PATHOPHYSIOLOGY PATHOPHYSIOLOGY OF CEREBRAL ISCHEMIAOF CEREBRAL ISCHEMIA

Prof. J. HANACEKProf. J. HANACEK, M.D., Ph.D., M.D., Ph.D.

Anatomy of brain vesselsAnatomy of brain vessels

Carotic and vertebral arteriesCarotic and vertebral arteries

View to medulla, brainstem and inferior brain vesselsView to medulla, brainstem and inferior brain vessels

Brain arteries - anterior and posterior circulationBrain arteries - anterior and posterior circulation

Brain arteries – lateral viewBrain arteries – lateral view

Brain arteries: lateral and medial aspectsBrain arteries: lateral and medial aspects

Cerebral vascular Cerebral vascular eventsevents- - sudden damage of brain sudden damage of brain iinducednduced by decreasing or suspending substrate delivery by decreasing or suspending substrate delivery (oxygen and glucose) to the brain due to disturbace(oxygen and glucose) to the brain due to disturbacess of of bbrainrain vessels vessels

Classification of cerebral vascularClassification of cerebral vascular events events(cerebral strokes)(cerebral strokes)

1.1. focal cerebral ischemia focal cerebral ischemia (the most often(the most often–80-88%–80-88%))

2.2. intracerebral hemorrhageintracerebral hemorrhage (9-15%)(9-15%)

3. 3. subarachnoid hemorrhagesubarachnoid hemorrhage (3-5%)(3-5%)

Normal values of cerebral blood flowNormal values of cerebral blood flow

Cerebral blood flow (Q):Cerebral blood flow (Q): cortex - 0.8 ml/g/mincortex - 0.8 ml/g/min whwhite mite maatter –tter – 0.2ml/g/min 0.2ml/g/min

Types of StrokeTypes of Stroke

Epidural hematomaEpidural hematoma

Subfrontal and occipital hematomaSubfrontal and occipital hematoma

Distribution of congenital cerebral aneurysmsDistribution of congenital cerebral aneurysms

Arteria cerebri media and penetrating arteriesArteria cerebri media and penetrating arteries

MicroaneurysmsMicroaneurysmsin penetratingin penetratingarteriesarteries

Intracerebral hemrrhageIntracerebral hemrrhage

DefinitionDefinitionss of cerebral ischemia of cerebral ischemia

It is the potentially reversible altered state of brain It is the potentially reversible altered state of brain

physiology and biochemistry that occurs when physiology and biochemistry that occurs when substrate delivery is cut off or substantially substrate delivery is cut off or substantially reduced by vascular stenosis or occlusionreduced by vascular stenosis or occlusion

Stroke is defined as an „acute neurologic dysfunction

of vascular origin with sudden (within seconds) or

at least rapid (within hours) occurence of symptoms

and signs corresponding to the involvement of focal

areas in the brain“ (Goldstein, Barnet et al, 1989)

AA. . Etiopathogenesis of cerebral ischemiaEtiopathogenesis of cerebral ischemia

Main pathogenetic Main pathogenetic mechanismsmechanisms::

1.1. microembolisation microembolisation to brain vesselsto brain vessels ((due to due to myocardial infarction, mitral valve damage,myocardial infarction, mitral valve damage, others)others)

2. 2. sstenosis of cerebral artery tenosis of cerebral artery ++ decreasing of decreasing of systemic blood pressuresystemic blood pressure

3. 3. tromboembolism of large brain vesselstromboembolism of large brain vessels

4. 4. decreased cardiac outputdecreased cardiac output ((due to decreased due to decreased myocardial contractility, massive hemorrhagemyocardial contractility, massive hemorrhage, others, others))

Cardiac sources Cardiac sources of cerebral emboliof cerebral emboli

B.B. Pathogenetic mechanisms involved in Pathogenetic mechanisms involved in ddevelopmentevelopment of cerebral ischemia (CI)of cerebral ischemia (CI)

1. 1. The brain is protected against focal interruption ofThe brain is protected against focal interruption of bloodblood supplysupply by aby a number of extra- and intracranialnumber of extra- and intracranial collateral collateral vesselsvessels

a)a) number and vascular tone of the leptomeningeal number and vascular tone of the leptomeningeal

collateral channelscollateral channels

b)b) blood viscosityblood viscosity

c) blood perfusion pressure

Actual size of the cerebral ischemia depends onActual size of the cerebral ischemia depends on::

The richThe rich anastomoticanastomotic connections connections between thebetween the carotid carotid

and and vvertebralertebral arteries provide a powerfull collateral arteries provide a powerfull collateral

system whichsystem which isis able toable to ccompensateompensate for the occlusionfor the occlusion

of up to three of theseof up to three of these arteries arteries (known from animal (known from animal

experiment)experiment)

The The good collateral systemgood collateral system results in results in lesserlesser ischemic ischemic area area than is athan is a territory territory supplied by occluded arterysupplied by occluded artery

The The bad collateral system bad collateral system resultsresults in ischemic area equal in ischemic area equal toto a territory supplied by ocluded arterya territory supplied by ocluded artery

ssince these regions represent the ince these regions represent the border linesborder lines betwee betweenn

the supplyingthe supplying territories of the main cerebral arteries, the territories of the main cerebral arteries, the

resulting lesion have beenresulting lesion have been termedtermed "border zone""border zone" or or

watershed infarctswatershed infarcts

systemic BP systemic BP ++ multifocal narrowing of extracerebral multifocal narrowing of extracerebral

arteriesarteries blood flow initially in the periphery of blood flow initially in the periphery of

arterial territoriesarterial territories

Mechanisms ivolved in failure of collateral system

systemic BP systemic BP blood flow through collateral blood flow through collateral

circulationcirculation base for base for hemodynamihemodynamicc

theory of stroketheory of stroke development development

Types of ischemic Types of ischemic and hemorrhagic and hemorrhagic strokestroke

Ischemic cascadeLack of oxygen supply to ischemic neurones

ATP depletion

Membrane ions system stops functioning

Depolarisation of neurone

Influx of calcium

Release of neurotransmitters, including glutamate, activation of N-metyl -D- aspartate and other excitatory receptors

at the membrane of neurones

Further depolarisation of cells

Further calcium influxCarrol and Chataway,2006

Energy failure / depolarisationEnergy failure / depolarisation

Transmitter releaseTransmitter releaseand receptor activationand receptor activation CaCa2+2+

LipolysisLipolysis ((DAG DAG PKCPKC)) ProteinProteinphosphorylationphosphorylation

ProteolysisProteolysis DisaggregationDisaggregationof microtubuliof microtubuli

(FFAs(FFAs.LPLs.LPLs)) EnzymeEnzymeconversionconversion

Breakdown ofBreakdown ofcytoskeletoncytoskeleton

Damage to membraneDamage to membranestructure and functionstructure and function

Dysfunction ofDysfunction ofreceptors andreceptors andion channelsion channels

Free radicalFree radicalformationformation

Inhibition of axonalInhibition of axonalttransportransport,, blebbing blebbing

Cosequences of brain ischemiaCosequences of brain ischemia

Úplná ischémia Hypoglycemia

SDSD PenumbrPenumbraa

Total ischemiaTotal ischemia

Ischemia

Intra- and extracellular changes of Ca++

exc

inc

Spreading depression (SD) waves - occur in focal cerebral ischemia of the brain

- a selfpropagating neurohumoral reaction mediated by release

of potassium ions and excitotoxic amino acids from depolarized areas of cerebral cortex

- depolarization of neurons and astrocytes and up-regulation of glucose consumption, is thought to lower the threshold of

neuronal death during and immediately after ischemia (Miettinen et al., 1997)

- COX-2, the inducible form of the enzyme converting arachidonic acid to prostaglandins, is induced within hours after SD and transient focal ischemia in perifocal cortical neurons by a mechanism dependent on

NMDA-receptors and PLA2 (Miettinen et al., 1997) - preconditioning CSD applied 3 days before middle cerebral artery

occlusion may increase the brain's resistance to focal ischemic

damage and may be used as a model to explore the neuroprotective

molecular responses of neuronal and glial cells (Matsushima et al., 1996)

2.2. Hemorheology and microcirculation - their Hemorheology and microcirculation - their importance in development CIimportance in development CI

Relationship between Relationship between bloodblood viscosity viscosity and microcirculationand microcirculation::

QQ = flow rate = flow rate

P = pressure gradientP = pressure gradient

r = r = radius of radius of tubetubell = length of the tube = length of the tube = viscosity of the fluid= viscosity of the fluid

P. P. rr44 QQ = = . . 88 . . ll

•• It is clear that It is clear that flow rate (Q) flow rate (Q) indirectly indirectly dependsdepends on blood on blood viscosityviscosity – – Q will decrease with increase blood viscosityQ will decrease with increase blood viscosity

Blood viscosity depends on:Blood viscosity depends on: - - hematocrit, hematocrit, - - erythrocyte deformibility, erythrocyte deformibility, - - flowflow velocity, velocity, - - diameter of the blood vesselsdiameter of the blood vessels

In the brain In the brain macrocirculationmacrocirculation (in vessels larger than 100 (in vessels larger than 100 ):):

BBlood viscositylood viscosity depends mainly on:depends mainly on: -- hematocrithematocrit,,

- - flowflow velocityvelocity

blood viscosity blood viscosity :: by decreasing flow velocity by decreasing flow velocity by increasing hematocritby increasing hematocrit

•• This is important at low flow velocity, mainlyThis is important at low flow velocity, mainly

Why?Why?

-  Er aggregation (reversible)-  Er aggregation (reversible)

-  platelet aggregation (irreversible-  platelet aggregation (irreversible))

•• IIn the brain n the brain microcirculationmicrocirculation (vascular bed distal to(vascular bed distal to

the of 30 -the of 30 - 7070mm diameters diameters,, arterioles into th arterioles into thee brain brain parenchyma)parenchyma)

blood viscosityblood viscosity changes withchanges with changes of vesselschanges of vessels

diameter,diameter, mainlymainly

Summary:Summary:

Disturbancies of brain Disturbancies of brain microcirculationmicrocirculation accompanied accompanied bbyy hemorheologic changes at low hemorheologic changes at low blood blood flow velocityflow velocity are considered as are considered as important pathogenic factorimportant pathogenic factor promoting development of promoting development of cerebral ischemia cerebral ischemia and cerebral infarctionand cerebral infarction

•• Initially, asInitially, as diameter of vessels falls, the diameter of vessels falls, the bloobloodd viscosity falls,viscosity falls, too. too.

When vessels diameter isWhen vessels diameter is reduced to less reduced to less

thanthan

5-7 5-7 m m , , vviscosity iscosity againagain increases increases ((inversion inversion

phenomenonphenomenon))

3.3. NoNo -- reflow phenomenonreflow phenomenon Definition:Definition: Impaired microcirculatory filling after Impaired microcirculatory filling after temporary occlusion oftemporary occlusion of cerebral arterycerebral artery

Result:Result: TThhisis mechanism can contribute to development of mechanism can contribute to development of iirreversibilityrreversibility of of cell damage in cell damage in ischemic ischemic regregionion

Summary:Summary: It can be disputed if no-reflow after transient It can be disputed if no-reflow after transient focalfocal ischemia atischemia at normal blood pressure normal blood pressure is of is of pathogenic significancepathogenic significance for infarct for infarct developmentdevelopment or merelyor merely accompaniment of irreversible tissueaccompaniment of irreversible tissue injuryinjury

4.4. Changes in cerebral blood flow regulationChanges in cerebral blood flow regulation •• ccerebral ischemiaerebral ischemia both COboth CO22 reactivity and reactivity and autoregulationautoregulation of cerebral of cerebral vesselsvessels are disturbedare disturbed

In the center of ischemic territory:In the center of ischemic territory:

a)a) COCO22 reactivity reactivity – – abolished or even reversed abolished or even reversed (i.e. blood flow may (i.e. blood flow may

decrease with increasing PaCOdecrease with increasing PaCO22))

bb)) disturbance of autoregulationdisturbance of autoregulation –– mainly when BP is decreasedmainly when BP is decreased locallocal blood blood

perfusion pressure is below perfusion pressure is below the lower limit of thethe lower limit of the

autoregulatory capacity of the cerebrovascular autoregulatory capacity of the cerebrovascular

bed bed vesselsvessels areare maximally maximally dilateddilated

•• These disturbances contribute to the phenomenon of These disturbances contribute to the phenomenon of

postpost – ischemic– ischemic hypoperfusionhypoperfusion which is which is important important

pathophysiologicalpathophysiological mechanism mechanism for thefor the development of development of

secondary neuronal injurysecondary neuronal injury after global cerebral ischemia after global cerebral ischemia

•• Disturbancies of flow regulation Disturbancies of flow regulation luxury perfusionluxury perfusion

l luxury perfusion = oxygen supply to tissue exceeds the uxury perfusion = oxygen supply to tissue exceeds the

oxygenoxygen requirements of the tissuerequirements of the tissue

•• Disturbances of flow regulation after stroke are longlastingDisturbances of flow regulation after stroke are longlasting::

- - forfor autoregulation up to 30 days,autoregulation up to 30 days,

- - for COfor CO22 reactivity up to 12 days reactivity up to 12 days..

Possible mechanism involved:Possible mechanism involved:

- - vasoparalysis brought about by thvasoparalysis brought about by the e release release

ofof acidacidicic metabolites from th metabolites from the e ischemic ischemic tissuetissue

Forms of luxury perfusion:Forms of luxury perfusion:

a)  absolute (true hyperemia)a)  absolute (true hyperemia)

b)  relative (depending on the b)  relative (depending on the level of level of OO22 consumption) consumption)

5.5. Segmental vascular resistance - its importanceSegmental vascular resistance - its importance forfor development CIdevelopment CI Two different types of brain vessels have to beTwo different types of brain vessels have to be distinguisheddistinguished:: a)a) extracerebral extracerebral (conducting(conducting and superficial) and superficial) vessels vessels

-- extracerebral segment of the vascular bad extracerebral segment of the vascular bad (a.carotis, (a.carotis, a.basilaris,... and leptomeningeala.basilaris,... and leptomeningeal anastomoses)anastomoses)

b)b) nutrient (penetrating) vesselsnutrient (penetrating) vessels-- intracerebral segment of brain circulation (vessels intracerebral segment of brain circulation (vessels

penetratingpenetrating to brain tissue and capillaryto brain tissue and capillary networknetwork

supplied by them)supplied by them)

Both of segmentsBoth of segments are involved in are involved in autoregulationautoregulation

of blood flowof blood flow through brain, but through brain, but intracerebral intracerebral

segmentsegment react react to COto CO22, only, only

Middle cerebral artery constrictionMiddle cerebral artery constriction resistance of resistance of

eextracerebralxtracerebral conducting vessels conducting vessels pial arterial BPpial arterial BP

autoregulatory dilation ofautoregulatory dilation of intracerebral vascular intracerebral vascular

segmentsegment

6.6. Intracerebral steal phenomena (syndrome)Intracerebral steal phenomena (syndrome)

•• The The interconnection of ischemic and non-ischemicinterconnection of ischemic and non-ischemic vascular territoriesvascular territories

by anastomotic channelsby anastomotic channels may may divertdivert blood from one region to the blood from one region to the

other, depending on the other, depending on the magnitude and the magnitude and the ddirectionirection of BP gradientof BP gradient

across theacross the anastomotic connections anastomotic connections

•• The associated change of regional blood flow is called The associated change of regional blood flow is called "steal„"steal„ if it results in if it results in

a decrease of flow, or a decrease of flow, or "inverse steal""inverse steal" if it results in a increase of flow if it results in a increase of flow

(Robin Hood syndrome) in ischemic territories(Robin Hood syndrome) in ischemic territories

Mechanism in steal phenomena occurence:Mechanism in steal phenomena occurence:•• vasodilation in non-ischemic brain regions (vasodilation in non-ischemic brain regions (pCOpCO22 , anesthesia) , anesthesia) BP in BP in

pial arterial network pial arterial network of the collateral bloodof the collateral blood supply to the ischemic supply to the ischemic

territoryterritory

Summary:Summary: Despite of existing knowledge about steal and inverse Despite of existing knowledge about steal and inverse

sstealteal phenomena, phenomena, it is not possible to predict alterations of it is not possible to predict alterations of

ddegreeegree and extent ofand extent of ischemia when blood flow in the ischemia when blood flow in the

non-ischemic territories is manipulatednon-ischemic territories is manipulated.. Such manipulations Such manipulations

are not recommended up to now for the treatment ofare not recommended up to now for the treatment of strokestroke

Mechanism of inverse steal phenomena:Mechanism of inverse steal phenomena: •• vasoconstriction (vasoconstriction ( pCO2) in the intact brain regions (or pCO2) in the intact brain regions (or indirectly - to indirectly - to

a decrease of intracranial pressurea decrease of intracranial pressure causing an improvement of causing an improvement of

bloodblood

perfusion) perfusion) ofof blood flow in ischemic brain regionblood flow in ischemic brain region

7.7. Thresholds of ischemic injuryThresholds of ischemic injury

In the intact brain metabolic rate can be considered In the intact brain metabolic rate can be considered as the sum of:as the sum of:

a) a) activation metabolismactivation metabolism - - supports the supports the spontaneousspontaneous

electrical activityelectrical activity

(synaptic transmission, generation of action (synaptic transmission, generation of action

potentialspotentials))b) b) basal (residual) metabolismbasal (residual) metabolism - - supports the vital supports the vital

functionsfunctions of the cellof the cell (ion homeostasis, osmoregulation, (ion homeostasis, osmoregulation,

transport mechanisms, transport mechanisms, productionproduction of of structural structural

molecules)molecules)

1/3 of its energy for maintenance of synaptic transmission1/3 of its energy for maintenance of synaptic transmission1/3 for transport of Na1/3 for transport of Na++ and K and K++

1/3 for preserving of structural integrity1/3 for preserving of structural integrity

Gradual Gradual of oxygen delivery of oxygen delivery

a) reversible disturbances of a) reversible disturbances of cocoordinatordinating ing and and electrophysiological functionselectrophysiological functions

b) irreversible structural damage occursb) irreversible structural damage occurs

Ischemic thresholds for functional and structural Ischemic thresholds for functional and structural damage damage of brainof brain due to ischemia due to ischemia are are showed inshowed in scheme scheme (Fig. 1)(Fig. 1)

The working brain consumes about:The working brain consumes about:

Thresholds of ischemia

Thresholds for functionalThresholds for functionalll disturbances: disturbances:

a) a) the appearance of functional changesthe appearance of functional changes (clinical (clinical symptoms symptoms

andand signs) when focal blood flow rate was belowsigns) when focal blood flow rate was below 0.23 0.23

ml/g/minml/g/min b)b) complete hemiplegiacomplete hemiplegia was present when blood flow rate was present when blood flow rate

decline todecline to 0.08 - 0.09 ml/g/min0.08 - 0.09 ml/g/min

c)c) threshold of the suppression of EEG activitythreshold of the suppression of EEG activity begins at the flow begins at the flow

raterate 0.20ml/g/min and EEG became isoelectric0.20ml/g/min and EEG became isoelectric when blood flow when blood flow

rate israte is between between 0.15-0.16 ml/g/min0.15-0.16 ml/g/min

d)d) depolarization of cell membranes occursdepolarization of cell membranes occurs at flow levels below at flow levels below

0.08 -0.08 - 0.10 ml/g/min0.10 ml/g/min (sudden increase extracellular K (sudden increase extracellular K++ and and

associated fallassociated fall of extracellular Ca++ (threshold for ion pump of extracellular Ca++ (threshold for ion pump

failure - it is the lowerfailure - it is the lower level of the penumbra range)level of the penumbra range)

Threshold for morphological injuryThreshold for morphological injury

Development of morphological lesions requires:Development of morphological lesions requires:

a)   minimal time (manifestation or maturation time)a)   minimal time (manifestation or maturation time)

b)  certain density of ischemiab)  certain density of ischemia

•• ppermanent ischemia 0.17 - 0.18 ml/g/minermanent ischemia 0.17 - 0.18 ml/g/min histological changeshistological changes

•• 2 hours ischemia 0.12 ml/g/min2 hours ischemia 0.12 ml/g/min histological changes histological changes

•• 1 hour ischemia 0.05 - 0.06 ml/g/min1 hour ischemia 0.05 - 0.06 ml/g/min histological changes histological changes

8.8. The concept of ischemic penumbraThe concept of ischemic penumbra

The termThe term penumbrapenumbra was coined in analogy to the half-was coined in analogy to the half- shadedshaded zonezone aroundaround the center of a complete solar eclipsethe center of a complete solar eclipse in in order to order to describe thedescribe the ring-likering-like area of reduced flowarea of reduced flow around the around the more more densely ischemic center of andensely ischemic center of an infarctinfarctIn pathophysiological termsIn pathophysiological terms::

•• it is the it is the bloodblood flow range between theflow range between the thresholds of thresholds of

transmitterstransmitters release release andand cell cell membranes failure membranes failure

SoSo: functional activity of the neurons is suppressed although the: functional activity of the neurons is suppressed although the metabolic metabolic

acitivity for maintenance of structural integrity oacitivity for maintenance of structural integrity of f the cell is the cell is

still still

preserved preserved - - neurons are injured but stillneurons are injured but still viableviable

Penumbra should be defined as a flow range betweenPenumbra should be defined as a flow range between0.10 - 0.23 ml/g/min0.10 - 0.23 ml/g/min

Within the penumbra zone:Within the penumbra zone:  

- autoregulation of blood flow is disturbedautoregulation of blood flow is disturbed- CO2 reactivity of blood vessels is partially preservedCO2 reactivity of blood vessels is partially preserved- ATP is almost normalATP is almost normal- slight decrease of tissue glucose content slight decrease of tissue glucose content (begining insufficiency of(begining insufficiency of substrate availability)substrate availability)

Summary:Summary: Penumbra concept is important because it providesPenumbra concept is important because it provides a rational basis for a rational basis for functional improvementsfunctional improvements injured injured brain tissuebrain tissue occuring long occuring long after after the onset of strokethe onset of stroke

Úplná ischémia Hypoglycemia

SDSD PenumbrPenumbraa

Total ischemiaTotal ischemia

The changes of Ca++ concentration intra- and extracellularyduring different pathological brain processes

9. The concept of diaschisis9. The concept of diaschisis

DiaschisisDiaschisis = = the term for remote disturbancesthe term for remote disturbances of brain of brain cellscells

due to the suppression ofdue to the suppression of neurons neurons

connected to connected to

the injuredthe injured (ischemic) region(ischemic) region

Possible mechanism Possible mechanism involved in diaschisis occurenceinvolved in diaschisis occurence::

•• the neurons in remote focus of brain from ischemic the neurons in remote focus of brain from ischemic

injury injury suffer asuffer a kind of shockkind of shock when they are deprived when they are deprived

from some of their afferentfrom some of their afferent input input comming from comming from

ischemic focusischemic focus

Time characteristicTime characteristic of diaschisis development of diaschisis development

•• diaschisisdiaschisis appears within 30 min after the onset of appears within 30 min after the onset of ischemiaischemia

•• reversal of the phenomena has been observed after a few month reversal of the phenomena has been observed after a few month

•• it is reasonable to assume that deactivation of it is reasonable to assume that deactivation of nerve nerve fiber system fiber system

connectingconnecting the areas involved causes a the areas involved causes a depresiondepresion of functionalof functional

activityactivity becausebecause decrease of blood flow and metabolic rate decrease of blood flow and metabolic rate areare

coupledcoupled

•• a possible molecular mediator of diaschisis is a a possible molecular mediator of diaschisis is a disturbeddisturbed

neurotransmitter metabolismneurotransmitter metabolism

C. Consequences of cerebral ischemiaC. Consequences of cerebral ischemia

Neurophysiological disturbancesNeurophysiological disturbances

a)a) neurological deficitneurological deficit (forced ambulation with circling, tonic (forced ambulation with circling, tonic deviationdeviation

ofof the head and neck toward the side ofthe head and neck toward the side of thethe occluded artery... occluded artery...

aactivective

movements cease movements cease opposite limbs opposite limbs become weak, become weak,

development ofdevelopment of

apathetic or akineticapathetic or akinetic statestateb)  suppresion of electrocortical activityb)  suppresion of electrocortical activity

c)  suppresion of cortical evoked potentialsc)  suppresion of cortical evoked potentials

2.2. Changes in ECF:Changes in ECF:

a)a) changes changes inin extracellular extracellular fluid fluid content:content:

concentration of Kconcentration of K++

concentration of Naconcentration of Na++

concentration of Ca concentration of Ca ++++

b) b) changes changes in in extracellular extracellular fluid volume: fluid volume: volume of ECFvolume of ECF

IncreaseIncrease of the of the intracellular cytosolicintracellular cytosolic calciumcalcium concentration is concentration is one one

of three majorof three major factors involved in factors involved in iischemicschemic brain damagebrain damage. .

Other two factors are: Other two factors are: acidosis and production of freeacidosis and production of free radicalsradicals

c) changes of Cac) changes of Ca++++ –– look at slook at schematic diagrams illustratchematic diagrams illustratinging changes changes in Cain Ca++++ concentration in concentration in extra- and intracellulary extra- and intracellulary spacespace

3.3. Biochemical changesBiochemical changes

a)a) energy metabolism:energy metabolism:

cerebral ischemia cerebral ischemia first step:first step: shortage of O shortage of O22

second step:second step: shortage of glucose shortage of glucose Results:Results: NADH, NADH, ATP and KP, ATP and KP, concentration of lactate concentration of lactate shortage shortage

of energy, acidosisof energy, acidosis

b)b) lipid metabolism:lipid metabolism:

- - intracellular Ca++ intracellular Ca++ activation of membra activation of membrannee phospholipase phospholipase

AA22

release of poly-unsaturated fattyrelease of poly-unsaturated fatty acids into intracellular acids into intracellular

compartmentcompartment -- activation of phospholipase C activation of phospholipase C arachidonic acid arachidonic acid PGL, LT, PGL, LT,

TBXTBX

c)c) neurotransmitter metabolism:neurotransmitter metabolism:

  - - disturbances exist in synthesis, degradation, releasingdisturbances exist in synthesis, degradation, releasing and and

bindingbinding of of

neurotransmittersneurotransmitters WWith prolong or severe ischemia:ith prolong or severe ischemia:

norepinephrine, serotonin, dopaminnorepinephrine, serotonin, dopamin

alanin and GABA (inhibitory neurotransmitters)alanin and GABA (inhibitory neurotransmitters)

asparate and glutamate (excitatory neurotransmitters)asparate and glutamate (excitatory neurotransmitters)

d)d) protein synthesis: disturbances (protein synthesis: disturbances ( ) ) of protein of protein

synthesissynthesis ihibition of reparating processes ihibition of reparating processes

4.4. Ischemic brain edemaIschemic brain edema

DefinitionDefinition:: It is the abnormal accumulation of fluid within the brainIt is the abnormal accumulation of fluid within the brain parenchyma leading to the volumetric enlargementparenchyma leading to the volumetric enlargement of the tissueof the tissue

a) a) by interfering with the water and electrolyte homeostasisby interfering with the water and electrolyte homeostasis

of the tissueof the tissue

b) b) by its adverse effect on myelinated nerve fibersby its adverse effect on myelinated nerve fibers

c) c) by its volumetric effect causing local compression of theby its volumetric effect causing local compression of the microcirculation, rise intracranial pressure, dislocationmicrocirculation, rise intracranial pressure, dislocation

of parts of the brainof parts of the brain

BBrain edema agrain edema agggravates the pathological process induced by ischemiaravates the pathological process induced by ischemia in different waysin different ways::

MechanismsMechanisms involved in involved in ischemic brain edema ischemic brain edema developmentdevelopment

IIschemic brain edemaschemic brain edema has two phases: has two phases: 1)1) Initially is main mechanism damage of cells: Initially is main mechanism damage of cells:

cytotoxic cytotoxic componentcomponent

- - disturbances of cell volume regulationdisturbances of cell volume regulation intracellular intracellular edemaedema ((not major changesnot major changes of theof the blood-brain barrier blood-brain barrier permeability to macromoleculespermeability to macromolecules))

2)2) Later on:Later on:•• vvasogenic componentasogenic component::

-- disruption disruption of the blood - brain barrier to circulatingof the blood - brain barrier to circulating macromoleculesmacromolecules extracellular edema extracellular edema

Ischemic preconditioning in the brain

„What does't kill you makes you stronger“

- Preconditioning CSD applied 3 days before middle cerebral artery

occlusion may increase the brain's resistance to focal ischemic

damage and may be used as a model to explore the neuroprotective

molecular responses of neuronal and glial cells

(Matsushima et al., 1996)