Early Mitochondrial Dysfunction after Cortical Contusion Injury

Gilmer, Lesley K.; Roberts, Kelly N.; Joy, Kelly; Sullivan, Patrick G.; Scheff, Stephen W.

doi:10.1089/neu.2008.0857

Cited by 86 publications

(56 citation statements)

References 47 publications

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“…Cyclosporin A, a calcineurin inhibitor, has shown good neuroprotective effect in preclinical animal studies of TBI (89)(90)(91), presumably by inhibiting the Ca 2+ -induced mitochondrial membrane permeability transition leading to less mitochondrial swelling and rupture of the outer mitochondrial membrane (92). In a randomized controlled trial treating severe TBI patients with cyclosporin A, monitored with MD, brain energy metabolism improved significantly in the treated group (25).…”

Section: Pharmacokinetics Of Neuroprotective Agentsmentioning

confidence: 99%

Microdialysis Monitoring in Clinical Traumatic Brain Injury and Its Role in Neuroprotective Drug Development

Thelin

Carpenter

Hutchinson

et al. 2017

AAPS J

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Abstract.Injuries to the central nervous system continue to be vast contributors to morbidity and mortality; specifically, traumatic brain injury (TBI) is the most common cause of death during the first four decades of life. Several modalities are used to monitor patients suffering from TBI in order to prevent detrimental secondary injuries. The microdialysis (MD) technique, introduced during the 1990s, presents the treating physician with a robust monitoring tool for brain chemistry in addition to conventional intracranial pressure monitoring. Nevertheless, some limitations remain, such as limited spatial resolution. Moreover, while there have been several attempts to develop new potential pharmacological therapies in TBI, there are currently no available drugs which have shown clinical efficacy that targets the underlying pathophysiology, despite various trials investigating a plethora of pharmaceuticals. Specifically in the brain, MD is able to demonstrate penetration of the drug through the blood-brain barrier into the brain extracellular space at potential site of action. In addition, the downstream effects of drug action can be monitored directly. In the future, clinical MD, together with other monitoring modalities, can identify specific pathological substrates which require tailored treatment strategies for patients suffering from TBI.

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Section: Pharmacokinetics Of Neuroprotective Agentsmentioning

confidence: 99%

Microdialysis Monitoring in Clinical Traumatic Brain Injury and Its Role in Neuroprotective Drug Development

Thelin

Carpenter

Hutchinson

et al. 2017

AAPS J

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“…The majority of the previous animal studies of mitochondrial function in TBI have shown that mitochondrial damage occurs rapidly as early as 1 h postinjury (3,4), with peak mitochondrial respiratory chain dysfunction at 12-24 h (5). However, the effects of TBI on mitochondrial function at later stages of secondary brain damage remain unclear.…”

Section: Tbimentioning

confidence: 99%

Essential Roles of Neutral Ceramidase and Sphingosine in Mitochondrial Dysfunction Due to Traumatic Brain Injury

Novgorodov

Riley

et al. 2014

Journal of Biological Chemistry

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Background: A cardinal feature of many neurological disorders is mitochondrial dysfunction. Results: Knocking down neutral ceramidase reduces mitochondrial sphingosine, preserves mitochondrial function, and improves brain function recovery after trauma. Conclusion: Activation of the sphingosine-generating pathway plays a significant role in promoting mitochondrial injury. Significance: This is the first direct evidence of endogenous sphingosine involvement in regulation of mitochondrial function.

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“…TBI precipitates a complex, secondary pathophysiological process which can result in a cascade of deleterious side effects often far from the site of the initial injury, and which places tissue that survives the initial insult at risk for functional failure, neurodegeneration, apoptosis, and death (Hattori et al, 2003; Marcoux et al, 2008b; Ragan et al, 2013; Xu et al, 2010). A growing body of literature suggests that a main component of this secondary injury cascade is altered mitochondrial bioenergetics and cerebral metabolic crisis (Gilmer et al, 2009; Robertson et al, 2006). Mitochondria play a pivotal role in cerebral metabolism and regulation of oxidative stress, excitotoxicity, and apoptosis (Balan et al, 2013; Gilmer et al, 2009; Lifshitz et al, 2003; Robertson, 2004).…”

Section: Introductionmentioning

confidence: 99%

“…A growing body of literature suggests that a main component of this secondary injury cascade is altered mitochondrial bioenergetics and cerebral metabolic crisis (Gilmer et al, 2009; Robertson et al, 2006). Mitochondria play a pivotal role in cerebral metabolism and regulation of oxidative stress, excitotoxicity, and apoptosis (Balan et al, 2013; Gilmer et al, 2009; Lifshitz et al, 2003; Robertson, 2004). Cerebral metabolic crisis displays regional heterogeneity, varies temporally post-injury and with gradation of injury severity, and is often sustained for a prolonged period of time (Lifshitz et al, 2003; Marcoux et al, 2008b; Ragan et al, 2013; Robertson et al, 2006, 2009; Saito et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial bioenergetic alterations after focal traumatic brain injury in the immature brain

Kilbaugh

Karlsson

Byro

et al. 2015

Experimental Neurology

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Traumatic brain injury (TBI) is one of the leading causes of death in children worldwide. Emerging evidence suggests that alterations in mitochondrial function are critical components of secondary injury cascade initiated by TBI that propogates neurodegeneration and limits neuroregeneration. Unfortunately, there is very little known about the cerebral mitochondrial bioenergetic response from the immature brain triggered by traumatic biomechanical forces. Therefore, the objective of this study was to perform a detailed evaluation of mitochondrial bioenergetics using high-resolution respirometry in a high-fidelity large animal model of focal controlled cortical impact injury (CCI) 24 h post-injury. This novel approach is directed at analyzing dysfunction in electron transport, ADP phosphorylation and leak respiration to provide insight into potential mechanisms and possible interventions for mitochondrial dysfunction in the immature brain in focal TBI by delineating targets within the electron transport system (ETS). Development and application of these methodologies have several advantages, and adds to the interpretation of previously reported techniques, by having the added benefit that any toxins or neurometabolites present in the ex-vivo samples are not removed during the mitochondrial is olation process, and simulates the in situ tricarboxylic acid (TCA) cycle by maximizing key substrates for convergent flow of electrons through both complexes I and II. To investigate alterations in mitochondrial function after CCI, ipsilateral tissue near the focal impact site and tissue from the corresponding contralateral side were examined. Respiration per mg of tissue was also related to citrate synthase activity (CS) and calculated flux control ratios (FCR), as an attempt to control for variability in mitochondrial content. Our biochemical analysis of complex interdependent pathways of electron flow through the electron transport system, by most measures, reveals a bilateral decrease in complex I-driven respiration and an increase in complex II-driven respiration 24 h after focal TBI. These alterations in convergent electron flow though both complex I and II-driven respiration resulted in significantly lower maximal coupled and uncoupled respiration in the ipsilateral tissue compared to the contralateral side, for all measures. Surprisingly, increases in complex II and complex IV activities were most pronounced in the contralateral side of the brain from the focal injury, and where oxidative phosphorylation was increased significantly compared to sham values. We conclude that 24 h after focal TBI in the immature brain, there are significant alterations in cerebral mitochondrial bioenergetics, with pronounced increases in complex II and complex IV respiration in the contralateral hemisphere. These alterations in mitochondrial bioenergetics present multiple targets for therapeutic intervention to limit secondary brain injury and support recovery.

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Early Mitochondrial Dysfunction after Cortical Contusion Injury

Cited by 86 publications

References 47 publications

Microdialysis Monitoring in Clinical Traumatic Brain Injury and Its Role in Neuroprotective Drug Development

Microdialysis Monitoring in Clinical Traumatic Brain Injury and Its Role in Neuroprotective Drug Development

Essential Roles of Neutral Ceramidase and Sphingosine in Mitochondrial Dysfunction Due to Traumatic Brain Injury

Mitochondrial bioenergetic alterations after focal traumatic brain injury in the immature brain

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