Acute CNS injury: anoxia, re-oxygenation & oxidative stress

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Acute CNS injuryanoxia, re-oxygenation
oxidative stress

• (or What happens to brain cells during a stroke)

Jay B. Dean, Ph.D.
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Overview

• Introduction What is a disability?
• Important CNS regions (disabilities)
• Oxygen and CNS function
• Cerebral blood flow Oxygen transport
• CNS Hypoxia / Anoxia
• Stroke
• Head Injury intracranial hypertension
• Respiratory failure
• Re-oxygenation (blood flow is restored)
• Disturbed electrical signaling

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1. What is a Disability?

• Neuromuscular impairment
• Sensory deprivation (vision, hearing or speech)
• Cognitive dysfunction (learning, higher
  processing)

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Motor (muscle) system
Neuromuscular junction (NMJ)
http//www.fi.au.dk/uk/jl/bc14/fig1403.jpg
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Sensory Vision
http//general.rau.ac.za/psych/Resources/Honours/N
europsych/Images.htm
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Sensory Hearing
http//www.brainconnection.com/med/medart/l/anat/9
90705.jpg
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Sensory Speech
http//home.uchicago.edu/skipper/pages/skipper.et
.al.2005b.html
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Sensory Speech
http//www.cerebromente.org.br/n02/historia/areabr
oca.gif
Brocass Area -- Broca's aphasia involves a lack
of ability to produce coherent language,
including spoken, written and signed
forms. Wernicke's area have difficulty
understanding language in any form. They can
speak fluently, forming long and complex
sentences, but their strings of words often lack
coherent meaning.
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Cognition
http//ifcsun1.ifisiol.unam.mx/Brain/speech.htm
The cortical association areas are thought to be
the anatomical basis for thought and perception,
since stimulation of these areas produce little
or no obvert behavioral changes, but receive
sensory input from high-order sensory systems and
project to motor cortex.
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2. Oxygen and CNS Function
http//health.allrefer.com/health/stroke-secondary
-to-cardiogenic-embolism-central-nervous-system.ht
ml
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Neuron
http//www-ermm.cbcu.cam.ac.uk/02004477h.htm
http//www.mb.jhu.edu/tins/media/200420Neuron20S
chema1.jpg
http//caspar.bgsu.edu/courses/Images/Neur/Synaps
e.jpg
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Mitochondria
Mitochondria are structures that turn oxygen and
glucose into energy. This process is especially
vital to brain cells. Although the brain accounts
for only 2 of the body's weight, it consumes
more than 20 of the body's oxygen. All of this
energy is required because neurons transmit
signals among themselves to an even greater
extent than do cells in the rest of the body.
Three-dimensional model was reconstructed by
electron tomography. The outer membrane and
cristae are shown in purple and yellow,
respectively.
Transmission electron micrograph (TEM) of
mitochondrion
http//www.scripps.edu/mem/biochem/ayagi/mito.html
http//www.cytochemistry.net/Cell-biology/mitoch1.
htm
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Aerobic metabolism
O2 fuel (glucose) ?
? biosynthetic work ADP ? CELLULAR ?
ATP ? mechanical work RESPIRATION
transport work ? ?
CO2 H2O
CO2 H2O ? H2CO3 ? H HCO3?
?
pH
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PET can yield metabolic information with
high-resolution images, and thus it has the
ability to detect small malignant lesions with
increased metabolism for enhanced cell
proliferation.
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Sensory Vision
http//general.rau.ac.za/psych/Resources/Honours/N
europsych/Images.htm
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CNS Oxygen Consumption
Eyes open
Eyes closed
Congenital blindness
Blind, recently
http//www.topo.ucl.ac.be/neuro_blindness.html
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CNS Oxygen Consumption
regional metabolic activity glucose utilization
infants
http//www.md.ucl.ac.be/gren/Projets/Adv/childhood
Epilepsy.html
Normal adult
Children, epilepsy
Electrical signaling energy (ATP) production
consumption to maintain ionic gradients,
biosynthesis, action potentials synaptic
transmission
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Hyperoxia Dorsal medulla oblongata
D.K. Mulkey et al. (2003) J Appl Physiol
95910-921
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?CBF ? ?PtO2
CNS Oxygen Consumption
Changes in brain oxygenation correlate with
execution of a mental task (i.e. numerical
calculation)
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Cerebral pulse pressure tissue PO2
http//ccforum.com/content/9/6/R670
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What is a normal O2 level in the brain (Normoxia)?

• Normoxia (CNS) lt10 to 35 mm Hg
• Inspired air 21 O2 at sea level, PB760 mmHg
• PIO2 0.21 x 760 159.6 mm Hg O2
• Lung (Alveoli) PAO2 100 mm Hg O2
• Arterial blood PaO2 85-100 mm Hg O2

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Gas exchange O2-CO2 homeostasis 3 general
processes
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Plumbing
From J.B. Wests Respiratory Physiologythe
essentials
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Pathway for Diffusion of O2 CO2

• Alveolar-capillary membrane where the
  respiratory and cardiovascular systems come
  together.

Berne Levy Fig. 32-9, p.525 Fig. 32-5, p.522
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Pathway for Diffusion of O2 CO2
J.B.Wests Respiratory Physiologythe essentials
O2
Hb
BerneLevy Figs. 32-6, p. 522
CO2
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3. Cerebral Blood Flow Oxygen Transport
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O2 Transport
J.B.Wests Respiratory Physiologythe essentials
O2
HbO2
PaO2
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Review of important points in oxygen transport

• Blood carries O2 in two forms
• in physical solution as O2 dissolved in the
  aqueous phase (5 of the total blood O2
  content).
• in a loose reversible chemical combination
  with hemoglobin Hb O2 ? HbO2 (95 of the
  total blood O2 content).
• In both cases, the amount of O2
• held depends on the PO2 or loading
• pressure to which the blood is
• exposed.

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Cerebral Vasculature
MR Angiography
http//www.mgh-interventional-neurorad.org/diagnos
tic/mra.html
http//www.psyweb.com/Brain/Bimages/blood2.gif
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O2 Carrying Capacity
The maximum amount of O2 that can be made to
combine chemically with Hb in a unit volume of
blood. Where... 1g Hb combines with 1.34 ml O2
normal Hb content 15 g Hb/100 ml of blood ?
O2 carrying capacity (15 g Hb/100 ml) ?
(1.34 ml/1 g Hb) 20.1 ml O2/100 ml
of blood saturation of Hb
HbO2 ? 100 O2 carrying
capacity
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PO2 of blood vs. HbO2
http//www.cvm.okstate.edu/Courses/vmed5412/FIGURE
S/lecture03/fig3_12.gif
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• CNS Hypoxia / Anoxia( Hypoxemia )

• Recall
• Normoxia (CNS) lt10 to 35 mm Hg
• Inspired air 21 O2 at sea level, PB760 mmHg
• PIO2 0.21 x 760 159.6 mm Hg O2
• Lung (Alveoli) PAO2 100 mm Hg O2
• Arterial blood PaO2 85-100 mm Hg O2

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Stroke
http//www.mcg.edu/medart/images/2002-AR-Stroke.jp
g
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What is a stroke?

• A stroke is the sudden death of brain cells due
  to interruption of blood supply. When blood flow
  to the brain is impaired, oxygen and important
  nutrients cannot be delivered. The result is
  abnormal brain function.
• A stroke is also referred to as a
  cerebrovascular accident or CVA.

http//www.medicinenet.com/stroke/article.htm
35
http//www.ling.upenn.edu/courses/Summer_2004/ling
001/images/brain_localization.gif
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Causes of stroke, 1

• Blockage of artery
• Hardening of the arteries leading to the brain

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Causes of stroke, 2

• Blockage of artery
• Clogging of arteries within the brain (e.g.
  lacunar stroke)

http//www.strokecenter.org/education/ais_vessels/
ais050.html
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Causes of stroke, 3

• Blockage of artery
• Embolism to the brain from the heart or an artery
  

http//health.allrefer.com/health/stroke-secondary
-to-cardiogenic-embolism-stroke-1.html
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Causes of stroke, 4

• Rupture of an artery
• (i.e. hemorrhage)
• Cerebral hemorrhage (bleeding within the brain
  substance)
• Subarachnoid hemorrhage (bleeding between the
  brain and the inside of the skull)

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Necrosis
http//medic.uth.tmc.edu/edprog/PATH/NeuroIIa.HTM
Anemic Infarct. (In general from in situ
thrombotic occlusion).
Hemorrhagic Infarct. There is necrosis in
addition to the hemorrhage. (In general results
from embolic occlusion). Distribution of middle
cerebral artery. (Infarct of end-arterial zone).
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Head trauma

• This is what's left of a Mustang that was being
  driven by a 17 year old high school student who
  decided that they needed a few beer's before
  going to school to "loosen up" before class. Bad
  idea!! A Palm tree got in his way.

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Cranial Volumes
10 Blood
10 CSF
10 Extracellular
70 Intracellular (35 Neuronal - 35 glial)
100 Total Cranial Volume
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How is ICP measured?
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Monitoring ICP
Intraventricular Pressure Catheter
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Intracranial Pressure

• brain swelling
• blood
• (tumor)

The pressure-volume curve of the intracranial
contents. As the volume of an expanding mass
increases, ICP rises only slightly until the
compensatory mechanisms are overcome. This point
is reached at the elbow of the curve when further
expansion of the mass causes a steep rise in ICP.
http//www.fsm.ac.fj/sms/anaesthesia/WFSA/html/u09
/u09_019.htm
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Normally Blood Pressure gt Intracranial Pressure
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Causes of stroke

• Rupture of an artery
• (i.e. hemorrhage)
• Cerebral hemorrhage (bleeding within the brain
  substance)
• Subarachnoid hemorrhage (bleeding between the
  brain and the inside of the skull)

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Increased Tissue Mass
? ICP
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What does intracranial hypertension do to
neurological function?
Cerebral Perfusion Pressure (mean
arterial blood pressure) - (ICP) If ICP gt MAP
then blood flow to the CNS ceases!
MAP
ICP
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Acute Respiratory Failure
( drug overdose )
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Disorders of Ventilatory Control

• Acute respiratory failure results from
  overdosing
• sedatives
• opiates
• narcotics
• anesthesia
• In each case, ? lung ventilation due to
• ? input from brainstem reticular activating
  system
• ? input from respiratory rhythm generator
• ? CO2 sensitivity of the central peripheral
  chemoreceptors (brain cells that increase
  breathing)

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Respiratory Failure

• Ultimately, results in abnormal breathing
  patterns
• which ? pulmonary ventilation,
• which decreases ventilation-perfusion matching,
• leading to poor blood gases,
• CNS hypoxia
• and eventually, death (brain cells cease to
  function).

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5. Re-oxygenation
???
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Reactive Oxygen Species (ROS)
J.D. Balentine (1982), p. 53
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Reperfusion Injury
http//www.theresurrector.com/img/freeradicals.jpg
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Re-oxygenation ? superoxide
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Hyperoxia excess oxygen Superoxide
production(CA1 hippocampus)
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Oxidative Stress
SIGMA-ALDRICH
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Re-oxygenation injury
Reactive Oxygen Species
( oxidative stress, too many O2 free radicals )
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6. Disturbed Electrical Signaling
http//cti.itc.virginia.edu/psyc220/kalat/JK237.f
ig8.8.principle_area.jpg
61
http//camilolab.slu.edu/444/graphics/Leeson6-12.j
pg
http//www.alscenter.org/images/human_motor_system
_400pix.gif
62
http//www.ia.wvu.edu/magazine/issues/spring2003/
htmlfiles/wheelchair.html
http//stuserv.fullcoll.edu/images/Wheel20chair2
0student2.jpg
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Homunculus
http//www.phrenology.com/homunculus.html
http//lcbr.ss.uci.edu/Courses/cog_neuro/lecture_s
lides/motor_system/Slide4.jpg
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Neuron
http//www.mb.jhu.edu/tins/media/200420Neuron20S
chema1.jpg
http//www.awa.com/norton/figures/fig0209.gif
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Action Potential
http//www.awa.com/norton/figures/fig0209.gif
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Action Potential
http//www.awa.com/norton/figures/fig0209.gif
http//gargoyle.arcadia.edu/psychology/blustein/ne
uro/Lecture_Notes/Week_1/Week_2/Action_Potential.j
pg
67
D.K. Mulkey et al. (2003) J Appl Physiol
95910-921
68
March 1999 (Volume 40, Number 3) CMJEarly
Effects of Hypoxia on Brain Cell
FunctionKrešimir KrnjeviæAnaesthesia Research
Department, McGill University, Montréal, Quebec,
Canada
http//www.cmj.hr/1999/40/3/400311.htm
69
CA1 population spike response to CA3 stimulation
during HBO2
Evoked Population Spike
Evoked Field EPSP
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Overview

• Introduction What is a disability?
• Important CNS regions (disabilities)
• Oxygen and CNS function
• Cerebral blood flow Oxygen transport
• CNS Hypoxia / Anoxia
• Stroke
• Head Injury intracranial hypertension
• Respiratory failure
• Re-oxygenation (blood flow is restored)
• Disturbed electrical signaling