http://myprofile.cos.com/eugenefox eugene yevstratov md
TRANSCRIPT
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+ channels
N-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 receptors
Non-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 experiments
Endothelium
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
