Exploring New Frontiers of Exploring New Frontiers of Brain Preservation and Brain Preservation and

ProtectionProtection

Vladimir Zelman, M.D., Ph.D.,Vladimir Zelman, M.D., Ph.D.,

Department of Anesthesiology, University of Department of Anesthesiology, University of Southern California, Keck School of MedicineSouthern California, Keck School of Medicine

Member of Russian Academy of Medical Member of Russian Academy of Medical ScienceScience

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Heart and Brain:Heart and Brain:From Cooling to Mutual From Cooling to Mutual

ComfortComfortNovosibirsk -> Moscow -> Los AngelesNovosibirsk -> Moscow -> Los Angeles

50,000 cases50,000 cases

Authors:Authors:Drs. V. Zelman, Cheung, GuvakovDrs. V. Zelman, Cheung, Guvakov

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"Primum non nocere" "Primum non nocere"

Our goal in healing Our goal in healing any disease or any disease or deficiency in the deficiency in the human body should human body should be to preserve the be to preserve the individual profile and individual profile and cognitive function of cognitive function of each patient.each patient.

Leonardo da Vinci: Vitruvian Man

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Brain Injury after Cardiac Brain Injury after Cardiac SurgerySurgery

Brain injury (including brain Brain injury (including brain damage, stroke and awareness) damage, stroke and awareness) represents the single largest represents the single largest fraction fraction (17%) of malpractice (17%) of malpractice claimsclaims..

The US study found a The US study found a 6% incidence6% incidence of major brain injury following of major brain injury following myocardial revascularization, myocardial revascularization, whereas the international study, whereas the international study, performed on patients at least performed on patients at least 60 60 years of ageyears of age, noted an alarming , noted an alarming 26% incidence26% incidence of marked cognitive of marked cognitive decline postoperatively.decline postoperatively.

Giovanni Caracciolo: Saint Onophrius

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HistoryHistory

1955 P.D. Bedford "Adverse cerebral effects of

anaesthesia on old people“– ““Postoperative medication should not be a Postoperative medication should not be a

routine matter.”routine matter.” 1998 — the first International Study of 1998 — the first International Study of

Postoperative Cognitive Dysfunction (ISPOCD)Postoperative Cognitive Dysfunction (ISPOCD) The incidence of CD in non-cardiac patients The incidence of CD in non-cardiac patients

older than 59 wasolder than 59 was– 22% higher than in age-matched control in 1week 22% higher than in age-matched control in 1week

after surgeryafter surgery– 10% at 3 months (identical to Bedford’s findings)10% at 3 months (identical to Bedford’s findings)

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Congress of the USA named Congress of the USA named 1990-2000 as the 1990-2000 as the “Decade of Brain” “Decade of Brain”

Stanley van den Noort 1970, Irvine

Joseph P. Van Der Meulen 1971. USC

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Genomically-Guided Evolutionary Genomically-Guided Evolutionary Mechanisms of Brain PreservationMechanisms of Brain PreservationVladimir Zelman, MD, PhD, Keck School of Medicine, University of Southern California

NeuroscienceNeuroscience 2010-2020 2010-2020

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Improved Understanding of Improved Understanding of What We have LearnedWhat 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…..

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Excitatory Neurotoxicity and Excitatory Neurotoxicity and Cerebral IschemiaCerebral Ischemia

Ischemic Injury↓

Presynaptic Neuronal Depolarization

↓Neurotransmitter Release(ie glutamate, aspartate)

↓Postsynaptic Neuronal

Depolarization ↓

Calcium Influx ↓

Early gene activation↓

Proteolysis, apoptosis, cell death

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We still do not know how to prevent We still do not know how to prevent delayed (apoptotic) neuronal death delayed (apoptotic) neuronal death secondary to ischemia and stress….secondary to ischemia and stress….

pre-

post-delayed

Forms of Conditioning

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ApoptosisApoptosis

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.

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Postischemic RepairPostischemic 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

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Brain DevelopmentBrain 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 O2, ATP and CBF

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The Neonatal Brain Possesses the…The Neonatal Brain Possesses the…

Intrinsic ability to tolerate Intrinsic ability to tolerate hypoxia/ischemiahypoxia/ischemia

Tolerance due to hypoxic uterine Tolerance due to hypoxic uterine environmentenvironment

Propensity for apoptosis in Propensity for apoptosis in developing braindeveloping brain

Many protective mechanisms in Many protective mechanisms in effect:effect:– Lower rates of resting glucose Lower rates of resting glucose

metabolismmetabolism– Lower densities of NMDA Lower densities of NMDA

channels, resulting in reduced channels, resulting in reduced excitotoxicityexcitotoxicity

– Diminished ATP homeostasisDiminished ATP homeostasis

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NeurogenesisNeurogenesis

Not just for the youngNot just for the young Adult neurogenesis is Adult neurogenesis is

probably functionalprobably functional Compensates for stroke Compensates for stroke

losses by producing new losses by producing new neuronsneurons

May be enhanced withMay be enhanced with

growth factorsgrowth factorsThe Phoenix

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Building Healthy Brain Building Healthy Brain Architecture – The IngredientsArchitecture – The Ingredients

Our genes, and ultimately our Our genes, and ultimately our

developing brain architecture, developing brain architecture,

are influenced powerfully by are influenced powerfully by

positive early experiences—positive early experiences—

and negative ones, too.and negative ones, too.

Genes provide the hardware, Genes provide the hardware,

but early experience is the but early experience is the

software that drives the software that drives the

system. system.

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The FutureThe Future Create a DNA atlas of when and Create a DNA atlas of when and

where genes are expressed during where genes are expressed during key periods of development.key periods of development.

Document which genes are turned Document which genes are turned on and off in different regions of on and off in different regions of the brain during development and the brain during development and stress situationsstress situations

““This will lead to new This will lead to new breakthroughs in determining breakthroughs in determining disease risk and disease risk and prevention….provide investigators prevention….provide investigators with a fantastically rich resource with a fantastically rich resource for future research.” for future research.”

(P. Levitt and J.A. Knowles, MD, at Zilkha Neurogenetics Institute, University of Southern California)

Skolkovo 2011 20http://medportal.ru/mednovosti/main/2010/01/10/brainwork/

New Discoveries - 2010New Discoveries - 2010Last 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.

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PlasticityPlasticity Neuronal plasticity is enhanced in Neuronal plasticity is enhanced in

the developing brain and it is the developing brain and it is unusually adaptive and beneficial unusually adaptive and beneficial but also can be maladaptive and but also can be maladaptive and responsible for neurological responsible for neurological disorders in some situations.disorders in some situations.

Plasticity includes programmed Plasticity includes programmed cell death, activity-dependent cell death, activity-dependent synaptic plasticity, neurogenesis, synaptic plasticity, neurogenesis, and neovascularization (improves and neovascularization (improves delivery of Odelivery of O22 and growth factors). and growth factors).

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Toxic Stress Changes Brain Toxic Stress Changes Brain ArchitectureArchitecture

NormalNormal

Toxic Toxic stressstress

Prefrontal Cortex Prefrontal Cortex andand

HippocampusHippocampus

Typical neuron— many connections

Damaged neuron— fewer connections

Sources: Radley et al. (2004); Sources: Radley et al. (2004); Bock et al. (2005)

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BackgroundBackground

Over the past 3 decades we Over the past 3 decades we have seen the failure of multiple have seen the failure of multiple clinical trials of exogenously clinical trials of exogenously administered drugs as potential administered drugs as potential stroke neuroprotectantsstroke neuroprotectants

Suppressing neuronal activity Suppressing neuronal activity stimulates apoptosis stimulates apoptosis mechanisms and retards mechanisms and retards plasticity, tolerance and plasticity, tolerance and preconditioningpreconditioning

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Neuroprotective Drug Trials in PatientsNeuroprotective Drug Trials in PatientsCalcium 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)

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Current Practice vs. Current Practice vs. EvolutionEvolution

We are acting contrary to We are acting contrary to evolutionary mechanisms of evolutionary mechanisms of brain preservation and brain preservation and protectionprotection

As a result, there has been a As a result, there has been a drive to identify endogenously drive to identify endogenously modulated mechanisms modulated mechanisms activated after cerebral stress activated after cerebral stress and ischemia that can be and ischemia that can be harnessed as neuroprotectantsharnessed as neuroprotectants

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Endogenous Endogenous NeuroprotectionNeuroprotection

Tissue damage and functional Tissue damage and functional impairment after cerebral impairment after cerebral ischemia result from the ischemia result from the interaction of endogenous interaction of endogenous neuroprotective mechanisms neuroprotective mechanisms with the events that with the events that ultimately lead to cell death. ultimately lead to cell death. Screening approaches in focal Screening approaches in focal cerebral ischemia reveal the cerebral ischemia reveal the upregulation as well as upregulation as well as downregulation of hundreds downregulation of hundreds of genes associated with of genes associated with either survival or cell death.either survival or cell death.

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Endogenous Endogenous NeuroprotectionNeuroprotection

Because neuroprotection is not Because neuroprotection is not as readily apparent as cell as readily apparent as cell death, ischemia research has death, ischemia research has emphasized cytotoxic emphasized cytotoxic mechanisms. In this context, mechanisms. In this context, the ischemic preconditioning or the ischemic preconditioning or ischemic tolerance (IP/IT) ischemic tolerance (IP/IT) paradigm gives the rare paradigm gives the rare opportunity to study opportunity to study neuroprotection that is not neuroprotection that is not “masked” behind tissue “masked” behind tissue damage and potentially damage and potentially presents a “fast track” to presents a “fast track” to human neuroprotection.human neuroprotection.

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Endogenous Endogenous NeuroprotectionNeuroprotection

Some common key mechanisms of Some common key mechanisms of differing relevance in the various differing relevance in the various species, have been identified: species, have been identified:

1.1. suppression or arrest of metabolism, suppression or arrest of metabolism, 2.2. regulation of key glycolytic enzymes, regulation of key glycolytic enzymes, 3.3. reduction in the conductance of ion reduction in the conductance of ion

channels (ion-flux arrest), channels (ion-flux arrest), 4.4. suppression of neural activity, suppression of neural activity, 5.5. expression of chaperones, expression of chaperones, 6.6. adaptations in blood rheology and adaptations in blood rheology and 7.7. expression and accumulation of expression and accumulation of

antioxidants.antioxidants.

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The Brain and ToleranceThe Brain and Tolerance

Ischemic tolerance is an Ischemic tolerance is an evolutionarilyevolutionarily and and genetically genetically conserved form of cerebral plasticity and conserved form of cerebral plasticity and preconditioningpreconditioning

Genetic alterations caused by preconditioning lead Genetic alterations caused by preconditioning lead to a cerebroprotective phenotypeto a cerebroprotective phenotype

Similar examples:Similar examples:– HibernationHibernation– Endotoxin exposureEndotoxin exposure– HypothermiaHypothermia

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DefinitionsDefinitions

Ischemic Ischemic tolerance/preconditioningtolerance/preconditioning– Acute and/or chronic reaction to a Acute and/or chronic reaction to a

potentially noxious stimuluspotentially noxious stimulus– Specifically, a noninjurious Specifically, a noninjurious

episode of ischemia is able to episode of ischemia is able to protect the brain from a protect the brain from a subsequent longer ischemic insultsubsequent longer ischemic insult

Post-conditioningPost-conditioning– Modified reperfusion subsequent Modified reperfusion subsequent

to a prolonged ischemia episode to a prolonged ischemia episode may also confer ischemic may also confer ischemic neuroprotectionneuroprotection

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PreconditioningPreconditioning

First described by Murray in First described by Murray in 19861986– Ability of the heart to ‘condition’ Ability of the heart to ‘condition’

itself to tolerate the effect of itself to tolerate the effect of acute ischemia-reperfusion injuryacute ischemia-reperfusion injury

They noted myocardial They noted myocardial infarction can be reduced 75%infarction can be reduced 75%– 40min of ischemic time vs. four-40min of ischemic time vs. four-

5min occlusions of coronary 5min occlusions of coronary artery were interspersed with artery were interspersed with 5min reperfusion just prior5min reperfusion just prior

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Ischemic Tolerance and Ischemic Tolerance and Cerebral PreconditioningCerebral 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 processesGidday J, Nature Neuroscience, 2006

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Activation of Neuronal Activation of Neuronal Preconditioning PathwaysPreconditioning Pathways

Known stressor Known stressor mechanisms that mechanisms that activate neuronal activate neuronal preconditioning preconditioning pathwayspathways– Hypoxia/ischemiaHypoxia/ischemia– HypoglycemiaHypoglycemia– HyperthermiaHyperthermia– GlutamateGlutamate– Volatile anestheticsVolatile anesthetics

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Preconditioning confers ischemia Preconditioning confers ischemia tolerance in most organ systems tolerance in most organ systems including:including:

BrainBrainHeartHeartLiverLiverKidneyKidney IntestinalIntestinal

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Types of PreconditioningTypes 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.

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Preconditioning FactorsPreconditioning Factors

There are a number of There are a number of nonischemic/nonhypoxic, nonpharmacologic nonischemic/nonhypoxic, nonpharmacologic interventions reported to date that trigger interventions reported to date that trigger robust ischemic tolerance in brain robust ischemic tolerance in brain

– ExerciseExercise– Caloric restrictionCaloric restriction– Hyperbaric oxygenHyperbaric oxygen– Transcranial magnetic stimulationTranscranial magnetic stimulation– AcupunctureAcupuncture– And others…And others…

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Pharmacologic PreconditioningPharmacologic 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

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ErythropoietinErythropoietin

Produced in the mammalian brain Produced in the mammalian brain by astrocytes in the ischemic by astrocytes in the ischemic penumbrapenumbra

EPO receptors are up-regulated EPO receptors are up-regulated by neurons in the ischemic by neurons in the ischemic penumbrapenumbra

Stimulates repair proteins, Stimulates repair proteins, decreases neuronal excitotoxicity, decreases neuronal excitotoxicity, reduces inflammation, inhibits reduces inflammation, inhibits neuronal apoptosisneuronal apoptosis

Stimulates neurogenesis and Stimulates neurogenesis and angiogenesis after cerebral injuryangiogenesis after cerebral injury

Agostino Carracci: Whispering Angel

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Neuroprotective Role of EPONeuroprotective 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

Skolkovo 2011 40Neurovascular Unit

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Heart and BrainHeart 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.

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The Older BrainThe 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.

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MelatoninMelatonin 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-XL

Cheng y et al, 2006. PMID 16412260

The Birth of Venus – Sandro Botticelli

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ErythromycinErythromycin

Erythromycin has a Erythromycin has a significant affect on gene significant affect on gene expression associated with expression associated with brain ischemia.brain ischemia.

Erythromycin, unlike classic Erythromycin, unlike classic preconditioning, does not preconditioning, does not induce protective genes induce protective genes but diminished the but diminished the expression of genes, which expression of genes, which may induce secondary may induce secondary damage.damage.

Koerner IP, Gatting M: Anesthesiology 2007;106:538-547

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Future Horizons and Clinical Future Horizons and Clinical ImplicationsImplications

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

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Individualized Individualized PreconditioningPreconditioning

As the field of pharmacogenomic evolves, it will be exciting to define and implement individualized preconditioning treatments based on personal genetic profiles.

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PMC PMC

H. Damasio

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Brain Protection - EpilogueBrain Protection - Epilogue Ability to protect the brain Ability to protect the brain

is limited is limited Our ability to exacerbate Our ability to exacerbate

ischemic injury is limitlessischemic injury is limitless Focus should be on the Focus should be on the

prevention of ischemic of ischemicinjury or on the injury or on the minimization of further insultsto the injured brain.to the injured brain.

Emphasis should be on Emphasis should be on maintenance of physiologic maintenance of physiologic homeostasishomeostasis

Focus on activation of Focus on activation of evolutionary preserved evolutionary preserved mechanismmechanism

Anesthesia is an art, lightly embroidered with science

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Brain PreservationBrain Preservation

UNIVERSALCHANNEL BLOCKERS

RECEPTOR SPECIFICPHARMACOLOGY

STEM CELLS

HUMAN GENOMEDISCOVERIES

GENETIC ENGINEERING

CEREBRAL PLASTICITY

NEURONALPRECONDITIONING

NEW HORIZONS

NANOTECHNOLOGY

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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

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Micro-Philosophy in Micro-Micro-Philosophy in Micro-TimeTime

FeynmanFeynman’’s Micro Cosmoss Micro CosmosTwo minutes=120 seconds=120 quadrillon Two minutes=120 seconds=120 quadrillon

femto-secondsfemto-secondsOne femto-seconds(10-15)=construction or One femto-seconds(10-15)=construction or

destruction of a molecule (Ahmet Zewail)destruction of a molecule (Ahmet Zewail)Sixty quadrillon femto-seconds = conceiving of Sixty quadrillon femto-seconds = conceiving of

an ideaan idea

Being in TimeBeing in TimePresent of the pastPresent of the past = our memory= our memoryPresent of the presentPresent of the present = our vision-opinion= our vision-opinionPresent of the futurePresent of the future = our hope= our hopePast of the presentPast of the present = our performance= our performancePast of the futurePast of the future = our will= our willPast of the pastPast of the past = our = our ““individual individual

brainbrain””Future of the presentFuture of the present = our consciousness= our consciousnessFuture of the pastFuture of the past = our conscience= our conscienceFuture of the futureFuture of the future = our = our ““cultural braincultural brain””The Next Future = http://www.CCGCC.edu

(Computer Connected Global Cerebral Community)