Novel Mitochondrial Targets for Neuroprotection

Pérez-Pinzón, Miguel A.; Stetler, R. Anne; Fiskum, Gary

doi:10.1038/jcbfm.2012.32

Cited by 125 publications

(111 citation statements)

References 126 publications

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“…4 Pharmacologic approaches toward minimizing abnormal alterations in mitochondrial dynamics warrant exploration and might exert neuroprotection beyond what has been observed with inhibitors of the mitochondrial permeability transition that help maintain mitochondrial and cellular integrity. 66 Our data suggest that TBI therapeutic interventions might target mitochondria in Far and Penumbral zones to protect and preserve potentially viable cortical tissue. In contrast to Near zone, these zones appear to exhibit high levels of reversibly altered mitochondria within the first few days to 1 week post-injury, depending on the severity (GCS) of the injury.…”

Section: Discussionmentioning

confidence: 99%

Cellular Alterations in Human Traumatic Brain Injury: Changes in Mitochondrial Morphology Reflect Regional Levels of Injury Severity

Balan

Saladino

Aarabi

et al. 2013

Journal of Neurotrauma

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Mitochondrial dysfunction may be central to the pathophysiology of traumatic brain injury (TBI) and often can be recognized cytologically by changes in mitochondrial ultrastructure. This study is the first to broadly characterize and quantify mitochondrial morphologic alterations in surgically resected human TBI tissues from three contiguous cortical injury zones. These zones were designated as injury center (Near), periphery (Far), and Penumbra. Tissues from 22 patients with TBI with varying degrees of damage and time intervals from TBI to surgical tissue collection within the first week post-injury were rapidly fixed in the surgical suite and processed for electron microscopy. A large number of mitochondrial structural patterns were identified and divided into four survival categories: normal, normal reactive, reactive degenerating, and end-stage degenerating profiles. A tissue sample acquired at 38 hours post-injury was selected for detailed mitochondrial quantification, because it best exhibited the wide variation in cellular and mitochondrial changes consistently noted in all the other cases. The distribution of mitochondrial morphologic phenotypes varied significantly between the three injury zones and when compared with control cortical tissue obtained from an epilepsy lobectomy. This study is unique in its comparative quantification of the mitochondrial ultrastructural alterations at progressive distances from the center of injury in surviving TBI patients and in relation to control human cortex. These quantitative observations may be useful in guiding the translation of mitochondrial-based neuroprotective interventions to clinical implementation.

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Section: Discussionmentioning

confidence: 99%

Cellular Alterations in Human Traumatic Brain Injury: Changes in Mitochondrial Morphology Reflect Regional Levels of Injury Severity

Balan

Saladino

Aarabi

et al. 2013

Journal of Neurotrauma

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“…Assessment of phospholipids, monolysophospholipids, and CL oxidation was performed by liquid chromatography-mass spectrometry (LC-MS) utilizing Dionex HPLC system coupled to a LXQTM ion trap MS or to a hybrid quadrupole-orbitrap mass spectrometer, Q-Exactive (ThermoFisher, Inc., San Jose, CA, USA) as described previously. [14][15][16] For additional detailed analysis of CL and monolyso-CL, normal phase column Luna 3 μm Silica (2) 100 Å column (Phenomenex, Torrance, CA, USA) and gradient solvent A (hexane/propanol/water, 47:57:1, v/v) and solvent B (hexane/propanol/ water, 47:57:10, v/v) each containing 5 mmol/L ammonium acetate and 0.01% formic acid was used. The column was eluted at a flow rate of 0.05 mL/min as follows; 0 to 3 minutes, linear gradient,10% to 37% solvent B; 3 to 12.5 minutes, isocratic at 37% solvent B; 12.5 to 20 minutes, linear gradient, 37% to 100% solvent B; 20 to 45 minutes, isocratic at 100% solvent B; 45 to 60 minutes, isocratic at 10% solvent B.…”

Section: Cardiac Arrest Modelmentioning

confidence: 99%

Deciphering of Mitochondrial Cardiolipin Oxidative Signaling in Cerebral Ischemia-Reperfusion

Baart

Vikulina

et al. 2014

J Cereb Blood Flow Metab

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It is believed that biosynthesis of lipid mediators in the central nervous system after cerebral ischemia-reperfusion starts with phospholipid hydrolysis by calcium-dependent phospholipases and is followed by oxygenation of released fatty acids (FAs). Here, we report an alternative pathway whereby cereberal ischemia-reperfusion triggered oxygenation of a mitochondria-specific phospholipid, cardiolipin (CL), is followed by its hydrolysis to yield monolyso-CLs and oxygenated derivatives of fatty (linoleic) acids. We used a model of global cerebral ischemia-reperfusion characterized by 9 minutes of asphyxia leading to asystole followed by cardiopulmonary resuscitation in postnatal day 17 rats. Global ischemia and cardiopulmonary resuscitation resulted in: (1) selective oxidation and hydrolysis of CLs, (2) accumulation of lyso-CLs and oxygenated free FAs, (3) activation of caspase 3/7 in the brain, and (4) motor and cognitive dysfunction. On the basis of these findings, we used a mitochondria targeted nitroxide electron scavenger, which prevented CL oxidation and subsequent hydrolysis, attenuated caspase activation, and improved neurocognitive outcome when administered after cardiac arrest. These data show that calcium-independent CL oxidation and subsequent hydrolysis represent a previously unidentified pathogenic mechanism of brain injury incurred by ischemia-reperfusion and a clinically relevant therapeutic target.

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“…The binding properties of 18 F-BCPP-EF were assessed in an ischemic brain model of living monkey using high-resolution PET, and its cerebral uptake was compared with the regional cerebral blood flow (rCBF), regional cerebral metabolism of oxygen (rCMRO 2 ) measured with 15 O-gases, 11 C-flumazenil ( 11 C-FMZ) binding to the central-type benzodiazepine receptor (CBR), 11 C-PBR28 binding to the translocator protein, and regional cerebral blood flow (rCMRglc) measured with 18 F-FDG at Day-7/8 after 3-hour MCAO ischemic insult in the monkey brain.…”

Section: Introductionmentioning

confidence: 99%

PET Imaging of Ischemia-Induced Impairment of Mitochondrial Complex I Function in Monkey Brain

Tsukada

Ohba

Nishiyama

et al. 2014

J Cereb Blood Flow Metab

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To assess the capability of 18 F-2-tert-butyl-4-chloro-5-{6-[2-(2-fluoroethoxy)-ethoxy]-pyridin-3-ylmethoxy}-2H-pyridazin-3-one ( 18 F-BCPP-EF), a novel positron emission tomography (PET) probe for mitochondrial complex I (MC-I) activity, as a specific marker of ischemia-induced neuronal death without being disturbed by inflammation, translational research was conducted using an animal PET in ischemic brains of Cynomolgus monkeys (Macaca fascicularis). Focal ischemia was induced by the right middle cerebral artery occlusion for 3 hours, then PET scans were conducted at Day-7 with 15 O-gases for regional cerebral blood flow (rCBF) and regional cerebral metabolism of oxygen (rCMRO 2 ), and 18 F-BCPP-EF for MC-I with arterial blood sampling. On Day-8, the additional PET scans conducted with 11 C-flumazenil ( 11 C-FMZ) for central-type benzodiazepine receptors, 11 C-PBR28 for translocator protein, and 18 F-fluoro-2-deoxy-D-glucose ( 18 F-FDG) for regional cerebral metabolic rate of glucose (rCMRglc). The total distribution volume (V T ) values of 18 F-BCPP-EF showed the significant reduction in MC-I activity in the damaged area at Day-7. When correlated with rCBF and rCMRO 2 , the V T values of 18 F-BCPP-EF provided better correlation with rCMRO 2 than with rCBF. In the inflammatory regions (region of interest, ROI PBR ) of the ischemic hemisphere detected with 11 C-PBR28, higher 18 F-FDG uptake and lower V T of 18 F-BCPP-EF, 11 C-FMZ, and rCMRO 2 than those in normal contralateral hemisphere were observed. These results strongly suggested that 18 F-BCPP-EF could discriminate the neuronal damaged areas with neuroinflammation, where 18 F-FDG could not owing to its high uptake into the activated microglia.

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Novel Mitochondrial Targets for Neuroprotection

Cited by 125 publications

References 126 publications

Cellular Alterations in Human Traumatic Brain Injury: Changes in Mitochondrial Morphology Reflect Regional Levels of Injury Severity

Cellular Alterations in Human Traumatic Brain Injury: Changes in Mitochondrial Morphology Reflect Regional Levels of Injury Severity

Deciphering of Mitochondrial Cardiolipin Oxidative Signaling in Cerebral Ischemia-Reperfusion

PET Imaging of Ischemia-Induced Impairment of Mitochondrial Complex I Function in Monkey Brain

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