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IMAGING CELLULAR MECHANISMS OF MIGRAINE

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Title: IMAGING CELLULAR MECHANISMS OF MIGRAINE


1
IMAGING CELLULAR MECHANISMS OF MIGRAINE
Andrew Charles, M.D. Professor Director, Headache
Research and Treatment Program Department of
Neurology UCLA School of Medicine
2
Bilateral Spreading Cerebral Hypoperfusion during
Spontaneous Migraine HeadacheRoger P. Woods,
Marco Iacoboni, and John C. MazziottaNEJM
3311689-92, 1994
3
(No Transcript)
4
Oleson, et al. 1981
Woods et al., 1994
Hadjikhani et al., 2001
Cao et al., 1999
5
CELLULAR IMAGING MODALITIES FOR INVESTIGATION OF
MIGRAINE
  • Fluorescence imaging
  • Cells are loaded or labeled with indicators that
    change their fluorescence intensity in response
    to changes in cellular characteristics (calcium,
    other ions, membrane potential, cellular
    messengers)
  • Optical intrinsic signal imaging
  • Brain tissue is directly illuminated and light
    that is either reflected or transmitted is
    recorded. Recording at different wavelengths
    emphasizes different components of signal (blood
    volume, hemoglobin oxygenation, change in
    extracellular space, ? mitochondrial swelling,
    etc.)

6
POTENTIAL CELLULAR SUBSTRATES FOR PROPAGATED
CORTICAL PHENOMENA IN MIGRAINE
  • NEURONS
  • GLIAL CELLS
  • ASTROCYTES, OLIGODENDROCYTES, MICROGLIA
  • VASCULAR CELLS
  • ENDOTHELIAL CELLS, PERICYTES, SMOOTH MUSCLE CELLS

7
FLUORESCENCE IMAGING OF INTRACELLULAR
Ca2 Cortical Neuronal Culture
8
ASTROCYTES
  • OUTNUMBER NEURONS BY UP TO 5x
  • RATIO OF NEURONS TO ASTROCYTES DIFFERENT IN
    DIFFERENT BRAIN REGIONS (E.G. GREATEST IN
    OCCIPTIAL CORTEX)
  • CLOSE RELATIONSHIP WITH SYNAPSE AND WITH
    VASCULATURE
  • RECEPTORS FOR A VARIETY OF NEUROTRANSMITTER
    RECEPTORS
  • CAPABLE OF EXTENSIVE INTERCELLULAR SIGNALING

9
Intercellular Calcium Wave Mixed Glial Culture
Real Time
10
Neurotransmitters
Mechanical Stimulation
Low Extracellular Ca
2
Ca
2
PLC
Ca
2
V
D
V
D
D
V
D
V
m
m
m
m
IP
IP
IP
3
3
PIP
3
2
IP
Ca
2
IP
3
3
Ca
2
Ca
2
Ca
2
Ca
2
Ca
2
?
Ca
2
Ca
2
Ca
2
Ca
2
Ca
2
Ca
2
Ca
2
Ca
2
Ca
2
Ca
2
Ca
2
Ca
2
Ca
2
A MODEL FOR GLIAL CALCIUM WAVES
11
AN EXTRACELLULAR MESSENGER
12
GLIAL CALCIUM WAVES ARE MEDIATED BY RELEASE OF ATP
  • LUCIFERASE ASSAY DEMONSTRATES RELEASE OF ATP
  • PURINERGIC RECEPTOR ANTAGONISTS BLOCK CALCIUM
    WAVES
  • APYRASE (ATP DEGRADING ENZYME) BLOCKS CALCIUM
    WAVES
  • DETECTOR CELLS EXPRESSING PURINERGIC RECEPTORS
    RESPOND TO GLIAL CALCIUM WAVES

13
GLIAL CALCIUM WAVES
  • ASSOCIATED WITH ACTIVE RELEASE OF
  • ATP
  • GLUTAMATE
  • K
  • EICOSANOIDS
  • LACTATE
  • MODULATE
  • NEURONAL ACTIVITY VIA TRANSMITTER RELEASE (Araque
    et al., 1999 Fellin et al., 2004)
  • NEURONAL/VASCULAR METABOLISM VIA LACTATE RELEASE
    (Paemeleire, 2000 Bernadelli et al., 2004)
  • VASCULAR TONE VIA ARACHIDONIC ACID, EICOSANOID
    RELEASE, AND ATP (?) RELEASE (Zonta et al., 2003
    Filosa et al., 2004 Mulligan et al., 2004)

14
.
.
Endothelial Cell
Endothelial Cell
Meningeal
Cell
Meningeal
Cell
Neurons
Neurons
Glutamate
ATP Adenosine
ATP Adenosine
Neurotransmitters
Neurotransmitters
2
Ca
Ca
K
-
-
ATP
ATP
Mechanical stimulus
Mechanical stimulus
Mg
2
Mg

DAG
PLC
Glutamate
PLC
ATP
Glutamate
ATP
PLC
K
PLC


PIP
PIP
IP
IP
2
2
2
2
Ca
Ca
3
3
IP
IP
PIP
PIP
3
IP
3
IP
2
2
3
3
Connexin Hemichannel
Ca
2
Ca
2
Ca
2
Ca
2
Ca
2
Ca
2
2
2
Ca
Ca
Ca
2
Ca
2
?
?
Ca
2
Ca
2
Ca
2
Ca
2
Ca
2
Ca
2
2
2
2
2
Ca
Ca
Ca
Ca
2
2
Ca
Ca
Ca
2
Ca
2
Ca
2
Ca
2
ASTROCYTE
ASTROCYTE
ASTROCYTE
ASTROCYTE
15
Glial Ca2 Waves in Hippocampal Slice
Culture Time Lapse Sequence of 5 Minute Recording
16
DO GLIAL WAVES PLAY A ROLE IN MIGRAINE?
  • SIMILAR TEMPORAL AND SPATIAL CHARACTERISTICS AS
    MIGRAINE EVENTS
  • ASSOCIATED RELEASE OF ATP, GLUTAMATE, AND OTHER
    NEURO- AND VASO-ACTIVE SUBSTANCES
  • ASSOCIATED CHANGES IN EXTRACELLULAR IONIC
    COMPOSITION
  • INTIMATE SPATIAL RELATIONSHIPS WITH SYNAPSE AND
    VASCULATURE
  • COULD EXPLAIN DRAMATIC PROPAGATION WITH
    RELATIVELY MILD NEUROLOGICAL SYMPTOMS

17
ATP RELEASED BY GLIAL CELLS IS RAPIDLY METABOLIZED
TO ADENOSINE, WHICH INHIBITS NEURONS
18
ADENOSINE CAUSES RAPID AND REVERSIBLE
INHIBTION OF NEURONAL ACTIVITY
19
ADENOSINE INHIBITS SPONTANEOUS ACTIVITY IN
CORTICAL NEURONS
20
ADENOSINE AS A NEURO-MODULATOR AND VASO-MODULATOR
  • MULTIPLE RECEPTOR SUBTYPES WITH CELL-SPECIFIC
    ACTIONS
  • PRIMARILY INHIBITORY EFFECT ON NEURONS
  • MAY ACTIVATE GLIAL CELLS
  • DILATES PIAL BLOOD VESSELS
  • CAFFEINE IS AN ADENOSINE RECEPTOR ANTAGONIST

21
HYPOTHESIS
GLIAL CALCIUM WAVES MEDIATE PROPAGATED CORTICAL
PHENOMENA IN MIGRAINE VIA RELEASE OF ATP WHICH IS
METABOLIZED TO ADENOSINE
22
(No Transcript)
23
GLIAL CALCIUM WAVES AND SPREADING DEPRESSION
  • GLIAL CALCIUM WAVES ARE OBSERVED IN CONJUNCTION
    WITH ELECTROPHYSIOLOGICAL SPREADING DEPRESSION IN
    BRAIN SLICES (Basarsky et al., 1998 Kunkler et
    al., 1998 Peters et al., 2003)
  • GLIAL CALCIUM WAVES CAN BE DISSOCIATED FROM
    SPREADING DEPRESSION IN THESE PREPARATIONS
  • RELATED BUT DISTINCT PHENOMENA WITH INDEPENDENT
    MECHANISMS OF PROPAGATION

24
Luis Beltran-Parrazal
K.C. Brennan
Calcium imaging Electrophysiology
OIS Imaging and Electrophysiology Cortical
spreading depression
25
OPTICAL INTRINSIC SIGNAL SPREADING DEPRESSION
EVOKED BY KCl PULSE RAT CORTEX (Compressed 5 min
recording)
26
Regions of interest
27
Arteriolar dilatation precedes parenchymal onset
of CSD
28
OIS IMAGING OF CSD
  • PROPAGATED WAVE OF CHANGE IN REFLECTANCE WITH AT
    LEAST 4 PHASES
  • IMAGING AT DIFFERENT WAVELENGTHS EMPHASIZES
    DIFFERENT CELLULAR/VASCULAR PHENOMENA
  • MULTIPHASIC ARTERIAL RESPONSE THAT MAY PRECEDE
    WAVE OF OPTICAL SIGNAL

29
HYPOTHESIS
GLIAL CALCIUM WAVES MEDIATE PROPAGATED CORTICAL
PHENOMENA IN MIGRAINE VIA RELEASE OF ATP,
GLUTAMATE, AND K
30
Glial Calcium Waves In Hippocampal Slice
Recurrent CSD Evoked By KCL Crystal
SIMILAR TEMPORAL AND SPATIAL PATTERNS OF GLIAL
CALCIUM WAVES AND OIS SIGNAL OF CSD
31
CONNEXIN CHANNEL BLOCKER FLUFENAMIC ACID INHIBITS
GLIAL Ca2 WAVES AND ATP RELEASE
IN 50 mM FLUFENAMIC ACID
CONTROL
32
FLUFENAMIC ACID REVERSIBLY INHIBITS SPREADING
DEPRESSION
33
Control
CGS 15943 10 mM
AN ADENOSINE RECEPTOR ANTAGONIST (CGS15943)
INHIBITS THE VASCULAR RESPONSE TO CSD
34
CGS 15943 attenuates vascular reactivity during
CSD
250 µm
250 µm
35
RELATED PHENOMENA
  • GLIAL CALCIUM WAVES
  • SPREADING DEPRESSION
  • SPREADING HYPER/OLIGEMIA OF MIGRAINE SEEN ON PET,
    fMRI
  • CLINICAL MANIFESTATIONS OF MIGRAINE AURA

36
NEURONAL ACTIVATION
GLIAL WAVES?
GLUTAMATE RELEASE
ATP RELEASE (?)
INCREASED K
SPREADING DEPRESSION
SPREADING HYPER/ OLIGEMIA
BRAINSTEM ACTIVATION
PEPTIDERELEASE
VESTIBULAR SYMPTOMS
PAIN
AURA
Nausea
37
CONCLUSIONS
  • MICROSCOPIC IMAGING REVEALS MULTIPLE POTENTIAL
    CELLULAR COMPONENTS OF MIGRAINE
  • GLIAL CELLS MAY PLAY AN IMPORTANT ROLE
  • INDIVIDUAL MIGRAINE PHENOMENA MAY INVOLVE
    DISTINCT CELLULAR SIGNALING PATHWAYS WITH
    DISTINCT THRESHOLDS

38
(No Transcript)
39
ACKNOWLEDGEMENTS
  • CHARLES LAB
  • Marni Harris-White
  • Luis Beltran-Parrazal
  • K.C. Brennan
  • UCLA LABORATORY OF NEUROIMAGING
  • Arthur Toga
  • Michael Guiou
  • MICHAEL SANDERSON - University of Massachussetts
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