http://myprofile.cos.com/eugenefox

Eugene Yevstratov MD

Pathogenesis of ischaemic Pathogenesis of ischaemic brain injurybrain injury

•DepolarizationDepolarization•Biochemical cascadeBiochemical cascade•Reperfusion injuryReperfusion injury

DepolarizationDepolarizationCessation of neuronal electrical ativityCessation of neuronal electrical ativity

Energy lossEnergy loss

Impair ion homeostasisImpair ion homeostasis

Depletion of high energy phosphatesDepletion of high energy phosphates

Membrane ion pump failureMembrane ion pump failure

Efflux of cellular KEfflux of cellular K

Influx of Na ,Cl and HInflux of Na ,Cl and H22OO

Biochemical cascadeBiochemical cascadeGlutamateGlutamate

Glutamatergic receptorsGlutamatergic receptors

Calcium influxCalcium influx

Nitric oxideNitric oxide

CalpainsCalpains

GelsolinGelsolin

Cell death/ApoptosisCell death/Apoptosis

Evidence for a role of Glutamate Evidence for a role of Glutamate in Ischemic Neuronal Injuryin Ischemic Neuronal Injury

• High concentrations of Glutamte receptors occur in High concentrations of Glutamte receptors occur in seletively vulnerable neuronsseletively vulnerable neurons

• High concentrations of Glutamateare released in ischemic High concentrations of Glutamateare released in ischemic brain regionsbrain regions

• Lesioning of glutamergic pathways reduces ischemic injuryLesioning of glutamergic pathways reduces ischemic injury• NMDA or AMPA receptors blockade reduces ischemic NMDA or AMPA receptors blockade reduces ischemic

injuryinjury• Delayed CaDelayed Ca2+2+ overload occurs in selectively vulnerable overload occurs in selectively vulnerable

neurons, which is not blocked by Caneurons, which is not blocked by Ca2+2+ channel blockers channel blockers

Reperfusion injuryReperfusion injuryHallmarkHallmark – Ischaemic brain – Ischaemic brain leukocyte infiltrationleukocyte infiltration

Inflamatory cascade activationInflamatory cascade activation

Released large amounts of OFRReleased large amounts of OFR

Proinflamatory cytokine expressionProinflamatory cytokine expression

Neutrophils activationNeutrophils activation

Cerebral oedemaCerebral oedema

The Ischemic penumbraThe Ischemic penumbra

Strategies for mitigating Strategies for mitigating ischaemic brain injuryischaemic brain injury

• HypothermiaHypothermia• Biochemical interventionBiochemical intervention• Pharmacological interventionPharmacological intervention• Modification of techniques or Modification of techniques or

mechanical devicesmechanical devices

HypothermiaHypothermia(HCA)(HCA)

Mild systemic hypotermia 34CMild systemic hypotermia 34Coo

Mild to moderade hypotermia Mild to moderade hypotermia 34 – 30 C34 – 30 Coo

Moderade Hypotermia 30 – 28 Moderade Hypotermia 30 – 28 CCoo

Severe Hypotermia 28 –18 CSevere Hypotermia 28 –18 Coo

Profound Hypotermia 18 – 15 Profound Hypotermia 18 – 15 CCoo

Biochemical Biochemical InterventionIntervention

• Ingibitors of presynaotic glutamate releaseIngibitors of presynaotic glutamate release• Inhibitors of postsynaptic glutamate releaseInhibitors of postsynaptic glutamate release• MonosialogangliosidesMonosialogangliosides• CaCa2+2+ channel blockers channel blockers• Nitric oxide synthase inhibitorsNitric oxide synthase inhibitors• Calpain inhibitorsCalpain inhibitors• Gelsolin-like chemical agentsGelsolin-like chemical agents• Caspase inhibitorsCaspase inhibitors

Pharmacological Pharmacological strategiesstrategies

•CorticosteroidsCorticosteroids•Free radical inhibitionFree radical inhibition•Cytokine inhibitionCytokine inhibition•Anti-adhesion molecule Anti-adhesion molecule

antibodiesantibodies

Presynaptic

Ca2+ channelsN-type

ω -conotoxins

SNX-111

Hypotension

Na+ channels

Pyramidines: Lamotrigine

Licensed for epilepsy

BW1003C87

In vitro and in vivo experimentsBW

619C87In vitro and in vivo experimentsLubeluzo

le;Studied clinically for strokeRiluzole In vitro and in vivo experimentsLifarizine Hypotension, cardiac side-effects

Postsynaptic

NMDA receptorsNon-competitive

Aptiganel

CNS1102 (Cerestat)

Hypotension, hallucinogenicDizoclipi

neMK801 Toxicity

NPS 1506

Less toxic than MK801

Ketamine

Anaesthetic, blood pressure effects

Dextromethorphan

AHN649 Blood pressure effectsMemanti

neLicensed for Parkinsonism

Remacemide desglycine

FPL 12495

Clinical study with CABG

Competitive

Selfotel

CGS 19755

Toxicity / psychomimetic

d-CPP In vitro and in vivo experiments studies

Glycine site

Felbamate

C-W 554

Lic.for epilepsy, protects in vitro

ZD9379

In vitro and in vivo experiments

Licostinel

ACEA-1021

In vitro and in vivo experiments

ACEA-1031

In vitro and in vivo experiments

ACEA-1416

In vitro and in vivo experiments

AMPA receptors

NBQX In vitro and in vivo experimentsGYKI

52466In vitro and in vivo experiments YM 90

KIn vitro and in vivo experiments Monosialo

gangliosides

GM1 In vitro and in vivo experimentsCa2+-

channels Nimodipine

Intracerebral haemorrhage

AT 877

In vitro and in vivo experiments

Gelsolin

Microfilaments

Cytochalalacin D

In vitro and in vivo experimentsCal

pain

Cbz-Val-Phe-H

In vitro and in vivo experiments MDL

28,170In vitro and in vivo experiments NO NO

synthase

7- nitroindazole

In vitro and in vivo experimentsTRIM In vitro and in vivo experiments1400

WIn vitro and in vivo experimentsBN

80933In vitro and in vivo experiments

Reperfusion

Cytokine inhibition

Soluble TNF reseptor I

In vitro and in vivo experimentsTNFα

MabIn vitro and in vivo experimentsEndo

thelium

Anti-adhesion molecules

In vitro and in vivo experimentsFree

radicals

Lazeroids

Tirilazad 74006F

In clinical trials

U-101033E

In vitro and in vivo experiments PBN In vitro and in vivo experiments studies

Apoptosis

Caspases

z-VAD-FMK

In vitro and in vivo experiments

z-DEVD.FMK

In vitro and in vivo experiments

Modification of techniques or Modification of techniques or mechanical devicesmechanical devices

SCP Selective Cerebral PerfusionSCP Selective Cerebral Perfusion

RCP Retrograde Cerebral RCP Retrograde Cerebral

PerfusionPerfusion

The EndThe Endostlandfox@yahoo.de

ostlandfox@medscape.comEugene Yevstratov MD

ICCC Anesthesiology DivisionBsAs.Argentina