brain ischemic

Oleh : dr. Jacobus Soleh, SpS

Urgent Condition Within the First 3 6 hEarly admissionIntensive stroke unit ( ISU ) Neuroimaging service ( CT / MRI ) Laboratory : glucose, electrolytes, blood gases, Neurosurgeon Neurologist trained in resucitation Cardiologistrheological & coagulation

MAIN DIRECTION of BASIC THERAPY> Correction of Respiratory & Cardio Vascular Disturbances> Water & Electrolyte imbalanced>Prevention & Treatment Intracranial Hypertension & Brain Edema > Autonomic Disorders >Complication of Ischemic Stroke

Within 3 h :Within 6 h :12 36 h after onset :2 3rd day :The energy failure is maximally pronounced- Glutamate exitotoxicity- Calcium homeostasis disorders- Lactic acidosisDecreasing by the end of the 3rd dayActivity of oxidant stress & Local inflammation reach a peakPeak activity of apoptosis

SCHEME of SEQUENTIAL ISCHEMIC CASCADE EVENTSCBF decreaseIon pump failure & glutamate exitotoxicityIntracellular accumulation of calciumActivation of intracellular enzymeIncreased NO synthesis & development of oxidative stressExpression of early response genesReactions of activated glia( local inflammation, microcirculation disturbances, BBB damage )Apoptosis

METABOLIC RESPONSES of BRAINCBF70 80 %First Critical Level< 50 55 ml / 100 grInhibition of Protein Synthesis CBF50 % ( 35 ml / 100 gr )2nd Critical LevelActivate Anaerobic Glycolysis LactateLactate Acidosis & Cytotoxic Edema

CBF30 % ( 20ml / 100 gr )3rd Critical LevelDepletion ATP SynthesisEnergetic DefisitDysfunction Active Ion Transport ChannelCell Membrans InstabilityExcessive Efflux of Excitatory Neurotransmiter a.aCBF20 % ( 10 15ml / 100 gr )Lose Ion GradientAmoxic Depolaritation of MembransIrreversible Cell Damage

Bila CBF < 10ml / 100 grIrreversible Damage Within 6 8 min( ISCHEMIC CORE )

TWO BASIC DIRECTIONS THERAPY1ST Stage :Improvement of Brain Tissue Perfusion( Therapeutic ReperfusionThrombolysis / Anticoagulan )2nd 8th :Neuroprotective / cytoprotective therapy Primary Neuroprotection : first minute ( 12 h ) Secondary Neuroprotection : 3 6 h

MAIN DIRECTION of the PRIMARY NEUROPROTECTION

Sheet1

DirectionBasic Drug GroupsRepresentativesPresent State of Study

Potential-dependentDihydropiridinesNimodipineEfficacy is not proven

Calcium channel

AntagonistsDarodipineEfficacy is not proven. X

( PY 108-068 )

IsradipineSevere adverse effects. X

FlunarizineEfficacy is not proven. X

CerebrokrastEfficacy is not proven. X

Glutamate recertorsNMDA receptor

Antagonistsantagonists

non-competitiveDizopcipineSevere adverse effects. X

MK-801

DextrorphanSevere adverse effects. X

DextromethorphanSevere adverse effects. X

CerestatSevere adverse effects. X

( CNS-1102,

aptiganel

hydrochloride )

RemacemideStudies are in progress

hydrochloride

Magnesium sulfateStudies are in progress

CompetitiveSelfotelSevere adverse effects. X

( CGS-19755 )

Selective :

- polyaminesEliprodilEfficacy is not proven. X

site blockers( SL-82.0715 )

- glycine siteGavestinelEfficacy is not proven. X

blockers( GV-150526A )

LicostinelEfficacy is not proven.

( ACEA-1021 )

AMPA receptorsNBOXSevere adverse effects. X

antagonists

ZK 200775Severe adverse effects. X

Inhibitors ofBW-619C89Severe adverse effects. X

synthesis and

presynaptic release

of glutamate

PropentofyllineSevere adverse effects. X

PhenytoinEfficacy is not proven.

Fos-PhenytoinEfficacy is not proven.

LubeluzoleEfficacy is not proven. X

GABA agonistsChlomethiazoleStudies are in progress

GlycineGlycineStudies are in progress

Notes : X - trials are stopped

Sheet2

Sheet3

MAIN DIRECTION of the PRIMARY NEUROPROTECTION

Sheet1

Calcium channel

( PY 108-068 )

MK-801

( CNS-1102,

aptiganel

hydrochloride )

hydrochloride

( CGS-19755 )

Selective :

( ACEA-1021 )

antagonists

synthesis and

presynaptic release

of glutamate

Sheet2

Sheet3

MAIN DIRECTION in SECONDARY NEUROPROTECTION

Sheet1

Calcium channel

( PY 108-068 )

MK-801

( CNS-1102,

aptiganel

hydrochloride )

hydrochloride

( CGS-19755 )

Selective :

( ACEA-1021 )

antagonists

synthesis and

presynaptic release

of glutamate

Sheet2

AntioxidantsFree radicalTirilazad mesylateEfficacy is not proven. X

scavengers( U-74006F )

Phenyl-t-butyl nitronePreclinical studies

( PBN )

NO-synthase7-NitroindazolePreclinical studies

blockers1-(2-Fluoromethyl-phenyl)-

imidazolePreclinical studies

AminoguanidinesPreclinical studies

Selen-organicEbselenStudies are in progress

compound of

complex

antioxidant action

InhibitorsAntibodies toEnlimomabSevere adverse effects. X

of localintercellular

inflammationadhesionHuman antibodies toPreclinical studies,

moleculesleukocyte integrins,start of clinical

( anti-ICAM )CD11 CD18studies

Pro-inflammatoryEndogenous antagonists of

cytokineTNF and IL-1 receptorsPreclinical studies

inhibitorsZinc protoporphyrin ( ZnPP )Preclinical studies

Endogenous anti-TGF-Preclinical studies

inflammatory

cytokinesIL-10Preclinical studies

StatinsStatins3-Hydroxy-3-methylglutarylPreclinical studies,

coenzyme A ( HMG-CoA )start of clinical

reductase inhibitorsstudies

EstrogensEstrogensEstrogensPreclinical studies,

start of clinical

studies

Trophic factorsNeurotrophicBasic fibroblastic growthStudies are in progress

factorsfactor ( bFGF )

Brain-derived neurotrophicPreclinical studies

factor ( BDXF )

Insulin-dependent growthPreclinical studies

factor ( IGF )

Osteogenic protein-1Preclinical studies

( OP-1 )

NeuromodulatorsNeuropeptidesSemax ( ACTH 4-10 )Studies are in progress

CerebrolysinStudies are in progress

NAP ( NAPVSIPQ )Preclinical studies, start of

clinical studies

RegulatorsGangliosidesGMIStudies are in progress

of receptor

structures

Sheet3

MAIN DIRECTION in SECONDARY NEUROPROTECTION

Sheet1

Calcium channel

( PY 108-068 )

MK-801

( CNS-1102,

aptiganel

hydrochloride )

hydrochloride

( CGS-19755 )

Selective :

( ACEA-1021 )

antagonists

synthesis and

presynaptic release

of glutamate

Sheet2

AntioxidantsFree radicalTirilazad mesylateEfficacy is not proven. X

scavengers( U-74006F )

Phenyl-t-butyl nitronePreclinical studies

( PBN )

NO-synthase7-NitroindazolePreclinical studies

blockers1-(2-Fluoromethyl-phenyl)-

imidazolePreclinical studies

AminoguanidinesPreclinical studies

Selen-organicEbselenStudies are in progress

compound of

complex

antioxidant action

InhibitorsAntibodies toEnlimomabSevere adverse effects. X

of localintercellular

inflammationadhesionHuman antibodies toPreclinical studies,

moleculesleukocyte integrins,start of clinical

( anti-ICAM )CD11 CD18studies

Pro-inflammatoryEndogenous antagonists of

cytokineTNF and IL-1 receptorsPreclinical studies

inhibitorsZinc protoporphyrin ( ZnPP )Preclinical studies

Endogenous anti-TGF-Preclinical studies

inflammatory

cytokinesIL-10Preclinical studies

StatinsStatins3-Hydroxy-3-methylglutarylPreclinical studies,

coenzyme A ( HMG-CoA )start of clinical

reductase inhibitorsstudies

EstrogensEstrogensEstrogensPreclinical studies,

start of clinical

studies

Trophic factorsNeurotrophicBasic fibroblastic growthStudies are in progress

factorsfactor ( bFGF )

Brain-derived neurotrophicPreclinical studies

factor ( BDXF )

Insulin-dependent growthPreclinical studies

factor ( IGF )

Osteogenic protein-1Preclinical studies

( OP-1 )

NeuromodulatorsNeuropeptidesSemax ( ACTH 4-10 )Studies are in progress

CerebrolysinStudies are in progress

NAP ( NAPVSIPQ )Preclinical studies, start of

clinical studies

RegulatorsGangliosidesGMIStudies are in progress

of receptor

structures

Sheet3

SECONDARY PREVENTION Blood Pressure, Glucose, Lipid Control Anti Platelets ( Aspirin, Cilostazol / pletaal, Clopidogrel, ticlopidine, dipiridomol )

REPARATIVE THERAPY It is difficult to define the borders between Neuroprotection & Reparative Therapy Piracetam Citicoline

Fungsi Otak Tergantung Pada Supply Glucose( menjaga metabolisme energy )Bila Glucose Use the free fraction of glycogenCardiac arrest, severe cardiac rhytm disorder Severe Systemic HypertensionGlobal Brain IschemicKalau mengenai 1 arteriTotal Brain Ischemic or TIAContoh :

Morphologic Changes :Stenosis & Occlunous, Vessel AnomaliesVessel Shape & ConfigurationGlobal & Cerebral HemodynamicsCBFC V InsuffPhysical & Chemical ChangesCoagulability, Aggregation, Viscosity & Other Rheological,Protein Fraction, Electrolytes.Individual & Age DependentCerebral Ischemia Brain Infaction ( Irreversible )

brain ischemic

Documents

h secondary neuroprotection

ischemic core

microcirculation disturbances

hmain direction

energy failure

grirreversible damage

intracellular enzymeincreased

neurosurgeon neurologist