Combined effects of mechanical and ischemic injury to cortical cells: Secondary ischemia increases damage and decreases effects of neuroprotective agents

Engel, Doortje C.; Slemmer, Jennifer E.; Vlug, Angela S.; Maas, Andrew I. R.; Weber, John T.

doi:10.1016/j.neuropharm.2005.05.021

Cited by 30 publications

(24 citation statements)

References 37 publications

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“…Â area (1.49 in 2 ), we calculated that at 2.9 p.s.i., J (on cells) E9.6 N s. We have shown earlier that this sublethal trauma does not confer delayed cell death on its own -as assessed by propidium iodide uptake 20 h after injury -or alter membrane permeability, as assessed by carboxyfluorescein uptake and retention of fluorescein di-acetate. 9 This model is highly consistent with other paradigms of in vitro TBI in the literature, 30,32 which have frequently been used to delineate the intracellular mechanisms that contribute to progressive neuronal injury after mechanical trauma.…”

Section: Methodssupporting

confidence: 65%

PICK1-mediated GluR2 endocytosis contributes to cellular injury after neuronal trauma

Bell

Park

et al. 2009

Cell Death Differ

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Constitutive and activity-dependent regulation of the AMPA receptor GluR2 content is recognized as an important mediator of both neuronal plasticity and vulnerability to excitotoxic neuron death. In the latter case, inclusion of GluR2 protects against glutamate excitotoxicity in CNS disease by lowering receptor single-channel conductance and preventing deleterious calcium influx. We investigated the hypothesis that aberrations in GluR2 trafficking after in vitro and in vivo cerebral trauma contribute to excitotoxicity and associated calcium-dependent cell death processes. First, in an in vitro model of traumatic brain injury (TBI), we observed PICK1 and N-methyl-D-aspartic acid (NMDA) receptor-dependent phosphorylation and internalization of GluR2. The contributing cell signaling mechanisms involved enhanced binding between PKCa (the kinase that phosphorylates GluR2) and PICK1 (its PDZ-binding partner), and a novel protein interaction between PKCa and the NMDA receptor scaffolding protein PSD-95. Functionally, these phenomena enhanced single cell AMPAR mEPSCs and protracted calcium extrusion. In vivo TBI similarly promoted GluR2 phosphorylation and internalization, with enhanced expression of calcium-permeable AMPARs in the injured hippocampus. Peptide-mediated perturbation of the PKCa/PICK1 protein interaction after trauma preserved surface GluR2 expression, attenuated AMPAR-mediated toxicity, and occluded the sensitivity of neuronal physiology to calcium-permeable AMPAR antagonists. These findings suggest that experimental TBI promotes the expression of injurious GluR2-lacking AMPARs, thereby enhancing cellular vulnerability to secondary excitotoxicity. Traumatic brain injury (TBI) continues to be a leading cause of morbidity and disability in North America. 1 At the cellular level, excitotoxic stimulation of N-methyl-D-aspartate (NMDA) and a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamatergic receptors has a major function in the deregulation of calcium homeostasis and acute cell swelling after TBI, ultimately leading to secondary neuronal cell death hours to days after the primary injury. 1 Unfortunately, global antagonism of these ionotropic channels (which has generally targeted the highly calciumpermeable NMDARs) is a clinically impractical approach because of interference with physiological receptor function. 2 As such, it remains of critical importance to identify novel potential intracellular targets of anti-excitotoxic therapy to mitigate delayed secondary cell loss, and improve functional outcome after TBI.Physiologically, AMPA receptors mediate the majority of excitatory ionotropic neurotransmission in the CNS. 3 Pathologically, however, AMPA receptors can also mediate excitotoxic neuronal damage when GluR2 subunits are absent from the tetrameric receptor complex 4 (composed of four subunits, GluR1-4). This is because receptors devoid of the GluR2 subunit (e.g. homomers of GluR1) exhibit two-to three-fold increases in single-channel conductance, increased calcium and zinc permeab...

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Section: Methodssupporting

confidence: 65%

PICK1-mediated GluR2 endocytosis contributes to cellular injury after neuronal trauma

Bell

Park

et al. 2009

Cell Death Differ

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“…The term ''progressive hemorrhagic injury'' has been used to refer to progression of an epidural hematoma, subdural hematoma, intraparenchymal contusion or hematoma, or subarachnoid hemorrhage (Oertel et al, 2002). Such broad usages are Lenzlinger et al, 2002;Morganti-Kossmann et al, 2002;Otto et al, 2002;Yatsiv et al, 2002;Lu et al, 2011;Hong et al, 2010 Excitotoxicity Yi andMetabolic derangements De et al, 2011Lakshmanan et al, 2010;Scafidi et al, 2009;Marcoux et al, 2008;Vespa et al, 2005 Apoptosis/necrosis/ autophagy Shojo et al, 2010;Nakajima et al, 2010;Hoh et al, 2010;Yamashima and Oikawa, 2009;Itoh et al, 2010;Robertson et al, 2009;Luo et al, 2010;Luo et al, 2011;Liao et al, 2009Ischemia Aoyama et al, 2008Stiefel et al, 2005;Engel et al, 2005;Mendez et al, 2004;Buczek et al, 2002;Oertel et al, 2005 imprecise, and the molecular mechanisms responsible for progression in each case is likely to be different. To avoid ambiguity, here we adopt the term ''hemorrhagic progression of a contusion'' (HPC).…”

Section: Hemorrhagic Progression Of a Contusionmentioning

confidence: 99%

Hemorrhagic Progression of a Contusion after Traumatic Brain Injury: A Review

Kurland

Hong

Aarabi

et al. 2012

Journal of Neurotrauma

294

220

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Кафедра нейрохірургії, Національна медична академія післядипломної освіти імені П.Л. Шупика МОЗ України, Київ, Україна 2 Нейрохірургічне відділення №1, Київська міська клінічна лікарня швидкої медичної допомоги, Київ, Україна Вторинна геморагічна прогресія вогнищ забою головного мозку у пацієнтів при черепно-мозковій травмі Вступ. Вторинні післятравматичні зміни головного мозку (ГМ) часто є визначальними в клінічному перебігу черепно-мозкової травми (ЧМТ). Попередження, виявлення та визначення лікувальної тактики при вторинній геморагічній прогресії забою (ВГПЗ) ГМ актуальні для нейротравматології. Матеріали і методи. Проаналізовані результати лікування потерпілих з ЧМТ, у яких діагностований забій ГМ. Результати. Встановлено, що ВГПЗ виникає у 50% пацієнтів при ЧМТ, як у місцях первинного ушкодження ГМ, так і у віддалених зонах за принципом протиудару протягом 12 год, хоча може виникати і через 3-4 доби після травми. ВГПЗ часто виявляють у пацієнтів з субдуральною гематомою (СДГ). Чим більше вогнище забою, тим більша ймовірність його прогресії та необхідності хірургічної декомпресії. Висновки. ВГПЗ є одним з найважливіших ускладнень після ЧМТ, пов'язана з значним підвищенням ризику клінічного погіршення. Лікувальна тактика залежить від вираженості впливу на навколишні структури та проявів компресійно-дислокаційного синдрому. Ключові слова: тяжка черепно-мозкова травма, забій головного мозку, вторинна геморагічна прогресія вогнищ забою, внутрішньочерепний тиск, ішемічні розлади. Introduction. Secondary posttraumatic changes of the brain often are determining in the clinical flow of traumatic brain injury (TBI). Prevention, detection and determination of treatment strategy at secondary hemorrhagic progression of contusion (SHPC) are very actual for neurotraumatology. Materials and methods. The results of 110 injured persons with TBI were analyzed. Results. It was found that SHPC occurs in 50% patients with TBI, as in areas of primary brain damage as in remote areas on the other side of the brain during 12 h ad also after 3-4 days. SHPC often is revealed in patients with subdural hematoma. The bigger contusion foci, the higher the probability of their progression and the need of surgical decompression. Conclusions. SHPC is one of most important TBI complications associated with considerable risk of clinical deterioration and serious cause of morbidity and lethality. Treatment tactics depends on severity of volumetric effect on surrounding brain structures and manifestations of compression-dislocation syndrome.

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“…Combined injury models have also been developed. For example, substrate deformation models and transection models have been combined with an ischemia=hypoxic or NMDA excitotoxic challenge, and the combination model demonstrated greater necrotic and apoptotic cell death than each injury model alone (Cargill and Thibault, 1996;Allen et al, 1999;Glass et al, 2002;Arundine et al, 2004;Glass et al, 2004;Engel et al, 2005). Rather than developing additional models, the in-vitro break-out group recommended that there be greater commercialization and standardization of existing models, and hands-on training programs to learn how to use them.…”

Section: In-vitro Tbi Modelsmentioning

confidence: 99%

Combination Therapies for Traumatic Brain Injury – Prospective Considerations

Margulies¹,

Hicks²

2009

Journal of Neurotrauma

114

152

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Traumatic brain injury (TBI) initiates a cascade of numerous pathophysiological events that evolve over time. Despite the complexity of TBI, research aimed at therapy development has almost exclusively focused on single therapies, all of which have failed in multicenter clinical trials. Therefore, in February 2008 the National Institute of Neurological Disorders and Stroke, with support from the National Institute of Child Health and Development, the National Heart, Lung, and Blood Institute, and the Department of Veterans Affairs, convened a workshop to discuss the opportunities and challenges of testing combination therapies for TBI. Workshop participants included clinicians and scientists from a variety of disciplines, institutions, and agencies. The objectives of the workshop were to: (1) identify the most promising combinations of therapies for TBI; (2) identify challenges of testing combination therapies in clinical and pre-clinical studies; and (3) propose research methodologies and study designs to overcome these challenges. Several promising combination therapies were discussed, but no one combination was identified as being the most promising. Rather, the general recommendation was to combine agents with complementary targets and effects (e.g., mechanisms and time-points), rather than focusing on a single target with multiple agents. In addition, it was recommended that clinical management guidelines be carefully considered when designing pre-clinical studies for therapeutic development. To overcome the challenges of testing combination therapies it was recommended that statisticians and the U.S. Food and Drug Administration be included in early discussions of experimental design. Furthermore, it was agreed that an efficient and validated screening platform for candidate therapeutics, sensitive and clinically relevant biomarkers and outcome measures, and standardization and data sharing across centers would greatly facilitate the development of successful combination therapies for TBI. Overall there was great enthusiasm for working collaboratively to act on these recommendations.

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Combined effects of mechanical and ischemic injury to cortical cells: Secondary ischemia increases damage and decreases effects of neuroprotective agents

Cited by 30 publications

References 37 publications

PICK1-mediated GluR2 endocytosis contributes to cellular injury after neuronal trauma

PICK1-mediated GluR2 endocytosis contributes to cellular injury after neuronal trauma

Hemorrhagic Progression of a Contusion after Traumatic Brain Injury: A Review

Combination Therapies for Traumatic Brain Injury – Prospective Considerations

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