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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)
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