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Zelman vladimir exploring new frontiers of brain preservation and protection
 

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  • In 1955 P.D. Bedford published "Adverse cerebral effects of anaesthesia on old people."55 He reviewed 1,193 (presumably non-cardiac) patients over 50 years old who had received general anesthesia .
  • In 1955 P.D. Bedford published "Adverse cerebral effects of anaesthesia on old people."55 He reviewed 1,193 (presumably non-cardiac) patients over 50 years old who had received general anesthesia .
  • Brain architecture is created by the formation of connections between neurons as a result of interactions with one’s environment, and then the pruning of connections that aren’t used. Neural connections in different areas of the brain are responsible for different kinds of activities. For example, the prefrontal cortex and hippocampus house activities related to memory and decision-making (executive function). As you can see from these depictions of neurons, brains subjected to chronic stress have underdeveloped connections in the areas of the brain most critical for success in school, work, and behavior.
  • In 1955 P.D. Bedford published "Adverse cerebral effects of anaesthesia on old people."55 He reviewed 1,193 (presumably non-cardiac) patients over 50 years old who had received general anesthesia .

Zelman vladimir exploring new frontiers of brain preservation and protection Zelman vladimir exploring new frontiers of brain preservation and protection Presentation Transcript

  • Exploring New Frontiers of Brain Preservation and Protection Vladimir Zelman, M.D., Ph.D., Department of Anesthesiology, University of Southern California, Keck School of Medicine Member of Russian Academy of Medical Science
  • Anesthesia Neurosurgery Cardiothoracic Surgery
  • Heart and Brain: From Cooling to Mutual Comfort Novosibirsk -> Moscow -> Los Angeles 50,000 cases Authors: Drs. V. Zelman, Cheung, Guvakov
  • "Primum non nocere"
    • Our goal in healing any disease or deficiency in the human body should be to preserve the individual profile and cognitive function of each patient.
    Leonardo da Vinci: Vitruvian Man
  • Brain Injury after Cardiac Surgery
    • Brain injury (including brain damage, stroke and awareness) represents the single largest fraction (17%) of malpractice claims .
    • The US study found a 6% incidence of major brain injury following myocardial revascularization, whereas the international study, performed on patients at least 60 years of age , noted an alarming 26% incidence of marked cognitive decline postoperatively.
    Giovanni Caracciolo: Saint Onophrius
  • History
    • 1955 P.D. Bedford "Adverse cerebral effects of anaesthesia on old people“
      • “ Postoperative medication should not be a routine matter.”
    • 1998 — the first International Study of Postoperative Cognitive Dysfunction (ISPOCD)
    • The incidence of CD in non-cardiac patients older than 59 was
      • 22% higher than in age-matched control in 1week after surgery
      • 10% at 3 months (identical to Bedford’s findings)
  • Congress of the USA named 1990-2000 as the “Decade of Brain” Stanley van den Noort 1970, Irvine Joseph P. Van Der Meulen 1971 . USC
  • Genomically-Guided Evolutionary Mechanisms of Brain Preservation
    • Vladimir Zelman, MD, PhD, Keck School of Medicine, University of Southern California
    Neuroscience 2010-2020
  • Improved Understanding of What We have Learned
    • Cerebral blood flow and metabolism (50 years)
    • Autoregulation and cerebral hemodynamics
    • Molecular biology: normal and pathologic brain (25 years)
    • Gene expression from human genome project (since 2000)
      • Thousands of newly discovered genes
      • Over 80% related to expression in nervous system
    • However, brain protection mechanisms have not significantly advanced over the last 50 years…..
  • Excitatory Neurotoxicity and Cerebral Ischemia Ischemic Injury ↓ Presynaptic Neuronal Depolarization ↓ Neurotransmitter Release (ie glutamate, aspartate) ↓ Postsynaptic Neuronal Depolarization ↓ Calcium Influx ↓ Early gene activation ↓ Proteolysis, apoptosis, cell death
  • We still do not know how to prevent delayed (apoptotic) neuronal death secondary to ischemia and stress…. pre- post- delayed Forms of Conditioning
  • Apoptosis
    • Apoptosis appears to be the default program of many excitable cell types, with cell-typical activity promoting proteins like anti-apoptotic Bcl-2’s that prevent the default program from running its course.
  • Postischemic Repair
    • Ischemia causes surrounding brain tissue to release a cascade of chemicals and gene-dependent responses to trigger repair mechanisms and neurogenesis
    • Neurons that are distant from the ischemic areas are signaled to induce repair and neurogenesis
  •  
  • Brain Development
    • The neocortex makes 700 synapses per second during the last trimester and first 18 months after birth (overproduction).
    • The brain averages 17,000 apoptotic neuronal deaths per second during the last 11 weeks of gestation
      • Therefore half of the 200 billion neurons made by the fetus die
      • This death results primarily from a lack of synaptic activity
    • Apoptosis is highly selective
      • Leaves the core material and sculpts the primary architecture for subsequent development
    • Apoptosis is a normal part of development
    • Synaptic activity may be as crucial to the survival of late term neurons as are O 2 , ATP and CBF
  • The Neonatal Brain Possesses the…
    • Intrinsic ability to tolerate hypoxia/ischemia
    • Tolerance due to hypoxic uterine environment
    • Propensity for apoptosis in developing brain
    • Many protective mechanisms in effect:
      • Lower rates of resting glucose metabolism
      • Lower densities of NMDA channels, resulting in reduced excitotoxicity
      • Diminished ATP homeostasis
  • Neurogenesis
    • Not just for the young
    • Adult neurogenesis is probably functional
    • Compensates for stroke losses by producing new neurons
    • May be enhanced with
    • growth factors
    The Phoenix
  • Building Healthy Brain Architecture – The Ingredients
    • Our genes, and ultimately our developing brain architecture, are influenced powerfully by positive early experiences—and negative ones, too.
    • Genes provide the hardware, but early experience is the software that drives the system.
  • The Future
    • Create a DNA atlas of when and where genes are expressed during key periods of development.
    • Document which genes are turned on and off in different regions of the brain during development and stress situations
    • “ This will lead to new breakthroughs in determining disease risk and prevention….provide investigators with a fantastically rich resource for future research.”
    • (P. Levitt and J.A. Knowles, MD, at Zilkha Neurogenetics Institute, University of Southern California)
  • New Discoveries - 2010
    • Last year (2010) was remarkable with fundamental discoveries in neuroscience. The researchers were able to describe different biochemical reactions in CNS, and other important factors.
    • Scientists from the University of California Davis managed to shoot the video formation of synapses.
    • In addition to visualizing the formation of synapses, the resulting recording has demonstrated a key role in the process of the protein neuroligin, as studies have shown that its synthesis is disrupted for some psychiatric disorders such as autism.
    http://medportal.ru/mednovosti/main/2010/01/10/brainwork/
  • Plasticity
    • Neuronal plasticity is enhanced in the developing brain and it is unusually adaptive and beneficial but also can be maladaptive and responsible for neurological disorders in some situations.
    • Plasticity includes programmed cell death, activity-dependent synaptic plasticity, neurogenesis, and neovascularization (improves delivery of O 2 and growth factors).
  • Toxic Stress Changes Brain Architecture Normal Toxic stress Prefrontal Cortex and Hippocampus Typical neuron— many connections Damaged neuron— fewer connections Sources: Radley et al. (2004); Bock et al. (2005)
  • Background
    • Over the past 3 decades we have seen the failure of multiple clinical trials of exogenously administered drugs as potential stroke neuroprotectants
    • Suppressing neuronal activity stimulates apoptosis mechanisms and retards plasticity, tolerance and preconditioning
  • Neuroprotective Drug Trials in Patients
    • Calcium Channel Blockers
      • Nimodipine
      • Flunarizine
    • Calcium Chelator
      • DP-b99
    • Free Radical Scavengers/Antioxidants
      • Ebselen
      • Tirilazad
    • GABA Agonists
      • Clomethiazole
    • AMPA Antagonists
      • GYKI 52466
      • NBQX
      • YM90K
      • YM872
      • ZK-200775 (MPQX)
    • Kainate Antagonists
    • SYM 2081
    • NMDA Antagonists
      • CGS 19755 (selfotel)
      • Aptiganel (Cerestat)
      • CP-101,606
      • Dextrorphan
      • Dextromethorphan
      • Magnesium
      • Memantine
      • MK-801
      • NPS 1506
      • Remacemide
    • Glycine Site NMDA Antagonists
      • ACEA 1021
      • GV150526
    • Polyamine Site Antagonists
      • Eliprodil
      • Ifenprodil
    • Growth Factors
      • FGF
    • Leukocyte Adhesion Inhibitors
      • Anti-ICAM Ab (Enlimomab)
      • Hu23F2G
    • NO Inhibitor
      • Lubeluzole
    • Opioid Antagonists
      • Naloxone
      • Nalmefene
    • Phosphatidylcholine Precursor
      • Citicoline
    • Serotonin Agonist
      • Bay x3072
    • Sodium Channel Blockers
      • Fosphenytoin
      • Lubeluzole
      • 619C89
    • Potassium Channel Opener
      • BMS-204352
    • Unknown Mechanism
      • Piracetam
      • Lubeluzole
    http://strokecenter.org/trials/dirs/int-categories.htm (Is Neuroprotection Dead? 2007)
  • Current Practice vs. Evolution
    • We are acting contrary to evolutionary mechanisms of brain preservation and protection
    • As a result, there has been a drive to identify endogenously modulated mechanisms activated after cerebral stress and ischemia that can be harnessed as neuroprotectants
  • Endogenous Neuroprotection
    • Tissue damage and functional impairment after cerebral ischemia result from the interaction of endogenous neuroprotective mechanisms with the events that ultimately lead to cell death. Screening approaches in focal cerebral ischemia reveal the upregulation as well as downregulation of hundreds of genes associated with either survival or cell death.
  • Endogenous Neuroprotection
    • Because neuroprotection is not as readily apparent as cell death, ischemia research has emphasized cytotoxic mechanisms. In this context, the ischemic preconditioning or ischemic tolerance (IP/IT) paradigm gives the rare opportunity to study neuroprotection that is not “masked” behind tissue damage and potentially presents a “fast track” to human neuroprotection.
  • Endogenous Neuroprotection
    • Some common key mechanisms of differing relevance in the various species, have been identified:
    • suppression or arrest of metabolism,
    • regulation of key glycolytic enzymes,
    • reduction in the conductance of ion channels (ion-flux arrest),
    • suppression of neural activity,
    • expression of chaperones,
    • adaptations in blood rheology and
    • expression and accumulation of antioxidants.
  • The Brain and Tolerance
    • Ischemic tolerance is an evolutionarily and genetically conserved form of cerebral plasticity and preconditioning
    • Genetic alterations caused by preconditioning lead to a cerebroprotective phenotype
    • Similar examples:
      • Hibernation
      • Endotoxin exposure
      • Hypothermia
  • Definitions
    • Ischemic tolerance/preconditioning
      • Acute and/or chronic reaction to a potentially noxious stimulus
      • Specifically, a noninjurious episode of ischemia is able to protect the brain from a subsequent longer ischemic insult
    • Post-conditioning
      • Modified reperfusion subsequent to a prolonged ischemia episode may also confer ischemic neuroprotection
  • Preconditioning
    • First described by Murray in 1986
      • Ability of the heart to ‘condition’ itself to tolerate the effect of acute ischemia-reperfusion injury
    • They noted myocardial infarction can be reduced 75%
      • 40min of ischemic time vs. four-5min occlusions of coronary artery were interspersed with 5min reperfusion just prior
  • Ischemic Tolerance and Cerebral Preconditioning
    • Preconditioning elicits various adaptive responses and programs to ischemic stimuli:
      • Rapid preconditioning: (minutes)
        • Ion channel permeability
        • Protein phosphorylation
      • Classical preconditioning: (hours to days)
        • Requires repeated stimuli
        • Gene activation and repression
        • Attenuation of excitotoxicity,
        • oxidative stress, metabolic dysfunction,
        • and apoptosis
        • Enhancing endogenous repair processes
    Gidday J, Nature Neuroscience, 2006
  • Activation of Neuronal Preconditioning Pathways
    • Known stressor mechanisms that activate neuronal preconditioning pathways
      • Hypoxia/ischemia
      • Hypoglycemia
      • Hyperthermia
      • Glutamate
      • Volatile anesthetics
    • Preconditioning confers ischemia tolerance in most organ systems including:
        • Brain
        • Heart
        • Liver
        • Kidney
        • Intestinal
  • Types of Preconditioning
    • Cross: Preconditioning stimulus is different from the noxious stimulus against which it protects
    • Remote: Precondtioning of one organ or system leads to protection of a different system organ
    • Immunological: Pharmacological compounds that trigger the signaling cascades of preconditioning without a physical stimulus
    • Anesthetic: Short application of any one of many different classes of anesthetics can induce an ischemia-protected state
    • Mimetics: Compounds that emulate the main danger signal can lead to preconditioning
    • Effectors: The downstream mediators of protection.
  • Preconditioning Factors
    • There are a number of nonischemic/nonhypoxic, nonpharmacologic interventions reported to date that trigger robust ischemic tolerance in brain
      • Exercise
      • Caloric restriction
      • Hyperbaric oxygen
      • Transcranial magnetic stimulation
      • Acupuncture
      • And others…
  • Pharmacologic Preconditioning
    • Effectiveness is proven experimentally and applied in practice
      • Inhalation anesthetics ( isoflurane, sevoflurane, and xenon )
      • Melatonin
      • Lithium
      • Magnesium sulfate
      • Lidocaine
    • Effectiveness is not proven experimentally, but applied in practice
      • Erythropoietin
      • Antibiotics
      • Opioids
      • Statins
      • Aspirin
      • Dexmedetomidin
    Transl. Stroke Res. (2010) 1:19-30 Лука Синьорелли. Проклятый верхом на дьяволе покидает Страшный суд
  • Erythropoietin
    • Produced in the mammalian brain by astrocytes in the ischemic penumbra
    • EPO receptors are up-regulated by neurons in the ischemic penumbra
    • Stimulates repair proteins, decreases neuronal excitotoxicity, reduces inflammation, inhibits neuronal apoptosis
    • Stimulates neurogenesis and angiogenesis after cerebral injury
    Agostino Carracci: Whispering Angel
  • Neuroprotective Role of EPO
    • EPO production and RBC production increases oxygen delivery to tissues including brain
    • EPO effect on endothelium can modify production of factors regulating blood flow, endothelial cell survival, endothelial progenitor cell mobilization and angiogenesis and factor secretion affecting neurogenesis
  • Neurovascular Unit
  • Heart and Brain
    • In a study of more than 1,500 men and women ages 34-84, with magnetic-resonance imaging scans, the brains of volunteers with lowest cardiac index appear 2 years older than those with normal cardiac index.
    • That means that even small reductions in blood flow to the brain may speed aging and potentially compromise cognitive function.
  • The Older Brain
    • Less resilience to neurological challenges. We have acquired genetic mutations that can alter outcomes. Genetic alleles that were silent when we were young manifest themselves (have phenotypic effects) as we age. And then there is free radical build-up with reduced levels of scavengers like vitamin C, melatonin, and vitamin E.
  • Melatonin
    • Melatonin is an endogenous substance whose enhancement may reduce the damage in the most vulnerable brain regions
    • May reduce the deleterious effect of anesthesia and acts as a neuroprotector by decreasing the anesthesia-induced activation of caspase-3
    • Causes up-regulation of anti-apoptotic protein bcl-X L
    Cheng y et al, 2006. PMID 16412260 The Birth of Venus – Sandro Botticelli
  • Erythromycin
    • Erythromycin has a significant affect on gene expression associated with brain ischemia.
    • Erythromycin, unlike classic preconditioning, does not induce protective genes but diminished the expression of genes, which may induce secondary damage.
    Koerner IP, Gatting M: Anesthesiology 2007;106:538-547
  • Future Horizons and Clinical Implications
    • Improved neuroprotection:
      • During surgery
      • (i.e. neurosurgery, cardiac surgery)
      • Transplant surgery
      • Stroke
      • Head Trauma
    • Understanding the pathophysiology of coma and neurodegenerative diseases
    • Regenerative and stem-cell therapy
    • Modulation of cerebral plasticity
  • Individualized Preconditioning
    • As the field of pharmacogenomic evolves, it will be exciting to define and implement individualized preconditioning treatments based on personal genetic profiles.
  • PMC PMC H. Damasio
  • Brain Protection - Epilogue
    • Ability to protect the brain is limited
    • Our ability to exacerbate ischemic injury is limitless
    • Focus should be on the prevention of ischemic injury or on the minimization of further insults to the injured brain.
    • Emphasis should be on maintenance of physiologic homeostasis
    • Focus on activation of evolutionary preserved mechanism
    Anesthesia is an art, lightly embroidered with science
  • Brain Preservation UNIVERSAL CHANNEL BLOCKERS RECEPTOR SPECIFIC PHARMACOLOGY STEM CELLS HUMAN GENOME DISCOVERIES GENETIC ENGINEERING CEREBRAL PLASTICITY NEURONAL PRECONDITIONING NEW HORIZONS NANOTECHNOLOGY
  • Carl Kesselman – Director of biomedical informatics research network Larry Swanson – Director of national brain connectome initiative Carlos Pato and Michelle Pato – Directors of National Psychosis Genomics Initiative Leaders of Neuroscience Research at USC Michael Jakowec Center for Vision Science and Technology Institute for Robotics and Intelligent Systems Brain and Creativity Institute Center for Neural Engineering Alfred E. Mann Institute for Biomedical Engineering Center for Excellence in Genomic Studies (CEGS) Laboratory for Molecular Robots Nanotechnology Research Lab Institute for Genetic Medicine Pat Levitt, Director, Zilkha Neurogenetic Institute and co-director of the National Developing Human Brain Transcriptomics initiative Dorne Cognitive Neuroscience Imaging Center USC is emerging as a leader in this respect because of the unique, multi-disciplinary approach to science. Key to advancing this research agenda is leadership. The very best scientists and leaders can bring together others and motivate them to work in highly collaborative ways to solve mysteries of brain diseases in ways that others cannot in their isolated laboratories. James Knowles- Director of the National Developing Human Brain Transcriptomics initiative
  • Micro-Philosophy in Micro-Time
    • Feynman ’ s Micro Cosmos
    • Two minutes=120 seconds=120 quadrillon femto-seconds
    • One femto-seconds(10-15)=construction or destruction of a molecule (Ahmet Zewail)
    • Sixty quadrillon femto-seconds = conceiving of an idea
    • Being in Time
    • Present of the past = our memory
    • Present of the present = our vision-opinion
    • Present of the future = our hope
    • Past of the present = our performance
    • Past of the future = our will
    • Past of the past = our “ individual brain ”
    • Future of the present = our consciousness
    • Future of the past = our conscience
    • Future of the future = our “ cultural brain ”
    The Next Future = http://www.CCGCC.edu ( C omputer C onnected G lobal C erebral C ommunity)