecular and cellular mechanisms underlying these effects are poorly defined. In the present study, we hypothesize that TBI‐induced loss of endocannabinoids exaggerate neurovascular injury and cause behavioral dysfunction. We determined the human CSF and plasma levels of endocannabinoids post‐TBI and correlated with a murine controlled cortical impact (CCI) model of TBI. Briefly, adult mixed sex C57Bl/6j or CD1 mice were anesthetized, placed in a stereotaxic frame, and a craniotomy was made in the right parietal bone, leaving the dura intact. Mice were impacted at 3 m/s with a 85 ms dwell time and 3 mm depression using a 3 mm diameter convex tip to mimic a moderate TBI. Sham‐operated control mice underwent the identical surgical procedures, but were not impacted. We observed acute loss of cerebral blood flow (CBF) with upregulated glial fibrillary acidic protein (GFAP), ionized calcium binding adaptor molecule 1 (IBA1) and aquaporin 4 (AQP4) up to 3 weeks with severe inflammation after TBI. Attenuated CBF resulted in loss of motor functions and induced anxiety behavior in TBI mice. However, inhibition of endocannabinoid 2‐arachidonyl glycerol (2‐AG) metabolism or supplementation of exogenous 2‐AG protected the blood flow, minimized inflammation, and reduced edema after injury. Taken together, our findings suggest an important modulatory role of 2‐AG and its metabolism in neurovascular injury and long‐term functional deficits.Keywords: Secondary Injury, Vascular, Inflammation/Immune Function, NeuropathologyDBA‐06 AMPLIFIED GLIOSIS AND INTERFERON‐ASSOCIATED INFLAMMATION IN AGED MICE FOLLOWING TRAUMATIC BRAIN INJURYMs. Lynde Wangler1, Mrs. Chelsea Bray, Jonathan Packer, Zoe Tapp, Amara Davis, Shane O'Neil, Dr. Jonathan Godbout1The Ohio State University, Columbus OH, United StatesTraumatic brain injury (TBI) is associated with an increased risk of cognitive and neurodegenerative complications that may develop and persist years after injury. Aged individuals are particularly susceptible to fall‐related TBIs and account for the most TBI‐related hospitalizations and deaths. We have shown that diffuse brain injury causes prolonged neuroinflammation associated with a pronounced increase in type 1 IFN signaling. Here, we compared the neuroinflammatory response to diffuse TBI between adult and aged mice. Adult (2 mo) and aged (16‐18 mo) C57BL/6 mice were subjected to a diffuse brain injury, induced by midline fluid percussion, after which several biochemical and behavioral parameters were assessed 7 days post injury (dpi). As expected, acute cognitive impairment was evident 7 dpi in both adult and aged TBI mice. There was enhanced reactive gliosis 7 dpi (IBA1, microglia and GFAP, astrocytes) in the cortex and hippocampus of aged mice. Neuropathology RNA analysis showed amplified cytokine/chemokine, complement, inflammatory, and interferon‐associated gene expression in the cortex of aged mice after TBI compared to adults. Ingenuity Pathway Analysis confirmed interferon (IFN) signaling was robustly enhanced in Aged‐TBI. Accordingly, we used a STING (stimulator of interferons) agonist, to determine if enhanced IFN signaling would worsen neuroinflammation after TBI in adult mice. There was a significant interaction between DMXAA and TBI. Adult TBI mice treated with the STING agonist had amplified expression of myriad genes that were also amplified in aged TBI mice. Overall, persistent IFN‐associated inflammation induced by TBI was especially prominent in aged mice.Keywords: Secondary Injury, Microglia, Aging, Inflammation/Immune FunctionDBA‐07 TRANSFORMING RESEARCH AND CLINICAL KNOWLEDGE IN GERIATRIC TBI (TRACK‐GERI): INITIAL ENROLLMENT AND OUTCOMESMr. Domenico Lombardi1, Ms. Katherine Kuang1, Dr. Michele Nelson1, Dr. Ava Puccio2, Dr. David Okonkwo2, Amber Nolan3, Dr. Esther Yuh1, Dr. Kristine Yaffe1, Ms. Sabah Hamidi1, Ms. Leila Etemad1, Dr. John Boscardin1, Mr. Chadwick Ho1, Dr. Sabrina Taylor4, Dr. Geoffrey Manley1, Dr. Raquel C. Gardner11University Of California San Francisco, San Francisco CA, United States, 2University of Pittsburgh Medical Center, Pittsburgh PA, United States, 3University of Washington, Seattle WA, United States, 4MedRhythms, Portland OR, United StatesBackground: Although older adults have the highest rate of traumatic brain injury (TBI) globally, few evidence‐based geriatric TBI guidelines exist to inform care decisions and older adults are under‐represented in TBI research. We are conducting a two‐site prospective geriatric TBI cohort study to develop age‐appropriate diagnostic and prognostic tools to guide research and clinical care that will be broadly generalizable to the geriatric TBI population.Methods: Aim: enroll a representative cohort of 270 adults age 65y+ presenting to participating Level 1 trauma centers within 72h of TBI and 90 controls. Participants are co‐enrolled with a study partner (to assess pre‐injury health and TBI recovery) and complete baseline, 2‐week, 3‐month, 6‐month, and 12‐month multi‐domain geriatric and TBI Common Data Element assessments. Blood is collected at baseline, 6‐months, and 12‐months. Patient, injury, and TBI recovery characteristics are reported.Results: 55 TBI‐participant/partner dyads were enrolled from 11/2020 – 02/2022. Mean age is 76y (range 65‐91y), 53% are female, 20% are non‐white, 45% have normal cognition, 39% have MCI, 16% have dementia. 94% arrived at ED with GCS 13‐15, 85% had a positive head CT. 6 participants died within 3 months of enrollment. GOSE completion at 2‐week, 3‐month, 6‐month and 12‐month was 79%, 78%, 71% and 91%, respectively. Complete TBI recovery (GOSE = 8) at each follow‐up visit was 10%, 16%, 20% and 30%, respectively.Discussion: Initial findings from this two‐site study of geriatric TBI has identified high rates of pre‐existing cognitive impairment. Future directions include determining how pre‐existing neurodegenerative disease impacts recovery and TBI biomarkers.Keywords: Cognition/Learning/Memory, Aging, Neurodegeneration, Concussion/mTBIDBA‐08 CNR2 IS UPREGULATED ON THE CEREBROVASCULATURE FOLLOWING EXPERIMENTAL TRAUMATIC BRAIN INJURY INDICATING THE POTENTIAL FOR CANNABINOID RECEPTOR 2 AS A DRUGGABLE INTERVENTION STRATEGYMr. Trent Bullock1,2, Ms. Jana Kahn1, Mr. Brian Leonard1, Dr. Paula Morales4, Dr. Nadine Jagerovic4, Allison Andrews1,2, Dr. Servio Ramirez1,2,31Department of Pathology and Laboratory Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia PA, United States, 2Center for Substance Abuse Research, Lewis Katz School of Medicine at Temple University, Philadelphia PA, United States, 3Shriners Hospitals Pediatric Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia PA, United States, 4Instituto de Quíca Médica, Consejo Superior de Investigaciones Científicas, Madrid, SpainTraumatic brain injury is a substantial public health issue for which there are no currently approved pharmacological interventions. Previous research shows Cannabinoid Receptor 2 (CB2) agonists promote resolution of inflammation in multiple neuroinflammatory disease states. Here, we hypothesized CB2 is a potential pharmacological target at the level of the cerebral vasculature following experimental TBI. First, C57BL/6 mice (n = 3/group) were given a moderate TBI (CCI, 4.5m/s, 2mm impact depth) and CNR2, the gene encoding for CB2, expression was analyzed via qRT‐PCR at 4, 8, 24, and 48 hours post injury. Results indicated a 20‐fold upregulation of CNR2 (p < 0.0001) in mouse microvessels isolated from the area of impact 24 hours after injury. To subsequently evaluate the translational aspects of targeting CB2 on the cerebral endothelium, we treated human brain microvascular endothelial cells with TNFα and a novel CB2 agonist, PM289 (n = 3/experiment). PM289 is a novel chromenopyrazole derivative featuring enhanced solubility and specificity for CB2. Utilizing an in vitro blood brain barrier model (BBB), we analyzed the effects of PM289 on the integrity of the BBB using Electrical Cell‐Substrate Impedance Sensing and Western Blot. These experiments demonstrated that PM289 significantly reduced TNFα induced disruptions to the physical barrier (p < 0.05). Moreover, PM289 attenuated TNFα‐induced endothelial activation (p < 0.05). Taken together, these results show that CB2 is a viable treatment target at the level of the cerebral vasculature following experimental neurotrauma. Ongoing studies are aimed at interrogating the intracellular signaling events responsible for these cerebrovascular protective effects.Keywords: Secondary Injury, Blood Brain Barrier, Vascular, Inflammation/Immune FunctionDBA‐09 WHETHER NOREPINEPHRINE TREATMENT AFTER SPINAL CORD INJURY INDUCES HEMORRHAGE DEPENDS UPON TIME OF ADMINISTRATION AND SEXMr. Travis Johnston1,2, Miss Grace Giddings1, Mrs. Hannah Borland1, Dr. Christopher West3, Dr James Grau1,21Department of Psychological & Brain Sciences, Texas A&M University, College Station TX, United States, 2Texas A&M Institute for Neuroscience, College Station, Unites States, 3Department of Cellular and Physiological Sciences, Faculty of Medicine, University of British Columbia, Vancouver, CanadaOur prior work focused on how pain after spinal cord injury (SCI) undermines locomotor recovery, and provides evidence pain increases the area of hemorrhage. We hypothesized that pain may be having this effect because it drives an acute rise in systolic blood pressure. The current study explores this issue by pharmacologically inducing hypertension with norepinephrine (NE). In all experiments, Sprague‐Dawley rats received a contusion injury at the T10‐T11 spinal level. Baseline BBB and/or tail blood pressure (BP) were assessed prior to treatment. In experiment 1, male rats received NE or vehicle 30 min or 24 hrs post‐SCI to assess the window of time in which the spinal cord is most vulnerable to hypertension. In experiment 2, male rats received NE or vehicle at the beginning of treatment and then again 1.5 hr later to examine the effects of maintained hypertension. In experiment 3, male and female rats received NE or vehicle 24‐hrs post‐SCI to assess for sex‐differences. BP and/or BBB scores were assessed 0, 1, 2, and 3 hours after treatment. Tissue was then collected and assessed for hemorrhage using spectrophotometry in experiments 1 & 2, and histology in experiment 3. NE produced an increase in BP and hemorrhage and the magnitude of these effects varied with time post‐SCI. NE also, undermines locomotor recovery when given 24 hrs post‐SCI in both males and females. Additional studies are being conducted to assess the mechanism by which NE is acting.Keywords: Behavioral Function, Secondary Injury, Neurotoxicity, HemorrhageDBA‐10 AGE‐ AND AGING‐WITH‐INJURY‐RELATED TEMPORAL MICROGLIAL MORPHOLOGICAL PROFILES INDICATE UNIQUE PATHOLOGICAL PROCESSES IN BEHAVIORALLY RELEVANT CIRCUIT RELAYSMr. Chaitanya Sanghadia1,4, Mr. Zackary Sabetta1,5, Mr. Bhavik Rajaboina1,5, Gokul Krishna1,2, Dr. David Adelson1,2,3, Dr. Theresa Currier Thomas1,2,31College of Medicine‐Phoenix, University of Arizona, Department of Child Health, Phoenix AZ, USA, 2BARROW Neurological Institute at Phoenix Children's Hospital, Phoenix AZ, USA, 3Phoenix VA Healthcare System, Phoenix AZ, USA, 4University of Arizona, Tucson AZ, USA, 5Arizona State University, Tempe AZ, USATraumatic brain injury(TBI)‐induced chronic neuroinflammation is implicated in the development of persisting neurological morbidities and age‐related neurodegenerative diseases. A chronic time course of neuroinflammation in a behaviorally relevant circuit in both sexes is needed to accurately and comprehensively assess the benefits and consequences of neuroinflammation. We used a temporal profile for structural, molecular, and functional mechanisms contributing to late‐onset persisting sensory hypersensitivity in the rat whisker‐barrel‐circuit (WBC) relays to assess neuroinflammation. Age‐matched male and female Sprague‐Dawley rats underwent midline fluid percussion injury (FPI) or sham surgery (n = 5‐6/group;total = 64). At 7‐, 56‐, and 168‐days post‐injury (DPI), Iba‐1 stained morphologies and morphological characteristics were quantified in cortical and thalamic WBC relays followed by three‐way ANOVAs (FPI, DPI, Sex). In the cortex and thalamus, microglia had shorter branches and fewer endpoints, indicative of microglial activation, as a function of FPI (p < 0.05), DPI (p < 0.05), and FPI ͯ DPI (p < 0.05), where FPI‐induced activation decreased and age‐related activation (shams) increased over time. By 168DPI, sham and FPI morphological characteristics were similar; However, hyper‐ramified microglia increased in sham versus FPI (p < 0.05). Cortical rod microglia were highest at 7DPI (p < 0.05) and present through 168DPI (FPI ͯ DPI interaction; p < 0.05). FPI ͯ DPI ͯ Sex interaction for thalamic cell counts (p < 0.05) indicated a greater FPI response in 7DPI males versus females (p < 0.05). Chronic TBI‐induced neuroinflammation has a distinct regional and sex‐dependent temporal profile compared to age‐related neuroinflammation, providing a template for more comprehensive interpretation of the impact of intervention on specific pathological processes associated with aging‐ and aging‐with‐injury‐related morbidities.Funding: NIH‐R01NS100793_Phoenix_Children's_Hospital_Mission_Support_SVPR_CoSKeywords: Microglia, Aging, Neurodegeneration, NeuropathologyDBA‐11 NTS‐105 DECREASES CELL DEATH AFTER IN VITRO STRETCH INJURYMs. Mary Kate Dwyer1, Miss Carolyn Kim1, Mr. Nevin Varghese1, Dr. Barclay Morrison, III11Department of Biomedical Engineering, Columbia University, United StatesAdministration of pleiotropic neurosteroids have demonstrated neuroprotective potential in experimental models of traumatic brain injury (TBI). NTS‐105 is a novel neurosteroid with demonstrated activity at multiple intracellular nuclear hormone receptor systems known to protect brain tissue after acute injury. To evaluate the potential for NTS‐105 to reduce cell death in an organotypic hippocampal slice culture (OHSC) stretch injury model of moderate‐severe TBI, P8‐10 Sprague Dawley hippocampi were sliced into 400 μm sections and cultured on PDMS wells. Propidium iodide (PI) staining was performed to confirm less than 5% cell death in OHSCs at least 10 days after culture. Healthy slices were stretched to an average equibiaxial strain of 26% at 9.8 1/s. One hour after injury, cultures were treated with NTS‐105, progesterone (1 nM as positive control) or vehicle. At 96 hours after injury cell death was quantified. Over a broad concentration range, NTS‐105 significantly reduced neuronal cell death compared to vehicle. The decrease in cell death over that range was similar to 1 nM progesterone (1.18 ± 0.44%; N = 13; p < 0.05 vs vehicle). The dose‐response of NTS‐105 indicated that prevention of cell death was lost at high exposure levels (i.e. neuroprotection observed with NTS‐105 concentrations as low as 0.1 nM (2.53 ± 0.77%; N = 20) but not at a high concentration of 300 nM (6.95 ± 3.13%; N = 16)). Thus, NTS‐105 produces significant stretch‐injured hippocampal neuroprotection over a broad concentration range and may be therapeutically beneficial for the treatment of TBI.This study was supported by NeuroTrauma Sciences.Keywords: Neuroprotection, Cell Death, Therapeutics/Drug Discovery, BiomechanicsDBA‐12 FIBRILLIN‐1 MUTATION ACCELERATES CEREBROVASCULAR AGING AND INCREASES NEUROVASCULAR VULNERABILITY TO MILD TRAUMATIC BRAIN INJURYTala Curry1,2,3, Ms Mary‐Eunice Barrameda2, Mrs Caitlin Bromberg1,3, Dr. Maha Saber1,3, Dr. Rachel Rowe1,4, Dr. Rayna Gonzales1, Dr. Mitra Esfandiarei1,2, Dr. Theresa Currier Thomas1,31University of Arizona College of Medicine‐Phoenix, Phoenix AZ, United States, 2Midwestern University, Glendale AZ, United States, 3Barrow Neurological Institute at Phoenix Children's Hospital, Phoenix AZ, United States, 4University of Colorado Boulder, Boulder CO, United StatesAge presents a significant risk for prolonged morbidity and mortality after traumatic brain injury (TBI), yet mechanisms associated with age‐related cerebrovascular vulnerability following TBI remain unclear. Age‐induced transforming growth factor‐β (TGF‐β) upregulation is implicated in cerebrovascular dysfunction, loss of blood‐brain barrier (BBB) integrity, and increased risk of neuroinflammation and cognitive impairment. Fibrillin‐1 (Fbn1) mutation increases TGF‐β availability and signaling in Fbn1+/‐ mice, inducing peripheral vascular dysfunction by 6‐months of age. This study investigated Fbn1 deficiency on cerebrovascular integrity and increased vulnerability to TBI using a transgenic mouse model with constitutively increased TGF‐β conditions. We hypothesize that during conditions of increased TGF‐β availability, cerebrovascular aging accelerates, leaving the brain vulnerable to mild‐TBI (mTBI). In male and female 6‐ and 12‐month‐old Fbn1+/‐ and C57BL/6 wildtype (WT) mice (n = 3‐11/group), posterior cerebral artery (PCA) blood flow, PCA rupture point, BBB permeability, injury viability, neurological severity scale (NSS) outcomes, and microglial perturbation were assessed. We observed that 6‐month‐old Fbn1+/‐ mice exhibited significantly decreased PCA blood flow and wall strength (p < 0.05), exacerbated BBB permeability (p < 0.05), microglial activation (p < 0.05), and NSS scores (p < 0.05) compared to age‐matched WT mice that were comparable to 12‐month‐old WT mice. Fbn1+/‐ mice required a 15% lower pressure to induce mTBI righting reflex times (5‐10 minutes) compared to WT (p < 0.05), and sex differences were observed. At 24h post‐TBI, Fbn1+/‐ mice demonstrated increased BBB permeability and microglial activation. These findings indicate that Fbn1 mutation alters cerebrovascular vulnerability following mTBI, where age‐related modulation could be neuroprotective, and sex could be a determinant. Funding‐Valley_Research_Partnership‐P1A‐5012, NIH‐R15HL145646, NIH‐R01NS100793Keywords: Aging, Blood Brain Barrier, Vascular, Cerebral Blood FlowDBA‐13 SEDATION TOXICITY IN PEDIATRIC TRAUMATIC BRAIN INJURYMs. Manisha Ramprasad1, Dr. Lauren Jantzie2, Dr. Manda Saraswati1, Paige Mathena1, Dr. Shenandoah Robinson3, Dr. C. David Mintz1, Dr. Courtney Robertson11Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore MD, United States, 2Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore MD, United States, 3Department of Neurology and Neurosurgery, Johns Hopkins University School of Medicine, Baltimore MD, United StatesFollowing severe pediatric TBI, patients commonly receive IV sedatives. Studies have shown negative effects of sedative exposure on the normal, developing brain. We hypothesized that early exposure to sustained sedation would worsen outcomes after TBI in immature rats. Male Sprague‐Dawley rats (PND 17) were divided into four groups: naive, naive‐sedation, TBI and TBI‐sedation. TBI groups underwent controlled cortical impact (CCI). Starting on post‐injury day (PID) 1, sedation groups received midazolam 12 h/day for 3 days. Histologic endpoints (PID 4) included Iba‐1, GFAP, TUNEL, Caspase‐8, and tissue loss. Separate groups of rats w
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