Agent For Traumatic Brain Injury Research Articles

Rapamycin protects against apoptotic neuronal death and improves neurologic function after traumatic brain injury in mice via modulation of the mTOR-p53-Bax axis

BackgroundRapamycin has proven to be a neuroprotective agent in traumatic brain injury (TBI). However, there is a lack of data regarding the effect of rapamycin on apoptotic neuronal death after TBI. Thus, the present study was designed to detect the modulatory role of rapamycin on apoptosis and explore the potential involvement of the mammalian target of rapamycin (mTOR)-p53-Bax axis after TBI. Material and methodsNeurologic severity score tests were performed to measure behavioral outcomes. The effect of rapamycin treatment on neuronal death was analyzed using immunofluorescence analysis of NeuN. Terminal deoxynucleotidyl transferase-mediated dUTP nick 3′-end labeling was performed to detect apoptotic cells. The expression of Bax and phosphorylated protein of p53 was detected using Western blotting analyses and immunofluorescence staining. Phosphorylated protein of the mTOR in the ipsilateral cortex was detected using Western blotting analyses. ResultsRapamycin administration after TBI was associated with an increased number of neurons, decreased apoptosis index, and improved neurobehavioral function, which was potentially mediated by inactivation of the mTOR-p53-Bax axis. ConclusionsRapamycin can protect neurons from apoptotic neuronal death after TBI. This study presents a new insight into the antiapoptosis mechanisms, which are responsible for the neuroprotection of rapamycin, with the potential involvement of the mTOR-p53-Bax axis.

Intravenous fluid choices in critically ill children.

To review the past year's literature, and selected prior literature relevant to these most recent findings, regarding intravenous fluid choices in the management of critically ill children. Twenty-eight publications were identified using the keywords pediatrics and intravenous fluid in the PubMed database. The subjects identified included intravenous fluid choices related to perioperative maintenance fluid management, rehydration for dehydration related to diarrhea losses, rehydration in diabetic ketoacidosis, intravenous fluid needs during mechanical ventilation, use of intravenous fluids as hyperosmolar agents in traumatic brain injury, isotonic fluid bolus resuscitation for sepsis-related capillary leak syndrome-induced hypovolemic shock, maintenance intravenous fluid and blood transfusion for malaria-associated euvolemic severe anemia shock, isotonic fluid and blood boluses for trauma-induced hemorrhagic shock, and isotonic fluid boluses and generous maintenance infusion for burn resuscitation. Because intravenous fluid can be helpful or harmful, it can only be safely done in critically ill children when using state-of-the-art monitoring of patient volume, electrolyte, osmolarity, pH, and glucose status.

The Cysteine Protease Cathepsin B Is a Key Drug Target and Cysteine Protease Inhibitors Are Potential Therapeutics for Traumatic Brain Injury

There are currently no effective therapeutic agents for traumatic brain injury (TBI), but drug treatments for TBI can be developed by validation of new drug targets and demonstration that compounds directed to such targets are efficacious in TBI animal models using a clinically relevant route of drug administration. The cysteine protease, cathepsin B, has been implicated in mediating TBI, but it has not been validated by gene knockout (KO) studies. Therefore, this investigation evaluated mice with deletion of the cathepsin B gene receiving controlled cortical impact TBI trauma. Results indicated that KO of the cathepsin B gene resulted in amelioration of TBI, shown by significant improvement in motor dysfunction, reduced brain lesion volume, greater neuronal density in brain, and lack of increased proapoptotic Bax levels. Notably, oral administration of the small-molecule cysteine protease inhibitor, E64d, immediately after TBI resulted in recovery of TBI-mediated motor dysfunction and reduced the increase in cathepsin B activity induced by TBI. E64d outcomes were as effective as cathepsin B gene deletion for improving TBI. E64d treatment was effective even when administered 8 h after injury, indicating a clinically plausible time period for acute therapeutic intervention. These data demonstrate that a cysteine protease inhibitor can be orally efficacious in a TBI animal model when administered at a clinically relevant time point post-trauma, and that E64d-mediated improvement of TBI is primarily the result of inhibition of cathepsin B activity. These results validate cathepsin B as a new TBI therapeutic target.

Phenoxybenzamine Is Neuroprotective in a Rat Model of Severe Traumatic Brain Injury

Phenoxybenzamine (PBZ) is an FDA approved α-1 adrenergic receptor antagonist that is currently used to treat symptoms of pheochromocytoma. However, it has not been studied as a neuroprotective agent for traumatic brain injury (TBI). While screening neuroprotective candidates, we found that phenoxybenzamine reduced neuronal death in rat hippocampal slice cultures following exposure to oxygen glucose deprivation (OGD). Using this system, we found that phenoxybenzamine reduced neuronal death over a broad dose range (0.1 μM–1 mM) and provided efficacy when delivered up to 16 h post-OGD. We further tested phenoxybenzamine in the rat lateral fluid percussion model of TBI. When administered 8 h after TBI, phenoxybenzamine improved neurological severity scoring and foot fault assessments. At 25 days post injury, phenoxybenzamine treated TBI animals also showed a significant improvement in both learning and memory compared to saline treated controls. We further examined gene expression changes within the cortex following TBI. At 32 h post-TBI phenoxybenzamine treated animals had significantly lower expression of pro-inflammatory signaling proteins CCL2, IL1β, and MyD88, suggesting that phenoxybenzamine may exert a neuroprotective effect by reducing neuroinflammation after TBI. These data suggest that phenonxybenzamine may have application in the treatment of TBI.

Neuroprotective Agents for Traumatic Brain Injury: Theoretical Therapy or the Future of Treatment?

An increasing awareness of concussions in sports has led researchers to uncover that brain tissue damage is not instantaneous, but rather a delayed process following the initial injury. Recently, neuroprotective agents have been developed that will be administered after injury to reduce the effects of Traumatic Brain Injury (TBI). These agents include NMDA receptor antagonists that aim to interfere with excitotoxicity and reduce neuronal death. While these agents have improved learning and cognitive performance in animal models, their effects have not been as positive in clinical trials. Calpain inhibitors have also shown neuroprotective effects, and protect against axonal damage in the white matter of the brain. In the future, a better understanding of the cellular mechanisms of TBI will allow better development of neuroprotective agents for clinical use.

Should ketamine be used as an induction agent in traumatic brain injury?

British Journal of Hospital MedicineVol. 74, No. 9 Anaesthetic and Critical Care DilemmaShould ketamine be used as an induction agent in traumatic brain injury?P McDermott, J SebastianP McDermottSearch for more papers by this author, J SebastianSearch for more papers by this authorP McDermott; J SebastianPublished Online:18 Nov 2013https://doi.org/10.12968/hmed.2013.74.9.538AboutSectionsView articleView Full TextPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareShare onFacebookTwitterLinked InEmail View article References Albanese J, Arnaud S, Rey M, Thomachot L, Alliez B, Martin C (1997) Ketamine decreases intracranial pressure and electroencephalographic activity in traumatic brain injury patients during propofol sedation. Anesthesiology 87(6): 1328–34 Crossref, Medline, Google ScholarBourgoin A, Albanese J, Wereszczynski N, Charbit M, Vialet R, Martin C (2003) Safety of sedation with ketamine in severe head injury patients: comparison with sufentanil. Crit Care Med 31(3): 711–17 Crossref, Medline, Google Scholar Gardner AE, Olson BE, Lichtiger M (1971) Cerebrospinal-fluid pressure during dissociative anesthesia with ketamine. Anesthesiology 35(2): 226–8 Crossref, Medline, Google ScholarHimmelseher S, Durieux ME (2005) Revising a dogma: ketamine for patients with neurological injury? Anesth Analg 101: 524–34 Crossref, Medline, Google ScholarManley G, Knudson MM, Morabito D, Damron S, Erickson V, Pitts L (2001) Hypotension, hypoxia and head injury: frequency, duration, and consequences. Arch Surg 136(10): 1118–23 Crossref, Medline, Google Scholar FiguresReferencesRelatedDetails 1 September 2013Volume 74Issue 9ISSN (print): 1750-8460ISSN (online): 1759-7390 Metrics History Published online 18 November 2013 Published in print 1 September 2013 Information© MA Healthcare LimitedPDF download

Exposure of Cyclosporin A in Whole Blood, Cerebral Spinal Fluid, and Brain Extracellular Fluid Dialysate in Adults with Traumatic Brain Injury

Cyclosporin A (CsA), an immunosuppressive medication traditionally used in the prevention of post-transplant rejection, is a promising neuroprotective agent for traumatic brain injury (TBI). Preliminary studies in animals and humans describe the efficacy and safety of CsA when administered following neurotrauma. The objective of this study is to describe CsA exposure in adults with severe TBI by assessing concentrations in whole blood, cerebrospinal fluid (CSF), and brain extracellular fluid (ECF) dialysate as measured by brain microdialysis. Severe TBI patients were enrolled in a randomized controlled trial following the written informed consent of their legal guardians. Patients received either CsA 5 mg/kg as a continuous infusion over 24 h, or matching placebo. Noncompartmental exposure analyses were performed using CsA concentrations in whole blood, CSF, and ECF dialysate. There were 37 patients randomized to the CsA arm of the trial and included in this exposure analysis. CsA was detected in the ECF dialysate and CSF at a fraction of the whole blood concentration. Mean CsA maximum concentrations were achieved at 24 and 30 h from the start of the 24 h infusion, in the CSF and ECF dialysate, respectively. A correlation was found between ECF dialysate and CSF concentrations. CsA was detected in the blood, CSF, and brain ECF dialysate. CsA exposure characteristic differences exist for whole blood, CSF, and ECF dialysate in severe TBI patients when administered as a continuous intravenous infusion. These exposure characteristics should be used for safer CsA dose optimization to achieve target CsA concentrations for neuroprotection in future TBI studies.

Sedation in traumatic brain injury.

Several different classes of sedative agents are used in the management of patients with traumatic brain injury (TBI). These agents are used at induction of anaesthesia, to maintain sedation, to reduce elevated intracranial pressure, to terminate seizure activity and facilitate ventilation. The intent of their use is to prevent secondary brain injury by facilitating and optimising ventilation, reducing cerebral metabolic rate and reducing intracranial pressure. There is limited evidence available as to the best choice of sedative agents in TBI, with each agent having specific advantages and disadvantages. This review discusses these agents and offers evidence-based guidance as to the appropriate context in which each agent may be used. Propofol, benzodiazepines, narcotics, barbiturates, etomidate, ketamine, and dexmedetomidine are reviewed and compared.

Gamma‐glutamylcysteine ethyl ester protects cerebral endothelial cells during injury and decreases blood–brain barrier permeability after experimental brain trauma

Oxidative stress is a pathway of injury that is common to almost all neurological conditions. Hence, methods to scavenge radicals have been extensively tested for neuroprotection. However, saving neurons alone may not be sufficient in treating CNS disease. In this study, we tested the cytoprotective actions of the glutathione precursor gamma-glutamylcysteine ethyl ester (GCEE) in brain endothelium. First, oxidative stress was induced in a human brain microvascular endothelial cell line by exposure to H(2)O(2). Addition of GCEE significantly reduced formation of reactive oxygen species, restored glutathione levels which were reduced in the presence of H(2)O(2), and decreased cell death during H(2)O(2)-mediated injury. Next, we asked whether GCEE can also protect brain endothelial cells against oxygen-glucose deprivation (OGD). As expected, OGD disrupted mitochondrial membrane potentials. GCEE was able to ameliorate these mitochondrial effects. Concomitantly, GCEE significantly decreased endothelial cell death after OGD. Lastly, our in vivo experiments using a mouse model of brain trauma show that post-trauma (10 min after controlled cortical impact) administration of GCEE by intraperitoneal injection results in a decrease in acute blood-brain barrier permeability. These data suggest that the beneficial effects of GCEE on brain endothelial cells and microvessels may contribute to its potential efficacy as a neuroprotective agent in traumatic brain injury.

The Hormone Ghrelin Prevents Disruption Of The Blood Brain Barrier Following Traumatic Brain Injury

Introduction: Traumatic brain injury (TBI) remains a leading cause of death and disability in the United States. Significant effort has been focused on reducing neuronal damage from post-TBI inflammation and blood brain barrier (BBB) mediated edema. The orexigenic hormone, ghrelin, decreases inflammation in sepsis models and has recently been shown to be neuroprotective following subarachnoid hemorrhage. We hypothesize that ghrelin prevents cerebral vascular permeability and breakdown of the BBB following TBI. Methods: A weight drop model was used to create severe TBI in Balb/c mice in the right parietal lobe. Animals were divided into 3 groups. Group TBI: TBI only; Group TBI/ghrelin: animals were treated with 10 μg of intraperitoneal ghrelin immediately prior to and 10 minutes following TBI; Group Sham: opening of the skull but no TBI, nor ghrelin treatment. Brain vascular permeability to injected 70kDa FITC-Dextran was determined 6 hours following injury using an IVIS spectrum measuring radiated fluorescence. Extracted brain tissue was also used to measure expression of S100B, a marker of BBB disruption, by Western blot. Results: Six hours following injury, TBI increased cerebral vascular permeability to FITC-Dextran by two-fold as measured by radiated fluorescence(4.9±2.8 vs. 2.5 ±1.0 [p/s/cm2/sr] / [μW/cm2]). Ghrelin treated animals restored vascular permeability to that of sham levels (2.5±1.2 [p/s/cm2/sr] / [μW/cm2]). The corresponding figure shows representative coronal brain imaging, higher color intensity is indicative of increased permeability. Similarly, expression of S100B was increased by 4 fold in TBI animals compared to sham. Again, ghrelin treated animals decreased post-TBI expression of S100B to that of sham. Conclusion: In a mouse model of TBI, ghrelin prevented post-TBI BBB disruption as measured by cerebral vascular permeability and S100B. These preliminary results demonstrate potential neuroprotective effects of ghrelin which could be developed as a future therapeutic agent in TBI.

Multifunctional Drug Treatment in Neurotrauma

Although the concepts of secondary injury and neuroprotection after neurotrauma are experimentally well supported, clinical trials of neuroprotective agents in traumatic brain injury or spinal cord injury have been disappointing. Most strategies to date have used drugs directed toward a single pathophysiological mechanism that contributes to early necrotic cell death. Given these failures, recent research has increasingly focused on multifunctional (i.e., multipotential, pluripotential) agents that target multiple injury mechanisms, particularly those that occur later after the insult. Here we review two such approaches that show particular promise in experimental neurotrauma: cell cycle inhibitors and small cyclized peptides. Both show extended therapeutic windows for treatment and appear to share at least one important target.

Erythropoietin as a neuroprotective agent in traumatic brain injury: Review

Background In the United States, TBI remains a major cause of morbidity and mortality in children and young adults. A total of 1.5 million Americans experience head trauma every year, and the yearly economic cost of this exceeds $56 billion. The magnitude of this problem has generated a great deal of interest in elucidating the complex molecular mechanism underlying cell death and dysfunction after TBI and in the development of neuroprotective agents that will reduce morbidity and mortality. Methods A review of recent literature on EPO, TBI, and apoptosis is conducted with analysis of pathophysiologic mechanisms of TBI. In addition, animal experiments and clinical trials pertaining to mechanisms of cell death in TBI and EPO as a neuroprotective agent are reviewed. Conclusion The literature and evidence for EPO as a potent inhibitor of apoptosis and promising therapeutic agent in a variety of neurological insults, including trauma, are mounting. With the recent interest in clinical trials of EPO in human stroke, it is both timely and prudent to consider the use of this pharmaceutical avenue in TBI in man.

IMPORTANCE OF SCREENING LOGS IN CLINICAL TRIALS FOR SEVERE TRAUMATIC BRAIN INJURY

The primary intent for obtaining screening logs in a randomized clinical trial is to assess selection bias in patient recruitment. This is particularly relevant to focused trials in heterogeneous populations such as traumatic brain injury (TBI) patients. We aimed to investigate the benefits of collecting screening logs in two randomized clinical trials conducted in TBI. Screening logs were collected as part of the conduct of two multicenter trials of neuroprotective agents in TBI: the Salzburg Atherosclerosis Prevention Program in Subjects at High Individual Risk study (n = 924) and the dexanabinol study (n = 861). Centers were requested to submit monthly information on all patients with TBI admitted to the intensive care unit, including demographics, time of injury and admission, injury severity, and, if not recruited, the reason(s) for exclusion. In the Salzburg Atherosclerosis Prevention Program in Subjects at High Individual Risk study, 52 centers submitted admission data on 4166 patients. In the dexanabinol trial, 96 centers submitted data on 7052 patients. On average, only 20% of patients screened for the Salzburg Atherosclerosis Prevention Program in Subjects at High Individual Risk study and 10% for the dexanabinol trial were enrolled. The main reasons for exclusion were neurological status (29 and 26%, respectively), age (24 and 30%, respectively), and admission outside of the time window (17 and 21%, respectively). Differences in patient characteristics between screened and enrolled patients, with substantial country-specific variation, were observed. The collection of screening logs is necessary to report trial results according to the Consolidated Standards of Reporting Trials guidelines and to assess the generalizability of findings. Our experience shows the feasibility of collecting screening logs and illustrates how the potential for selection bias may creep into well-designed randomized clinical trials as a result of factors outside the control of investigators. Consistency and accuracy in screening log completion may further serve as an early indicator of center performance in a trial.

'No Time to be Lost!' Ethical considerations on consent for inclusion in emergency pharmacological research in severe traumatic brain injury in the European Union.

Severe Traumatic Brain Injury (TBI) remains a major cause of death and disability afflicting mostly young adult males and elderly people, resulting in high economic costs to society. Therapeutic approaches focus on reducing the risk on secondary brain injury. Specific ethical issues pertaining in clinical testing of pharmacological neuroprotective agents in TBI include the emergency nature of the research, the incapacity of the patients to informed consent before inclusion, short therapeutic time windows, and a risk-benefit ratio based on concept that in relation to the severity of the trauma, significant adverse side effects may be acceptable for possible beneficial treatments. Randomized controlled phase III trials investigating the safety and efficacy of agents in TBI with promising benefit, conducted in acute emergency situations with short therapeutic time windows, should allow randomization under deferred consent or waiver of consent. Making progress in knowledge of treatment in acute neurological and other intensive care conditions is only possible if national regulations and legislations allow waiver of consent or deferred consent for clinical trials.

Postinjury Administration of Pituitary Adenylate Cyclase Activating Polypeptide (PACAP) Attenuates Traumatically Induced Axonal Injury in Rats

Pituitary adenylate cyclase activating polypeptide (PACAP) has several different actions in the nervous system. Numerous studies have shown its neuroprotective effects both in vitro and in vivo. Previously, it has been demonstrated that PACAP reduces brain damage in rat models of global and focal cerebral ischemia. Based on the protective effects of PACAP in cerebral ischemia and the presence of common pathogenic mechanisms in cerebral ischemia and traumatic brain injury (TBI), the aim of the present study was to investigate the possible protective effect of PACAP administered 30 min or 1 h postinjury in a rat model of diffuse axonal injury. Adult Wistar male rats were subjected to impact acceleration, and PACAP was administered intracerebroventricularly 30 min (n = 4), and 1 h after the injury (n = 5). Control animals received the same volume of vehicle at both time-points (n = 5). Two hours after the injury, brains were processed for immunohistochemical localization of damaged axonal profiles displaying either beta-amyloid precursor protein (beta-APP) or RMO-14 immunoreactivity, both considered markers of specific features of traumatic axonal injury. Our results show that treatment with PACAP (100 microg) 30 min or 1 h after the induction of TBI resulted in a significant reduction of the density of beta-APP-immunopositive axon profiles in the corticospinal tract (CSpT). There was no significant difference between the density of beta-APP-immunopositive axons in the medial longitudinal fascicle (MLF). PACAP treatment did not result in significantly different number of RMO-14-immunopositive axonal profiles in either brain areas 2 hours post-injury compared to normal animals. While the results of this study highlighted the complexity of the pathogenesis and manifestation of diffuse axonal injury, they also indicate that PACAP should be considered a potential therapeutic agent in TBI.

Cannabinoids as neuroprotective agents in traumatic brain injury.

The name Cannabinoid applies to a large and diverse family of compounds including plant derived, synthetic and endogenously produced chemicals, some but not all of which are psychotropic. Cannabinoids of all classes have the ability to protect neurons from a variety of insults that are believed to underlie delayed neuronal death after traumatic brain injury (TBI), including excitotoxicity, calcium influx, free radical formation and neuroinflammation. The pathways and experimental models supporting a neuroprotective role for the various classes of cannabinoids are critically reviewed vis a vis their potential to support the development of a clinically viable neuroprotective agent for human TBI.

Dose-response of cyclosporin A in attenuating traumatic axonal injury in rat.

Cyclosporin A has emerged as a promising therapeutic agent in traumatic brain injury (TBI), although its precise neuroprotective mechanism is unclear. Cyclosporin A, given as a single-dose intrathecal bolus, has previously been shown to attenuate mitochondrial damage and reduce axonal injury in experimental TBI. We assessed the effect of a range of intravenous cyclosporin A doses upon axonal injury attenuation to determine the ideal dose. Rats were subjected to experimental TBI and given one of five intravenous doses of cyclosporin A. At 3 h post-injury, brains were processed for brain tissue cyclosporin A concentration. In a second set of animals, at 24 h postinjury, brains were processed for amyloid precursor protein immunoreactivity, a widely used marker of axonal injury. Intravenous administration produced therapeutic levels of cyclosporin A in brain parenchyma. Higher concentrations were achieved with equivalent doses given intrathecally; this is consistent with the reported poor blood-brain barrier permeability of cyclosporin A. Cyclosporin A 10 mg/kg i.v. produced the greatest degree of neuroprotection against diffuse axonal injury; cyclosporin A 50 mg/kg i.v. was toxic. Intravenous cyclosporin A administration achieves therapeutic levels in brain parenchyma and 10 mg/kg is the most effective dose in attenuating axonal damage after traumatic brain injury.

A Review of Cholinergic Agents in the Treatment of Neurobehavioral Deficits Following Traumatic Brain Injury

Although traumatic brain injury (TBI) frequently results in significant handicap, empirical investigations of pharmacological treatment of the neurobehavioral sequelae of TBI are rare. This review presents evidence that supports hypotheses of a cholinergic mechanism underlying some neurobehavioral sequelae of TBI, as well as a critical review of the preliminary evidence supporting the efficacy of cholinergic agents in TBI. Despite numerous methodological limitations, preliminary evidence exists for the efficacy of cholinergic agents in ameliorating attention and memory deficits following TBI. The authors highlight the need for large, randomized, double-blind, placebo-controlled trials that include a broad range of cognitive and behavioral outcome measures.

Donepezil for Cognitive Deficits Following Traumatic Brain Injury: A Case Report

Donepezil for Cognitive Deficits Following Traumatic Brain Injury: A Case Report