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Fiskum, Gary
1. MITOCHONDRIAL MECHANISMS OF BRAIN INJURY AND TARGETS FOR NEUROPROTECTION Gary Fiskum University of Maryland School of Medicine Department of Anesthesiology and the Center for Shock, Trauma, and Anesthesiology Research (STAR)
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5. Elevated Intracellular Ca 2+ Impaired Oxidative Phosphorylation Generation of Reactive Oxygen Species Release of Mitochondrial Apoptogens Mitochondrial Ca 2+ Overload Trauma / Ischemia / Seizures Necrosis Apoptosis Abnormal Signal Transduction Inflammation Inflammation
9. REDOX REGULATION OF THE PTP E T C PTP NADH NAD + O 2 H 2 O O 2 - O 2 SH (closed) S-SR (open) H 2 O 2 X X + - ONOO - NO . ATP ADP + P i OH . Fe 2+ H 2 O GPX GSH GSSG TH NADPH NADP NADH + NADP NAD + NADPH + - SOD GR U Malic Enzyme, Isocitrate DH, Glutamate DH Ca 2+ Ca 2+ CyD CsA Trx-SH Trx-S-S NADPH NADP TrxR
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11. Nrf2-MEDIATED GENOMIC POST-CONDITIONING AGAINST BRAIN INJURY Enhancing expression of Nrf2-driven genes protects the blood brain barrier after brain injury. Zhao et al., J Neurosci. 2007 27:10240-8. Role of the Nrf2-ARE pathway in early brain injury after experimental subarachnoid hemorrhage. Chen et al., J Neurosci Res. 2011 89:515-23 The role of Nrf2 signaling in the regulation of antioxidants and detoxifying enzymes after traumatic brain injury in rats and mice. Hong et al., Acta Pharmacol Sin. 2010 31:1421-30. Sulforaphane improves cognitive function administered following traumatic brain injury. Dash et al., Neurosci Lett. 2009 460:103-7.
12. HYPOTHESIS Sulforaphane post-treatment protects against short-term neuronal death and neurologic impairment in a clinically translational, canine cardiac arrest and resuscitation model.
18. ACETYL-L-CARNITINE Present at high mid-micromolar concentrations in tissue and at low micromolar concentrations in serum. Can enter mitochondria through carnitine translocase and react with CoA to form acetyl-CoA plus free carnitine.
22. HYPOTHESIS ALCAR post-treatment protects against cell death and neurologic impairment in a rat model of pediatric brain injury.
23. ALCAR IMPROVES BEAM WALKING AND NOVEL OBJECT RECOGNITION AT 3-7 DAYS AFTER CCI IN PND 21 RATS Scafidi et al., Develop Neurosci, 2010 ALCAR 100 mg/kg ip at 1, 4, 12, and 24 hr after injury
24. ALCAR REDUCES LESION VOLUME AT 7 DAYS AFTER CCI IN PND 21 RATS Scafidi et al., Develop Neurosci, 2010
25. ALCAR ACETATE IS METABOLISED BY PND 21 RAT BRAIN TO OXIDATIVE ENERGY METABOLITES AND GABA Scafidi et al., J Neurochem, 2010 2- 13 C ALCAR ip at 100 mg/kg then NMR of frozen brain extracts at 15, 60, and 120 min
26. ALCAR, MITOCHONDRIAL BIOGENESIS AND Nrf2 Acetyl-L-carnitine feeding to unloaded rats triggers in soleus muscle the coordinated expression of genes involved in mitochondrial biogenesis. Cassano et al., Biochim Biophys Acta. 2006 1757:1421-8. Combined R-alpha-lipoic acid and acetyl-L-carnitine exerts efficient preventative effects in a cellular model of Parkinson's disease. Zhang et al., J Cell Mol Med. 2010 14:215-25. Acetyl-L-carnitine-mediated neuroprotection during hypoxia is attributed to ERK1/2-Nrf2-regulated mitochondrial biosynthesis Hota et al., Hippocampus. 2011 epub May 3. .
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28. Circulation 2010;122;S768-S786 Kronick Silvers, Arno L. Zaritsky, Raina Merchant, Terry L. Vanden Hoek and Steven L. Geocadin, Janice L. Zimmerman, Michael Donnino, Andrea Gabrielli, Scott M. Mary Ann Peberdy, Clifton W. Callaway, Robert W. Neumar, Romergryko G. for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Part 9: PostCardiac Arrest Care: 2010 American Heart Association Guidelines Animal data suggests that ventilations with 100% oxygen (generating PaO2 >350 mm Hg at 15 to 60 minutes after ROSC) increase brain lipid peroxidation, increase metabolic dysfunctions, increase neurological degeneration, and worsen short-term functional outcome when compared with ventilation with room air or an inspired oxygen fraction titrated to a pulse oximeter reading between 94% and 96%. 82–87 Provided appropriate equipment is available, once ROSC is achieved, adjust the FIO2 to the minimum concentration needed to achieve arterial oxyhemoglobin saturation >94%, with the goal of avoiding hyperoxia while ensuring adequate oxygen delivery.
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30. HYPOTHESIS In vitro experiments help elucidate mechanisms by which oxidative stress and other factors impair or improve mitochondrial bioenergetics.
31. 50 75 100 125 150 0 20 40 60 80 120 140 100 O 2 consumption (% baseline) Time (min) 175 100 Glu + DETA-NO Control DETA-NO (200 M) Glutamate (100 M) NITRIC OXIDE AND GLUTAMATE SYNERGISTICALLY IMPAIR NEURONAL RESPIRATION pyruvate DETA-NO ± Glut FCCP MK801/ CNQX
32. -50 -25 0 25 50 0 20 40 60 80 120 140 100 O 2 consumption (% baseline) Time (min) 75 100 PEROXYNITRITE DECOMPOSITION CATALYST FeTMPyP PROTECTS AGAINST RESPIRATORY INHIBITION control glutamate control or glu FCCP pyruvate MK801+ CNQX+Nif control glutamate control or glu or glu+NO FCCP pyruvate MK801+ CNQX+Nif glutamate + DETA-NO control glutamate control or glu or glu+NO FCCP pyruvate MK801+ CNQX+Nif glutamate + DETA-NO glutamate + DETA-NO + FeTM-PyP
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Notas do Editor
The “intrinsic” pathway toward apoptosis involves release of mitochondrial proteins, e.g., cytochrome c, that activates a caspase protease cascade, or apoptosis initiating factor (AIF) that causes caspase independent apoptosis. The “extrinsic” pathway is dependent on cell death receptor activation, e.g., Fas and TNFalpha, that activate caspase dependent apoptosis without necessarily involving mitochondria. In vivo, cells within damaged tissue often display evidence for both necrotic and apoptotic cell death. Apoptosis can be initiated by a number of agents or conditions, e.g., elevated intracellular calcium, reactive oxygen species (ROS), ceramide (from lipid metabolism), and cell death ligands, often released in response to inflammatory cytokines. Once released, cytochrome c forms an ATP-dependent complex between apoptosis activating factor-1 (Apaf-1) and caspase 9, resulting in caspase 9 enzyme activation. Caspase 9 proteolytically activates caspase 3, which then acts on many proteins to carry out the terminal steps of apoptosis, including chromatin condensation, DNA fragmentation and apoptotic vesicle formation. Cytochrome c is released from the intermembrane space through megapores formed by oligomerization of Bax (or Bak). “BH3 only” proteins, e.g., truncated Bid (tBid) compete with binding of Bax to anti-apoptotic proteins, e.g., Bcl-2 and Bcl-xl, thus releasing Bax, which then oligomerizes.
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