Mechanically-induced membrane poration causes axonal beading and localized cytoskeletal damage

Kilinc, Devrim; Gallo, Gianluca; Barbee, Kenneth A.

doi:10.1016/j.expneurol.2008.04.025

Cited by 127 publications

(110 citation statements)

References 54 publications

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“…158,[161][162][163][164] While there is debate of the mechanisms, poration may by a primary mechanical effect or a secondary event triggered by a chemical dissolution of the axolemma. 58,165 In either case, therapies that address membrane fluidity and repair, such as polyethylene glycol and the surfactant, Poloxamer 188, may be beneficial for axons with modest or transient openings of the axolemma or for those that are at risk of a breach of the axolemma.…”

Section: Ion Homeostasismentioning

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

169

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: Ion Homeostasismentioning

confidence: 99%

Section: Protease Inhibitionmentioning

confidence: 99%

Therapy Development for Diffuse Axonal Injury

Smith

Hicks

Povlishock

2013

Journal of Neurotrauma

169

146

View full text Add to dashboard Cite

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“…[2][3][4] Moreover, Pluronic have recently attracted a great deal of attention as excellent membrane sealants with low toxicity. [5][6][7] Of particular interest is poloxamer 188 (Pluronic F68), an approximately 8400 g/mol poloxamer of the form PEO 76 -PPO 29 -PEO 76 that has been proven as a surfactant sealing agent for permeabilized lipid bilayers. 5 When membrane permeability increases dramatically in the case of trauma or infectious diseases, the natural pathway for maintaining the normal permeability of cell membranes can be overwhelmed, rendering it incapable of arresting leakage in these permeabilized membranes.…”

Section: Introductionmentioning

confidence: 99%

Effects of pluronic F68 micellization on the viability of neuronal cells in culture

Samith

Mino

Ramos-Moore

et al. 2013

J of Applied Polymer Sci

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Triblock copolymers with surface-active properties, referred to as Pluronic, have shown potential medical applications such as drug delivery to selective targets in the human body. In particular, the transport of anti-inflammatory substances to the brain is required for illness treatment, thus the study of delivery agents that cross the blood-brain barrier is relevant. In this article we study the effects of the micelle formation on the morphologic and cytotoxic properties of Pluronic F68. We determinate the critical micellar concentration (CMC) by standard tensiometric and absorbance measurements, and also we analyze the morphology of polymers by atomic force microscopy. Our observations indicate that the morphological properties of F68 are drastically modified in the CMC range, as well as the ability to increase the viability of neuroblastoma cells maintained under culture conditions, as compared with nontreated cells. Our conclusions highlight the close correlation between morphological and physiochemical properties of Pluronic, which must be further understood in order to achieve highly controlled pharmacological uses.

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“…microtubules (MTs), which are typically bundled in healthy axons, appear disrupted at the beading sites in injured axons [12] . In addition, mitochondria are accumulated at the swelling sites, in contrast to healthy axons for which mitochondria are homogeneously distributed along the length of the axon [13] .…”

Section: Research Highlightmentioning

confidence: 99%

Dissecting the mechanical behavior of neuronal microcompartments by combining magnetic tweezers and protein micropatterns

Grevesse¹,

Lantoine²,

Delhaye³

et al. 2016

Neurosci Commun

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Alterations of the axonal morphology are key signatures of traumatic brain injury (TBI). Although the pathobiology of axonal injury has been extensively investigated, the vulnerability of the axonal microcompartment over the soma was still misunderstood. We hypothesized that the soma and the axon of neurons display opposite mechanical behaviors, rendering the axon more sensitive to a mechanical stress. To test this hypothesis, we used a microcontact printing method to control the growth of cortical neuron in a bipolar morphology and the viscoelastic properties of soma and axon microcompartments were measured with magnetic tweezers. Creep experiments showed that neuronal microcompartments exhibit distinct mechanical behaviors: the soma is softer and characterized by an elastic-like behavior, while the neurite is stiffer and viscous-like. By altering cytoskeletal filaments with pharmacological agents, we determined the origin of the compartmentalization of mechanical behaviors within cortical neurons. The nucleus determines the elastic and stress stiffening behavior of the soma, while the sliding of neurofilaments determines the viscous-like state of the neurite. In addition, our results revealed that at the contrary of the soma, the neurite can sense its mechanical environment and becomes softer and more viscous on soft surfaces, showing that, as for the mechanical behavior, the mechanosensitivity is localized to the neuronal microcompartments. Our findings shed light on the importance of the regionalization of neuronal properties to their microcompartments in response to a mechanical insult. Future works will need to investigate the relationship between the mechanical differences of neuronal microcompartments and their functions. In this context, we suggest to consider microprinted neuronal networks as an efficient tool for investigating the effect of the propagation of injury forces on the behavior of neuronal circuits.Keywords: Neuron; microcompartment; rheology; diffuse axonal injury; mechanosensitivity To cite this article: Thomas Grevesse, et al. Dissecting the mechanical behavior of neuronal microcompartments by combining magnetic tweezers and protein micropatterns. Neurosci Commun 2015; 1: e1003.

show abstract

Mechanically-induced membrane poration causes axonal beading and localized cytoskeletal damage

Cited by 127 publications

References 54 publications

Therapy Development for Diffuse Axonal Injury

Therapy Development for Diffuse Axonal Injury

Effects of pluronic F68 micellization on the viability of neuronal cells in culture

Dissecting the mechanical behavior of neuronal microcompartments by combining magnetic tweezers and protein micropatterns

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