Zelman vladimir exploring new frontiers of brain preservation and protectionPresentation 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
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
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…..
We still do not know how to prevent delayed (apoptotic) neuronal death secondary to ischemia and stress…. pre- post- delayed Forms of Conditioning
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.
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
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
Not just for the young
Adult neurogenesis is probably functional
Compensates for stroke losses by producing new neurons
May be enhanced with
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.
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.
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
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.
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.
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
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
Modified reperfusion subsequent to a prolonged ischemia episode may also confer ischemic neuroprotection
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
Classical preconditioning: (hours to days)
Requires repeated stimuli
Gene activation and repression
Attenuation of excitotoxicity,
oxidative stress, metabolic dysfunction,
Enhancing endogenous repair processes
Gidday J, Nature Neuroscience, 2006
Activation of Neuronal Preconditioning Pathways
Known stressor mechanisms that activate neuronal preconditioning pathways
Preconditioning confers ischemia tolerance in most organ systems including:
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.
There are a number of nonischemic/nonhypoxic, nonpharmacologic interventions reported to date that trigger robust ischemic tolerance in brain
Transcranial magnetic stimulation
Effectiveness is proven experimentally and applied in practice
Inhalation anesthetics ( isoflurane, sevoflurane, and xenon )
Effectiveness is not proven experimentally, but applied in practice
Transl. Stroke Res. (2010) 1:19-30 Лука Синьорелли. Проклятый верхом на дьяволе покидает Страшный суд
Produced in the mammalian brain by astrocytes in the ischemic penumbra
EPO receptors are up-regulated by neurons in the ischemic penumbra
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
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 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 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.
Understanding the pathophysiology of coma and neurodegenerative diseases
Regenerative and stem-cell therapy
Modulation of cerebral plasticity
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)