Prolonged Calpain-mediated Spectrin Breakdown Occurs Regionally Following Experimental Brain Injury in the Rat

Saatman, Kathryn E.; Bozyczko–Coyne, Donna; Marcy, Val R.; Siman, Robert; McIntosh, Tracy K.

doi:10.1097/00005072-199607000-00010

Cited by 220 publications

(177 citation statements)

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“…This occurs together with local mitochondrial and cytoskeletal damage that impairs axonal transport while triggering the axolemma to pinch together and rapidly seal off the distal end of the swelling. [33][34][35][36][37][38][39][40][41][42][43][44][45][46][47][48][49] FIG. 1.…”

Section: Histopathological Identification Of Daimentioning

confidence: 99%

“…Among these, recent studies have suggested that aII-spectrin breakdown products SBDP150 and 145, produced by calpain cleavage, have been linked to acute neuronal necrosis, while SBDP120, produced by caspase 3, has been linked to apoptotic cell death cascades. 41,122,[125][126][127][128][129][130][131] While these aII-spectrin breakdown products have been discussed within the context of neuronal damage, it is important to note that they have been associated with both TAI/DAI and its downstream target deafferentation and synaptic loss. 38,51,[132][133][134] In addition to spectrin breakdown products, other potential markers of axonal injury include various phosphoforms of the neurofilament-H subunit as well as cleaved tau suggesting damage to the axon cytoskeleton.…”

Section: Biomarkersmentioning

confidence: 99%

“…In particular, activated calpain has been well studied with regard to proteolysis of subaxolemmal spectrin, with the resultant breakdown products detected in damaged axons and in the CSF. 38,41,42,133,134,165,168,[170][171][172] Less well known is the role of calpain on ankyrin proteolysis, which may lead to disordered sodium channel arrangement at the nodes of Ranvier, and its altered binding to neurofascin, which may contribute to axolemmal instability. 173 Several in vivo studies have examined various axonal protective strategies targeting calcium-mediated responses by either direct or indirect means.…”

Section: Protease Inhibitionmentioning

confidence: 99%

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Therapy Development for Diffuse Axonal Injury

Smith

Hicks

Povlishock

2013

Journal of Neurotrauma

174

146

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Diffuse axonal injury (DAI) remains a prominent feature of human traumatic brain injury (TBI) and a major player in its subsequent morbidity. The importance of this widespread axonal damage has been confirmed by multiple approaches including routine postmortem neuropathology as well as advanced imaging, which is now capable of detecting the signatures of traumatically induced axonal injury across a spectrum of traumatically brain-injured persons. Despite the increased interest in DAI and its overall implications for brain-injured patients, many questions remain about this component of TBI and its potential therapeutic targeting. To address these deficiencies and to identify future directions needed to fill critical gaps in our understanding of this component of TBI, the National Institute of Neurological Disorders and Stroke hosted a workshop in May 2011. This workshop sought to determine what is known regarding the pathogenesis of DAI in animal models of injury as well as in the human clinical setting. The workshop also addressed new tools to aid in the identification of this axonal injury while also identifying more rational therapeutic targets linked to DAI for continued preclinical investigation and, ultimately, clinical translation. This report encapsulates the oral and written components of this workshop addressing key features regarding the pathobiology of DAI, the biomechanics implicated in its initiating pathology, and those experimental animal modeling considerations that bear relevance to the biomechanical features of human TBI. Parallel considerations of alternate forms of DAI detection including, but not limited to, advanced neuroimaging, electrophysiological, biomarker, and neurobehavioral evaluations are included, together with recommendations for how these technologies can be better used and integrated for a more comprehensive appreciation of the pathobiology of DAI and its overall structural and functional implications. Lastly, the document closes with a thorough review of the targets linked to the pathogenesis of DAI, while also presenting a detailed report of those target-based therapies that have been used, to date, with a consideration of their overall implications for future preclinical discovery and subsequent translation to the clinic. Although all participants realize that various research gaps remained in our understanding and treatment of this complex component of TBI, this workshop refines these issues providing, for the first time, a comprehensive appreciation of what has been done and what critical needs remain unfulfilled.

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Section: Histopathological Identification Of Daimentioning

confidence: 99%

Section: Biomarkersmentioning

confidence: 99%

Section: Protease Inhibitionmentioning

confidence: 99%

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Therapy Development for Diffuse Axonal Injury

Smith

Hicks

Povlishock

2013

Journal of Neurotrauma

174

146

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“…Several studies in cerebral ischemia and trauma have also implicated calcium-induced calpain-mediated proteolysis in the pathogenesis (Bartus et al, 1995;Buki et al, 1999a;Buki et al, 1999b;Hong et al, 1994;Posmantur et al, 1997;Saatman et al, 1996) of injury. The substrates for calpain effects have been shown to include many cytoskeletal proteins, membrane proteins, and various regulatory and signaling proteins.…”

Section: Cell Death Mechanismsmentioning

confidence: 99%

Pathophysiology of Cerebral Ischemia and Brain Trauma: Similarities and Differences

Bramlett

Dietrich

2004

J Cereb Blood Flow Metab

567

358

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Summary: Current knowledge regarding the pathophysiology of cerebral ischemia and brain trauma indicates that similar mechanisms contribute to loss of cellular integrity and tissue destruction. Mechanisms of cell damage include excitotoxicity, oxidative stress, free radical production, apoptosis and inflammation. Genetic and gender factors have also been shown to be important mediators of pathomechanisms present in both injury settings. However, the fact that these injuries arise from different types of primary insults leads to diverse cellular vulnerability patterns as well as a spectrum of injury processes. Blunt head trauma produces shear forces that result in primary membrane damage to neuronal cell bodies, white matter structures and vascular beds as well as secondary injury mechanisms. Severe cerebral ischemic insults lead to metabolic stress, ionic perturbations, and a complex cascade of biochemical and molecular events ultimately causing neuronal death. Similarities in the pathogenesis of these cerebral injuries may indicate that therapeutic strategies protective following ischemia may also be beneficial after trauma. This review summarizes and contrasts injury mechanisms after ischemia and trauma and discusses neuroprotective strategies that target both types of injuries.

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“…Excessive activation of post-synaptic NMDA and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors via glutamate allows massive influx of Ca 2+ into postsynaptic neurons. The abnormal accumulation of cytoplasmic Ca 2+ following an ischemic event ultimately reaches toxic levels to induce irreversible neuronal cell death via caspase-9-dependent apoptosis and necrosis (Kochanek et al, 2015;Saatman et al, 1996).…”

Section: Cellular Metabolismmentioning

confidence: 99%

Fatty acid methyl esters as a potential therapy against cerebral ischemia

Lee

Vasquez

Klein

et al. 2015

OCL

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-Saturated fatty acids have been traditionally thought to be detrimental in circulation. However, we describe the beneficial effects of palmitic and stearic acid methyl esters as it relates to neuroprotection and cerebral vasodilatory properties in global and focal cerebral ischemia. The methyl esterification of fatty acids is not prominent in nature. However, it seems to have biological activity related to neuroprotection/vasodilation. We will discuss the etiology of cerebral ischemia such as stroke and cardiac arrest in terms of current and future treatment modalitiesas it relates to fatty acid-based therapies. This review is based on the meeting presentation at the "The Journées Chevreul, Lipids & Brain III 2015" in Paris on 16-18 March, 2015.Keywords: Cerebral ischemia / cerebral blood flow / neuroprotection / palmitic acid methyl ester / protein arginine methyltransferase Résumé -Les esters méthyliques d'acides gras comme possible thérapie contre l'ischémie cérébrale. Les acides gras saturés ont été de longue date considérés comme délétères pour la circulation sanguine. Cependant, nous décrivons dans cet article les effets bénéfiques d'esters méthyliques d'acides palmitique et stéarique en ce qui concerne la neuroprotection, ainsi que les propriétés de vasodilatation au niveau cérébral face à l'ischémie cérébrale globale et focale. L'estérification méthylique d'acides gras n'est pas très répandue dans la nature. Cependant, elle semble avoir une activité biologique neuroprotectrice/vasodilatatrice. Nous discutons, dans cet article, de l'étiologie de l'ischémie cérébrale de type AVC et arrêt cardiaque, et ce en termes de modalités de traitement, actuels et futurs, en ce qui concerne les thérapies à base d'acide gras. Cette revue est basée sur la présentation faite à l'occasion de la conférence « Les Journées Chevreul, Lipids & Brain III 2015 » qui s'est tenue à Paris les 16-18 Mars 2015.Mots clés : Ischémie cérébrale / circulation sanguine cérébrale / neuroprotection / ester méthylique d'acide palmitique / arginine méthyltransférase

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Prolonged Calpain-mediated Spectrin Breakdown Occurs Regionally Following Experimental Brain Injury in the Rat

Cited by 220 publications

References 0 publications

Therapy Development for Diffuse Axonal Injury

Therapy Development for Diffuse Axonal Injury

Pathophysiology of Cerebral Ischemia and Brain Trauma: Similarities and Differences

Fatty acid methyl esters as a potential therapy against cerebral ischemia

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