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Biochemistry Exam III material > Ischemia Reperfusion > Flashcards

Ischemia Reperfusion Flashcards

1
Q

Human brain is _____/______ in terms of energy use

A

expensive/inefficient

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2
Q

The human brain is only ___% of total body weight but uses ___ % of energy consumed

A

2%, 20%

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3
Q

ATP consumption per gm/min used in signaling is equal to

A

energy used by leg muscle to complete a marathon

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4
Q

Approx. ___% of the ATP consumption of the brain is used for signaling, and ____% is used for maintaining essential cellular activity

A

75%, 25%

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5
Q

Metabolic rates of the brain are higher in ____ matter than in ____ matter

A

Higher in gray matter than in white matter

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6
Q

energy rich substrates enter the brain from blood via

A

blood brain barrier

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7
Q

Endothelial cells of Blood brain barrier and brain cells have transporter for uptake of ____ and _____

A

glucose and moncarboxylic acids

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8
Q

cerebral metabolic rate ______ during early development and ______ after maturation

A

increases, plateaus

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9
Q

Transporters are unique to _______, and determine specific ____ used by them

A

different cell types, substrates

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10
Q

Transporters of endothelial cells and brain cells are altered during

A

development and under pathological conditions

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11
Q

__________ (_________) shows that carbohydrate oxidation is the main source of energy in brain

A

respiratory quotient (CO2 produced/O2 consumed)

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12
Q

_____, ______, ______ (____) and ______ ( _______ and _____) are utilized by the brain for energy

A

Glucose, Glycogen, moncarboxylic acids (lactate) and ketone bodies (acetoacetate and betahydroxy butyrate)

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13
Q

Respiratory quotient (CO2 produced / O2 consumed) shows that _______ _______ is the main source of energy in the brain

A

carbohydrate oxidation

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14
Q

_____ is essentail for brain, most important energy source for adult brain

A

Glucose

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15
Q

______ is important to brain during immediate post natal period

A

lactate

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16
Q

_____ are used by brain during suckling due to high fat content of milk

A

Ketone bodies

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17
Q

______ is actively utilized by nerve cells (2% of total metabolic rate compared to glucose)

A

Glycogen

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18
Q

______ continuous cerebral circulation is required to sustain brain function

A

Continuous

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19
Q

Both excitatory and inhibitory neurons consume ________ energy

A

equivalent

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20
Q

oxygen concentration in cerebral venous blood is _____ than in cerebral arterial blood

A

lower

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21
Q

high extortion of O2 by brain cells (___-____%) while glucose extracted is only ____%

A

(50-70%), 10%

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22
Q

What are the metabolic pathways of the brain

A
  • Glycolysis
  • Glycogenolysis
  • Pentose phosphate shunt
  • Malate Aspartate shuttle
  • TCA cycle
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23
Q

What is the excitatory neural transmitter in cerebellar granule neurons

A

glutamate

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24
Q

what is the inhibitory neurotransmitter in cortical neurons

A

GABA

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25
Q

What are the experimental models for brain research

A
  • Primary neuronal cultures or co-cultures
  • Cell lines
  • Brian
    • Isolated organelles
      • Synaptosomes
      • Mitochondria
      • Cytosol
    • Brain slice cultures
  • surgical methods performed in live animals
  • in vivo imaging techniques (humans)
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26
Q

What are some of the isolated brain organelles used in experimental models

A
  • synaptosomes
  • mitochondria
  • Cytosol
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27
Q

Examples of surgical methods of experimental model in animals

A
  • Middle cerebral artery occlusion- focal ischemia

- Carotid Artery occlusion- Global occlusion

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28
Q

Carotid artery occlusion is an example of a

A

global occulsion

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29
Q

Middle cerebral artery occlusion is an example of a

A

focal ischemia

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30
Q

examples of in vivo imagine techniques used of experimental models of the brain

A

MRI, CT, PET scan

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31
Q

Metabolic studies in brain: imaging and spectroscopy

A
  • global imaging of whole brain: brain metabolic rates with assays of artery-venous differences
  • Glucose and oxygen primary fuels
  • Various analogs used
  • Useful technique, but effect averages out across various brain structures. Changes in small structures not detectable
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32
Q

What does PET imaging stand for

A

Positron Emission Tomography

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33
Q

Local rates of glucose and O2 utilization can be measured by

A

PET imaging (positron emission tomography)

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34
Q

PET imaging uses analogs of _____ (_____, in experimental animals) and _______ (in humans)

A

glucose (2-deoxy glucose, in experimental animals) and 2-fluoro-deoxy glucose (in humans)

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35
Q

PET imaging rely on

A

quantitative intracellular trapping of the major phosphorylated metabolite DG-6-phosphate, which enables assays of hexokinase reaction in all regions of the brain in conscious individuals

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36
Q

MRS (Magnetic resonance spectroscopy ) utilizes ____ labeled with radioactive (___, ____, ____) or stable isotope (___)

A

glucose labeled with radioactive (3H, 14C, 11C) or stable isotope (13C) (note that the numbers before the litters suggest there atomic number)

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37
Q

MRS allows assessment of glucose metabolites as they are

A

formed in different pathways

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38
Q

MRS is used to determine metabolism of precursors via

A

specific neuronal and glial pathways

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39
Q

MRS allows for method-NMR spectra to be obtained. each very _____ and ____

A

characteristic and unique

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40
Q

Brain engr. metabolism has what unique features

A
  • High metabolic rate
  • Limited intrinsic energy stores
  • Critical dependence on circulation to provide glucose and other fuels
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41
Q

_______ techniques are useful for studying brain metabolism in humans

A

in Vivo imaging

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42
Q

According to WHO, ___ million people has stroke each year, ____ million of whom die

A

15, 6

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43
Q

Ischemia and brain infarct is the ___ leading cause of death and disabilities worldwide

A

2nd

44
Q

___ good treatments for stroke available

A

No

45
Q

Outcome of brain infarct depends on

A

which particular part of the brain and which cell types affected

46
Q

What are the two types of ischemia

A

Focal cerebral ischemia

Global cerebral ischemia

47
Q

Focal cerebral ischemia

A

focal disruption of blood flow to a part of the brain (e.g. due to occlusion of an artery by an embolus)

48
Q

Global cerebral ischemia

A

Transient impairment of blood flow to whole brain (e.g. during cardiac arrest)

49
Q

What kind of ischemia accounts for the majority of strokes

A

Focal cerebral ischemia

50
Q

The are of infarction in a focal ischemia is typically ____ than the entire distribution of the occluded artery due to what factor

A

less, due to collateral circulation

51
Q

Injury of a focal ischemia depend on

A

duration and degree of vascular occlusion and the magnitude of collateral blood supply

52
Q

What is the ischemic core or umbra seen in focal ischemia

A

injury grows over time-electrophysiological, molecular, metabolic, and perfusion disturbances in the area

53
Q

What is the rim/area surrounding ischemic core (umbra) is ________. What are its characteristics

A

penumbra

an area of reduced cerebral flow, impaired protein synthesis, preserved energy metabolism

54
Q

Prompt restoration of perfusion in penumbra by injection of ________ agents is key to minimizing damage in this region

A

thrombolytic

55
Q

In actue case of focal ischemia the focus is on saving the ______

A

penumbra

56
Q

The window of opportunity to save the penumbra is

A

short

57
Q

if adequate blood supply is not established within ___ hours necrosis extends to penumbra ( area of reversible damage )

A

3 hours

58
Q

Transient loss of blood flow to the entire brain as in cardiac arrest followed by resuscitation

A

Global ischemia

59
Q

neurons are ____ sensitive than glial cells to global ischemia

A

more

60
Q

Neurons present within same vascular position and juxtaposed to each other may be selectively ______ or _______ to insult

A

vulnerable or resistance

61
Q

What cells have the highest vulnerability to global ischemia

A
  • Hippocampal pyramidal cells of CA 1 region
  • Pyramidal neocortical neurons (layer 3,5, and 6)
  • Purkinje cells
  • Striatal neurons
62
Q

What cells are most resistant to global ischemia

A
  • CA3 in hippocampus

- Granule cells

63
Q

biochemistry of ischemia

A
  • Disruption of blood flow
  • Reduction or absence of O2 and glucose supply to brain
  • Impaired energy metabolism
  • Reduction of ATP metabolism
  • Ion pump dysfunction (pumps need ATP)
  • Disruption of ion gradients
  • Membrane depolarization
  • Opening of voltage-gated channels
  • Cascade of subsequent signaling events
  • Cell death in a given brain region
64
Q

Fall in _____ leads to enhanced lactate production (Pasteur effect)

A

PO2

65
Q

What is the pasteur effect

A

fall in PO2 leads to enhanced lactate production

66
Q

During an ischemic episode cells move from _____ metabolism to _____

A

Aerobic metabolism, glycolysis

67
Q

lactic acidosis caused by ischemic episode reduces pH of cells from ___ to ___-____-

A

7.3 to 6.8-6.2

68
Q

During ischemic episode there is an efflux of ___ through __ channels

A

potassium through potassium channels

69
Q

During an ischemic episode ____ or ____ propagates in brain tissue

A

cellular depolarization or ‘spreading depression’

70
Q

During an ischemic episode ____ and ____ gradients collapse

A

Na+ and Ca2+

71
Q

during an ischemic episode Voltage gated _____ channels open allowing influx of ___ into the cell

A

Ca2+, Ca2+

72
Q

The influx of Ca2+ into a cell after an ischemic episode leads to

A

release of NT

73
Q

Both ____ and ____/_____ over activation contribute to excitotoxicity

A

NMDA and AMPA/Kainate

74
Q

In excitotoxic injury loss of ion gradients leads to

A

build up of extracellular glutamate

75
Q

During an excitotoxic injury the activation of glutamate receptors causes an ______ and ____

A

influx of calcium, Zn2+

76
Q

During an excitotoxic injury elevated intracellular Ca2+ causes release of ___ thus leading to

A

Neurotransmitters- levels of extracellular neurotransmitters rise

77
Q

The increased levels of extracellular neurotransmitters leads to

A

impaired glutamate uptake and excess release

78
Q

The influx of Ca2+ and Zn2+ due to excitotoxic injury activates

A

cytotoxic intracellular pathways

79
Q

Mechanisms of excitotoxic injury

A
  • Prolonged availability of glutamate
  • Lethal derangements of ions
  • Sustained elevation in intracellular calcium
  • Activation of Calpain-Degrades cytoskeleton
  • Damage to mitochondria, impaired energy
  • Activation of NOS-Generation of NO and ROS (reactive oxygen species) (these lead to neuronal necrosis)
  • Activation of Phospholipase A2, formation of arachidonic acid, cyclooxygenases, lipoxygenases
  • Formation of lipid free radicals
  • membrane damage
80
Q

DAPK1 is linked with ____ receptor toxicity in stroke damage. explain

A

NMDA.

  • after a stroke, the increased extracellular concentration of glutamate causes overflow of synaptic glutamate and excitotoxic activation of extra-synaptic NMDARs. The increase in Ca2+ influx through NR2B-containing activates DAPK1 (death-associated protein kinase 1) and sequentially ing to NMDA receptor NR2B subunit, leading to neuronal cell death
81
Q

Injected _____ intravenously 2 hours after a stoke can protect against brain damage and improve neurological functions by inhibiting the binding of DAPK1 to NR2B subunit

A

NR2B CT

82
Q

What are some examples of injuries of reperfusion

A
  • ROS (reactive oxygen species)
  • Microvascular injury and Edema
  • Ischemic Apoptosis
83
Q

How are reactive oxygen species formed after ischemic episode

A
  • High amounts of polyunsaturated fatty acids (PUFA) in neuronal membrane
  • Presence of high concentration of iron in certain brain regions (ex. substantial nigra)
  • sensitive to lipid peroxidation
  • Mitochondria donate electrons to O2
    • forms ROS such as superoxide free radicals and hydroxyl free radicals , H2O2, and ONOO-
84
Q

Unpaired electrons are very

A

reactive

85
Q

Unpaired electrons (such as in ROS) react with

A

proteins, lipids, and DNA

86
Q

ROS cause _____ and _____ changes in biomolecules thus leading to cellular _____ and eventually cell ____

A

structural and functional, dysfunction and eventually cell death

87
Q

Blood brain barrier permeability increased at ____ min after reperfusion

A

15 min

88
Q

Acute disruption of blood brain barrier occurs after ____ post reperfusion

A

3-5 hours

89
Q

Damage to BBB (blood brain barrier) caused by reperfusion can lead to _____ cell death and promotes adhesion of ______ thus leading to

A

endothelial cell death, promotes adhesion of leukocytes thus leading to vessel plugging

90
Q

____ ________ also contribute to BBB damage after reperfusion

A

matrix metalloproteinases

91
Q

The damage to the BBB caused by reperfusion promotes _____ transformation and entry of _____ and _____ factors thus leading to _____ further secondary injury

A

hemorrhagic transformation, cytokines and pro-inflammatory factors
edema

92
Q

After microvascular injury due to reperfusion what is the secondary injury

A

Edema

93
Q

Ischemic apoptosis

A
  • programmed cell death
  • Deprivation of growth factor support
  • Oxidative stress
  • Exposure of inflammatory cytokines
  • Damage to micochondria
94
Q

What is the extrinsic pathway for apoptosis

A
  • Activation of death receptor (Fas) promotes formation of multi protein DISC that includes the receptor adaptor (FADD)
  • DISC is the site of activation for Procaspase-8
  • Propaspase-8 Becomes active by oligomerization (active form Caspase-8)
  • Caspase-8 can directly activate capase-3, an effector caspase
  • Caspase-8 aslo cleaves proapoptotic BID into tBID, which translocates to mitochondria to execute apoptosis
95
Q

What is the intrinsic pathway for apoptosis

A
  • Excessive influx of calcium into cytoplasm causes disruption of normal homeostasis
  • Affects the function of mitochondria and ER
  • Altered activity of protein phosphatase (e.g. calcineurin) causes translocation of BAD to promote mitochondria apoptotic pathway
  • The release of cytochrome C from mitochondrial inter membrane space results in caspase-3 activation via apoptosome complex
  • The AIF is released form mitochondria and is translocated to the nucleus
  • ER undergoes stress upon depletion of calcium form its lumen. ER stress induces activation of capsize 12, capsize-9, and capsize-3
  • Moreover, efflux of calcium form ER might trigger secondary activation of mitochondria. Anti- and pro- apoptotic Bcl-2 family members are localized to both the mitochondria and the ER
  • Caspases cleave key structural components of the cytoskeleton and nucleus, a characteristic feature of apoptosis
96
Q

Neuroprotective strategies: Multiprong approach

A
  • Thrombolytics
  • NMDA receptor antagonists
  • GABA agonists
  • Protein synthesis inhibitors (e.x. cycloheximide)
  • Caspase inhibitors
  • Omega 3 fatty acids (DHA)
  • Heat shock response (bind proteins and keep them form being harmed)
  • Antioxidants- free radical scavengers, e.x. Spin traps
  • Growth factors- basic fibroblast growth factor
  • Neurotrophins
97
Q

risks of tPA

A

may cause fatal edema or intracranial hemorhage

98
Q

DHA is an

A

omega 3 fatty acid

99
Q

DHA is involved in ____ and ____ development

A

brain and retinal

100
Q

DHA functions in important in memory and synaptic function

A

True

101
Q

DHA treatment has been beneficial for patients with

A

CAD, cancer, and RA

102
Q

DHA is protective in ____ and ____

A

ischemia and spinal cord injury

103
Q

DHA is a precursor of ____

A

NPD1

104
Q

a docosanoid called neuropectin or NPD1 acts functions

A

acts against apoptosis, promotes cell survival, inhibits brain ischemia, inhibits reperfusion mediated leukocyte infiltration and pro-inflammatory gene expression
reduces stroke volume, if administered within 48 hours after MCAO (middle cerebral artery occlusion)

105
Q

DHA has potent ______ activity

A

anti-infammatory

106
Q

DHA is found in

A

cold water fatty fish

Biochemistry Exam III material (13 decks)

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