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Stress and poor working conditions can affect the health and satisfaction of health professionals. Until now, the perspective of the staff has not been sufficiently considered in the development of solutions. The aim was to capture the wishes and recommendations of health professionals that could contribute to an improvement of the work situation from their perspective.

The workforce shortage in health care is a major challenge worldwide. In Switzerland, this shortage is not only demographically caused but also due to workload. Adequate measures require a good data basis. The aim of this study is to test instrument specially developed for the health professions to measure work-related stress in practice. Cognitive pretesting was used for the evaluation. Overall, 18 semi-structured single-interviews with nurses and nursing assistants were conducted. In two rounds, the question-answer-process was analysed for 11 questions. The STRAIN questionnaire was then pretested by 17 health professionals. In the first round, 42 problems were identified based on the phases of the “Cognitive Aspects of Survey Methodology”. Of these, 57 % were comprehension problems. This was shown by the polysemantic usage or unknowingness of terms. Further 38 % were problems with the answer categories, such as a missing category or an inappropriate formulation. Further questions were modified through a final pretest. The uniform comprehensibility has been achieved. Due to the questionnaire length, an online tool with a save function should be used. The results of this study are similar to those of comparable studies, which also show the most common problems with understanding. This is due to changes of concepts’ meanings over time and culture. A cognitive pretest is therefore recommended, especially for a heterogeneous target group such as health professions.

Traumatic brain injury (TBI) is characterized by complex secondary injury processes involving the p75 neurotrophin receptor (p75NTR), which has been proposed as a possible therapeutic target. However, the pathogenic role of the p75NTR co-receptor sortilin in TBI has not been investigated. In this study, we examined whether sortilin contributes to acute and early processes of secondary injury using a murine controlled cortical impact (CCI) model of TBI. Initial expression analysis showed a down-regulation of sortilin mRNA levels 1 and 5 day post injury (dpi) and a reduced expression of sortilin protein 1 dpi. Next, a total of 40 Sortilin ΔExon14 loss-of-function mouse mutants (Sort1 -/- ) and wild-type (Sort1 +/+ ) littermate mice were subjected to CCI and examined at 1 and 5 dpi. Neither sensorimotor deficits or brain lesion size nor CCI-induced cell death or calcium-dependent excitotoxicity as evaluated by TUNEL staining or Western blot analysis of alpha II spectrin breakdown products were different between Sort1 -/- and Sort1 +/+ mice. In addition, CCI induced the up-regulation of pro-inflammatory marker mRNA expression ( Il6 , Tnfa , Aif1 , and Gfap ) irrespectively of the genotype. Similarly, the mRNA expressions of neurotrophins ( Bdnf , Ngf , Nt3) , VPS10P domain receptors others than sortilin ( Ngfr, Sorl1 , Sorcs2 ), and the sortilin interactor progranulin were not affected by genotype. Our results suggest that sortilin is a modulatory rather than a critical factor in the acute and early brain tissue response after TBI., Competing Interests: The authors declare no competing interests or conflict of interest., (© 2024 The Authors.)

Traumatic brain injury (TBI) causes the release of danger-associated molecular patterns (DAMP) from damaged or dead cells, which contribute to secondary brain damage after TBI. Cell-free DNA (cfDNA) is a DAMP known to cause disruption of the blood-brain barrier (BBB), promote procoagulant processes, brain edema, and neuroinflammation. This study tested the hypothesis that administration of deoxyribonuclease-I (DNase-I) has a beneficial effect after TBI. Mice (n = 84) were subjected to controlled cortical impact (CCI) and posttraumatic intraperitoneal injections of low dose (LD) or high dose (HD) of DNase-I or vehicle solution at 30 min and 12 h after CCI. LD was most effective to reduce lesion volume (p = 0.003), brain water content (p < 0.0001) and to stabilize BBB integrity (p = 0.019) 1 day post-injury (dpi). At 6 h post injury LD-treated animals showed less cleavage of fibrin (p = 0.0014), and enhanced perfusion as assessed by micro-computer-tomography (p = 0.027). At 5 dpi the number of Iba1-positive cells (p = 0.037) were reduced, but the number of CD45-positive cells, motoric function and brain lesion volume was not different. Posttraumatic-treatment with DNase-I therefore stabilizes the BBB, reduces the formation of brain edema, immune response, and delays secondary brain damage. DNase-I might be a new approach to extend the treatment window after TBI., (© 2023. The Author(s).)

Traumatic brain injury (TBI) involves primary mechanical damage and delayed secondary damage caused by vascular dysfunction and neuroinflammation. Intracellular components released into the parenchyma and systemic circulation, termed danger-associated molecular patterns (DAMPs), are major drivers of vascular dysfunction and neuroinflammation. These DAMPs include cell-free RNAs (cfRNAs), which damage the blood-brain barrier (BBB), thereby promoting edema, procoagulatory processes, and infiltration of inflammatory cells. We tested the hypothesis that intraperitoneal injection of Ribonuclease-1 (RNase1, two doses of 20, 60, or 180 µg/kg) at 30 min and 12 h after controlled-cortical-impact (CCI) can reduce secondary lesion expansion compared to vehicle treatment 24 h and 120 h post-CCI. The lowest total dose (40 µg/kg) was most effective at reducing lesion volume (- 31% RNase 40 µg/kg vs. vehicle), brain water accumulation (- 5.5%), and loss of BBB integrity (- 21.6%) at 24 h post-CCI. RNase1 also reduced perilesional leukocyte recruitment (- 53.3%) and microglial activation (- 18.3%) at 120 h post-CCI, but there was no difference in lesion volume at this time and no functional benefit. Treatment with RNase1 in the early phase following TBI stabilizes the BBB and impedes leukocyte immigration, thereby suppressing neuroinflammation. RNase1-treatment may be a novel approach to delay brain injury to extend the window for treatment opportunities after TBI., (© 2022. The Author(s).)

Objective: It is unclear whether and to what extent COVID-19 infection poses health risks and a chronic impairment of performance in athletes. Identification of individual health risk is an important decision-making basis for managing the pandemic risk of infection with SARS-CoV-2 in sports and return to play (RTP). Methods: This study aims 1) to analyze the longitudinal rate of seroprevalence of SARS-CoV-2 in German athletes, 2) to assess health-related consequences in athletes infected with SARS-CoV-2, and 3) to reveal effects of the COVID-19 pandemic in general and of a cleared SARS-CoV-2 infection on exercise performance. CoSmo-S is a prospective observational multicenter study establishing two cohorts: 1) athletes diagnosed positive for COVID-19 (cohort 1) and 2) federal squad athletes who perform their annual sports medical preparticipation screening (cohort 2). Comprehensive diagnostics including physical examination, laboratory blood analyses and blood biobanking, resting and exercise electrocardiogram (ECG), echocardiography, spirometry and exercise testing added by questionnaires are conducted at baseline and follow-up. Results and Conclusion: We expect that the results obtained, will allow us to formulate recommendations regarding RTP on a more evidence-based level., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Niess, Widmann, Gaidai, Gölz, Schubert, Castillo, Sachs, Bizjak, Vollrath, Wimbauer, Vogel, Keller, Burgstahler, Quermann, Kerling, Schneider, Zacher, Diebold, Grummt, Beckendorf, Buitenhuis, Egger, Venhorst, Morath, Barsch, Mellwig, Oesterschlink, Wüstenfeld, Predel, Deibert, Friedmann-Bette, Mayer, Hirschmüller, Halle, Steinacker, Wolfarth, Meyer, Böttinger, Flechtner-Mors, Bloch, Haller, Roecker and Reinsberger.)

Progranulin (PGRN) is a neurotrophic and anti-inflammatory factor with protective effects in animal models of ischemic stroke, subarachnoid hemorrhage, and traumatic brain injury (TBI). Administration of recombinant (r) PGRN prevents exaggerated brain pathology after TBI in Grn-deficient mice, suggesting that local injection of recombinant progranulin (rPGRN) provides therapeutic benefit in the acute phase of TBI. To test this hypothesis, we subjected adult male C57Bl/6N mice to the controlled cortical impact model of TBI, administered a single dose of rPGRN intracerebroventricularly (ICV) shortly before the injury, and examined behavioral and biological effects up to 5 days post injury (dpi). The anti-inflammatory bioactivity of rPGRN was confirmed by its capability to inhibit the inflammation-induced hypertrophy of murine primary microglia and astrocytes in vitro. In C57Bl/6N mice, however, ICV administration of rPGRN failed to attenuate behavioral deficits over the 5-day observation period. (Immuno)histological gene and protein expression analyses at 5 dpi did not reveal a therapeutic benefit in terms of brain injury size, brain inflammation, glia activation, cell numbers in neurogenic niches, and neuronal damage. Instead, we observed a failure of TBI-induced mRNA upregulation of the tight junction protein occludin and increased extravasation of serum immunoglobulin G into the brain parenchyma at 5 dpi. In conclusion, single ICV administration of rPGRN had not the expected protective effects in the acute phase of murine TBI, but appeared to cause an aggravation of blood-brain barrier disruption. The data raise questions about putative PGRN-boosting approaches in other types of brain injuries and disease., (© 2021 The Authors. Journal of Neurochemistry published by John Wiley & Sons Ltd on behalf of International Society for Neurochemistry.)

The α-secretase A disintegrin and metalloprotease 10 (ADAM10) regulates various physiological and pathophysiological processes. Despite its broad functional implications during development, plasticity, and disease, no pharmacological approaches to inhibit ADAM10 in acute brain injury have been reported. Here, we examined the effects of the ADAM10 inhibitor GI254023X on the neurological and histopathological outcome after experimental traumatic brain injury (TBI). C57BL/6N mice were subjected to the controlled cortical impact (CCI) model of TBI or sham procedure and received GI254023X or vehicle during the acute phase of injury ( n = 40, 100 mg/kg, 25% DMSO, 0.1 M Na 2 CO 3 , intraperitoneal, 30 min and 24 h after TBI). GI254023X treatment did not improve neurological deficits from 1 to 7 days post-injury (dpi) but animals treated with GI254023X exhibited smaller brain lesions compared to vehicle treatment. Determination of brain mRNA expression by quantitative PCR showed that TBI-induced up-regulation of Adam10 and Adam17 was not influenced by GI254023X but the up-regulation of the matrix metalloproteinase genes Mmp2 and Mmp9 was attenuated. GI254023X treatment further increased the T cell marker Cd247 but did not affect blood brain barrier integrity, as assessed by Occludin mRNA expression and IgG brain extravasation. However, in agreement with neuroprotective effects of ADAM10 inhibition, GI254023X treatment attenuated axonal injury, as indicated by decreased generation of spectrin breakdown products (SBDPs) and decreased immunostaining using anti-non-phosphorylated neurofilament (SMI-32). Interestingly, reduced axonal injury in GI254023X-treated animals coincided with subtle mRNA dysregulation in the glutamate receptor subunit genes Gria1 and Grin2b . Quantitative PCR also revealed that GI254023X mitigated up-regulation of the pro-inflammatory markers Il6 , Tnfa , and Lcn2 but not the up-regulation of the pan-microglia marker Aif1 , the M2 microglia marker Arg1 and the reactive astrocyte marker Gfap . Taken together, the ADAM10 inhibitor GI254023X attenuates brain tissue loss, axonal injury and pro-inflammatory gene expression in the CCI model of TBI. These results suggest that ADAM10 may represent a therapeutic target in the acute phase of TBI., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Appel, Hummel, Weidemeier, Endres, Gölz and Schäfer.)

Background and Purpose: All-trans retinoic acid (ATRA) is a vitamin A metabolite, important in the developing and mature brain. Pre-injury ATRA administration ameliorates ischaemic brain insults in rodents. This study examined the effects of post-traumatic ATRA treatment in experimental traumatic brain injury (TBI)., Experimental Approach: Male adult mice were subjected to the controlled cortical impact model of TBI or sham procedure and killed at 7 or 30 days post-injury (dpi). ATRA (10 mg kg-1, i.p.) was given immediately after the injury and 1, 2 and 3 dpi. Neurological function and sensorimotor coordination were evaluated. Brains were processed for (immuno-) histological, mRNA and protein analyses (qPCR and western blot)., Key Results: ATRA treatment reduced brain lesion size, reactive astrogliosis and axonal injury at 7 dpi, and hippocampal granule cell layer (GCL) integrity was protected at 7 and 30 dpi, independent of cell proliferation in neurogenic niches and blood-brain barrier damage. Neurological and motor deficits over time and the brain tissue loss at 30 dpi were not affected by ATRA treatment. ATRA decreased gene expression of markers for damage-associated molecular pattern (HMGB1), apoptosis (caspase-3 and Bax), activated microglia (TSPO), and reactive astrogliosis (GFAP, SerpinA3N) at 7 dpi and a subset of markers at 30 dpi (TSPO, GFAP)., Conclusion and Implications: In experimental TBI, post-traumatic ATRA administration exerted brain protective effects, including long-term protection of GCL integrity, but did not affect neurological and motor deficits. Further investigations are required to optimize treatment regimens to enhance ATRA's brain protective effects and improve outcomes., (© 2020. The British Pharmacological Society.)

As the proportion of people over 60 years of age rises continuously in westernized societies, it becomes increasingly important to better understand aging processes and how to maintain independence in old age. Fine motor tasks are essential in daily living and, therefore, necessary to maintain. This paper extends the existing literature on fine motor control by manipulating the difficulty of a force maintenance task to characterize performance optima for elderly. Thirty-seven elderly (M = 68.00, SD = 4.65) performed a force control task at dynamically varying force levels, i.e. randomly changing every 3 s between 10%, 20%, and 30% of the individual's maximum voluntary contraction (MVC). This task was performed alone or with one or two additional tasks to increase task difficulty. The force control characteristics accuracy, variability, and complexity were analyzed. Lowest variability was observed at 20%. Accuracy and complexity increased with increasing force level. Overall, increased task difficulty had a negative impact on task performance. Results support the assumption, that attention control has a major impact on force control performance in elderly people. We assume different parameters to have their optimum at different force levels, which remain comparably stable when additional tasks are performed. The study contributes to a better understanding of how force control is affected in real-life situations when it is performed simultaneously to other cognitive and sensory active and passive tasks.

Clinical and animal studies have revealed sex-specific differences in histopathological and neurological outcome after traumatic brain injury (TBI). The impact of perioperative administration of sex steroid inhibitors on TBI is still elusive. Here, we subjected male and female C57Bl/6N mice to the controlled cortical impact (CCI) model of TBI and applied pharmacological inhibitors of steroid hormone synthesis, that is, letrozole (LET, inhibiting estradiol synthesis by aromatase) and finasteride (FIN, inhibiting dihydrotestosterone synthesis by 5α-reductase), respectively, starting 72 h prior CCI, and continuing for a further 48 h after CCI. Initial gene expression analyses showed that androgen (Ar) and estrogen receptors (Esr1) were sex-specifically altered 72 h after CCI. When examining brain lesion size, we found larger lesions in male than in female mice, but did not observe effects of FIN or LET treatment. However, LET treatment exacerbated neurological deficits 24 and 72 h after CCI. On the molecular level, FIN administration reduced calpain-dependent spectrin breakdown products, a proxy of excitotoxicity and disturbed Ca 2+ homeostasis, specifically in males, whereas LET increased the reactive astrocyte marker glial fibrillary acid protein specifically in females. Examination of neurotrophins (brain-derived neurotrophic factor, neuronal growth factor, NT-3) and their receptors (p75 NTR , TrkA, TrkB, TrkC) revealed CCI-induced down-regulation of TrkB and TrkC protein expression, which was reduced by LET in both sexes. Interestingly, FIN decreased neuronal growth factor mRNA expression and protein levels of its receptor TrkA only in males. Taken together, our data suggest a sex-specific impact on pathogenic processes in the injured brain after TBI. Sex hormones may thus modulate pathogenic processes in experimental TBI., (© 2019 International Society for Neurochemistry.)

Objective: Plasminogen activator inhibitor-1 (PAI-1) is the key endogenous inhibitor of fibrinolysis, and enhances clot formation after injury. In traumatic brain injury, dysregulation of fibrinolysis may lead to sustained microthrombosis and accelerated lesion expansion. In the present study, we hypothesized that PAI-1 mediates post-traumatic malfunction of coagulation, with inhibition or genetic depletion of PAI-1 attenuating clot formation and lesion expansion after brain trauma., Methods: We evaluated PAI-1 as a possible new target in a mouse controlled cortical impact (CCI) model of traumatic brain injury. We performed the pharmacological inhibition of PAI-1 with PAI-039 and stimulation by tranexamic acid, and we confirmed our results in PAI-1-deficient animals., Results: PAI-1 mRNA was time-dependently upregulated, with a 305-fold peak 12 hours after CCI, which effectively counteracted the 2- to 3-fold increase in cerebral tissue-type/urokinase plasminogen activator expression. PAI-039 reduced brain lesion volume by 26% at 24 hours and 43% at 5 days after insult. This treatment also attenuated neuronal apoptosis and improved neurofunctional outcome. Moreover, intravital microscopy demonstrated reduced post-traumatic thrombus formation in the pericontusional cortical microvasculature. In PAI-1-deficient mice, the therapeutic effect of PAI-039 was absent. These mice also displayed 13% reduced brain damage compared with wild type. In contrast, inhibition of fibrinolysis with tranexamic acid increased lesion volume by 25% compared with vehicle., Interpretation: This study identifies impaired fibrinolysis as a critical process in post-traumatic secondary brain damage and suggests that PAI-1 may be a central endogenous inhibitor of the fibrinolytic pathway, promoting a procoagulatory state and clot formation in the cerebral microvasculature. Ann Neurol 2019;85:667-680., (© 2019 The Authors. Annals of Neurology published by Wiley Periodicals, Inc. on behalf of American Neurological Association.)

It is well-established that expertise developed through continuous and deliberate practice has the potential to delay age-related decline in fine motor skills. However, less is known about the underlying mechanisms, that is, whether expertise leads to a higher performance level changing the initial status from which age-related decline starts or if expertise-related changes result in qualitatively different motor output and neural processing providing a resource of compensation for age-related changes. Thus, as a first step, this study aims at a better understanding of expertise-related changes in fine motor control with respect to force output and respective electrophysiological correlates. Here, using a multidimensional approach, we investigated fine motor control of experts and novices in precision mechanics during the execution of a dynamic force control task. On the level of force output, we analyzed precision, variability, and complexity. We further used dynamic mode decomposition (DMD) to analyze the electrophysiological correlates of force control to deduce brain network dynamics. Experts' force output was more precise, less variable, and more complex. Task-related DMD mean mode magnitudes within the α-band at electrodes over sensorimotor relevant areas were reduced in experts, and lower DMD mean mode magnitudes related to the force output in novices. Our results provide evidence for expertise dependent central adaptions with distinct and more complex organization and decentralization of sensorimotor subsystems. Results from our multidimensional approach can be seen as a step forward in understanding expertise-related changes and exploiting their potential as resources for healthy aging.

Acute cerebral lesions are associated with dysregulation of brain glucose homeostasis. Previous studies showed that knockdown of Na + -D-glucose cotransporter SGLT1 impaired outcome after middle cerebral artery occlusion and that widely expressed intracellular RS1 (RSC1A1) is involved in transcriptional and post-translational down-regulation of SGLT1. In the present study, we investigated whether SGLT1 is up-regulated during traumatic brain injury (TBI) and whether removal of RS1 in mice (RS1-KO) influences SGLT1 expression and outcome. Unexpectedly, brain SGLT1 mRNA in RS1-KO was similar to wild-type whereas it was increased in small intestine and decreased in kidney. One day after TBI, SGLT1 mRNA in the ipsilateral cortex was increased 160% in wild-type and 40% in RS1-KO. After RS1 removal lesion volume 1 day after TBI was reduced by 12%, brain edema was reduced by 28%, and motoric disability determined by a beam walking test was improved. In contrast, RS1 removal did neither influence glucose and glycogen accumulation 1 day after TBI nor up-regulation of inflammatory cytokines TNF-α, IL-1β and IL-6 or microglia activation 1 or 5 days after TBI. The data provide proof of principle that inhibition or down-regulation of SGLT1 by targeting RS1 in brain could be beneficial for early treatment of TBI., (© 2018 International Society for Neurochemistry.)

Age-related deterioration of force control is evident on behavioral and neural levels. Extensive and deliberate practice can decrease these changes. This study focused on detecting electrophysiological correlates of age- and expertise-related differences in force control. We examined young (20-27 years) and late middle-aged (57-67 years) novices as well as late middle-aged experts in the field of fine motor control. Therefore, EEG data were recorded while participants performed a force maintenance task. Variability and complexity of force data were analyzed. To detect electrophysiological correlates, dynamic mode decomposition (DMD) was applied to EEG data. DMD allows assessing brain network dynamics by extracting electrode interrelations and their dynamics. Defining clusters of electrodes, we focused on sensorimotor and attentional networks. We confirmed that force control in late middle-aged novices was more variable and less complex than in other groups. Analysis of task-related overall network characteristics, showed a decrease within the α band and increase within low β, high β, and  θ  band. Compared to the other groups young novices presented a decreased α magnitude. High β magnitude was lower in late middle-aged novices than for other groups. Comparing left and right hands' performance, young novices showed higher low β magnitude for the left hand. Late middle-aged novices showed high values for both hands while late middle-aged experts showed higher values for the right than for their left hand. Activation of attentional networks was lower in late middle-aged experts compared to novices. These results may relate to different control strategies of the three groups., (Copyright © 2018 IBRO. Published by Elsevier Ltd. All rights reserved.)

Neuronal degeneration following traumatic brain injury (TBI) leads to intracellular accumulation of dysfunctional proteins and organelles. Autophagy may serve to facilitate degradation to overcome protein debris load and therefore be an important pro-survival factor. On the contrary, clearing may serve as pro-death factor by removal of essential or required proteins involved in pro-survival cascades. Sequestosome 1 (SQSTM1/p62) is a main regulator of the autophagic pathway that directs ubiquinated cargoes to autophagosomes for degradation. We show that SQSTM1 protein levels are suppressed 24 h and by trend 5 days after trauma. In line with these data the expression of Sqstm1 mRNA is reduced by 30% at day 3 after and stays depressed until day 5 after injury, indicating an impaired autophagy post controlled cortical impact (CCI). To determine the potential role of SQSTM1-dependent autophagy after TBI, mice lacking SQSTM1 (SQSTM1-KO) and littermates (WT) were subjected to CCI and brain lesion volume was determined 24 h and 5 days after insult. Lesion volume is 17% smaller at 24 h and immunoblotting reveals a reduction by trend of cell death marker αII-spectrin cleavage. But there is no effect on brain damage and cell death markers 5 days after trauma in SQSTM1-KO compared with WT. In line with these data neurofunctional testing does not reveal any differences. Additionally, gene expression of inflammatory ( Tnf- α , iNos, Il-6 , and Il-1 β) and protein degradation markers ( Bag1 and Bag3 ) were quantified by real-time PCR. Protein levels of LC3, BAG1, and BAG3 were analyzed by immunoblotting. Real-time PCR reveals minor changes in inflammatory marker gene expression and reduced Bag3 mRNA levels 5 days after trauma. Immunoblotting of autophagy markers LC3, BAG1, and BAG3 does not show any difference between KO and WT 24 h and 5 days after TBI. In conclusion, genetic ablation of SQSTM1-dependent autophagy leads to a delay but shows no persistent effect on post-traumatic brain damage formation. SQSTM1 therefore only plays a minor role for secondary brain damage formation and autophagic clearance of debris after TBI.

The blood-brain barrier (BBB) is damaged during ischemic insults such as traumatic brain injury or stroke. This contributes to vasogenic edema formation and deteriorate disease outcomes. Enormous efforts are pursued to understand underlying mechanisms of ischemic insults and develop novel therapeutic strategies. In the present study the effects of PPARα agonist WY-14643 were investigated to prevent BBB breakdown and reduce edema formation. WY-14643 inhibited barrier damage in a mouse BBB in vitro model of traumatic brain injury based on oxygen/glucose deprivation in a concentration dependent manner. This was linked to changes of the localization of tight junction proteins. Furthermore, WY-14643 altered phosphorylation of kinases ERK1/2, p38, and SAPK/JNK and was able to inhibit proteosomal activity. Moreover, addition of WY-14643 upregulated PAI-1 leading to decreased t-PA activity. Mouse in vivo experiments showed significantly decreased edema formation in a controlled cortical impact model of traumatic brain injury after WY-14643 application, which was not found in PAI-1 knockout mice. Generally, data suggested that WY-14643 induced cellular responses which were dependent as well as independent from PPARα mediated transcription. In conclusion, novel mechanisms of a PPARα agonist were elucidated to attenuate BBB breakdown during traumatic brain injury in vitro .

Objectives: The gamma-aminobutyric acid modulator propofol induces neuronal cell death in healthy immature brains by unbalancing neurotrophin homeostasis via p75 neurotrophin receptor signaling. In adulthood, p75 neurotrophin receptor becomes down-regulated and propofol loses its neurotoxic effect. However, acute brain lesions, such as traumatic brain injury, reactivate developmental-like programs and increase p75 neurotrophin receptor expression, probably to foster reparative processes, which in turn could render the brain sensitive to propofol-mediated neurotoxicity. This study investigates the influence of delayed single-bolus propofol applications at the peak of p75 neurotrophin receptor expression after experimental traumatic brain injury in adult mice., Design: Randomized laboratory animal study., Setting: University research laboratory., Subjects: Adult C57BL/6N and nerve growth factor receptor-deficient mice., Interventions: Sedation by IV propofol bolus application delayed after controlled cortical impact injury., Measurements and Main Results: Propofol sedation at 24 hours after traumatic brain injury increased lesion volume, enhanced calpain-induced αII-spectrin cleavage, and increased cell death in perilesional tissue. Thirty-day postinjury motor function determined by CatWalk (Noldus Information Technology, Wageningen, The Netherlands) gait analysis was significantly impaired in propofol-sedated animals. Propofol enhanced pro-brain-derived neurotrophic factor/brain-derived neurotrophic factor ratio, which aggravates p75 neurotrophin receptor-mediated cell death. Propofol toxicity was abolished both by pharmacologic inhibition of the cell death domain of the p75 neurotrophin receptor (TAT-Pep5) and in mice lacking the extracellular neurotrophin binding site of p75 neurotrophin receptor., Conclusions: This study provides first evidence that propofol sedation after acute brain lesions can have a deleterious impact and implicates a role for the pro-brain-derived neurotrophic factor-p75 neurotrophin receptor pathway. This observation is important as sedation with propofol and other compounds with GABA receptor activity are frequently used in patients with acute brain pathologies to facilitate sedation or surgical and interventional procedures.

Traumatic brain injury (TBI) initiates an excessive mediator release of e.g. neurotrophins, which promote neuronal survival, differentiation, and modulate synaptic plasticity. Paradoxically, mature forms of neurotrophins promote neuronal survival, whereas unprocessed forms of neurotrophins induce cell death through p75 neurotrophin receptor (p75NTR) signaling. p75NTR is widely expressed during synaptogenesis and is subsequently downregulated in adulthood. Repair mechanisms after acute cerebral insults can reactivate its expression. Therefore, the influence of p75NTR on secondary brain damage was addressed. mRNA levels of p75NTR and its ligands were quantified in brain tissue up to 7 days after experimental TBI (controlled cortical impact; CCI). Brain damage, motor function and inflammatory marker gene expression were determined in mice lacking the proneurotrophin-binding site of the p75NTR protein (NGFR(-/-)) and wild type littermates (NGFR(+/+)) 24 h and 5 days after CCI. In addition, the effect of TAT-Pep5 (pharmacological inhibitor of the intracellular p75NTR death domain) on lesion volume was evaluated 24 h after insult. p75NTR mRNA levels were induced nine-fold by TBI. In NGFR(-/-) mice, lesion volume was reduced by 29% at 24 h and by 21% 5 days after CCI. Motor coordination was significantly improved 24 h after trauma compared with the wild type. Pharmacological inhibition of the p75NTR signaling reduced lesion volume by 18%. The present study presents first time evidence that genetic mutation of the neurotrophin interaction site of p75NTR strongly limits post-traumatic cell death. In addition, we revealed pharmacological targeting of the intracellular p75NTR cell death domain as a promising approach to limit acute brain damage.