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Brainstem 1H nuclear magnetic resonance (NMR) spectroscopy Marker of demyelination and repair in spinal cord.

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BRIEF COMMUNICATIONS
References
1. Rutland-Brown W, Langlois JA, Thomas KE, Xi YL. Incidence
of traumatic brain injury in the United States, 2003. J Head
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2. Baumann CR, Werth E, Stocker R, et al. Sleep-wake disturbances 6 months after traumatic brain injury: a prospective
study. Brain 2007;130:1873–1883.
3. Castriotta RJ, Wilde MC, Lai JM, et al. Prevalence and consequences of sleep disorders in traumatic brain injury. J Clin
Sleep Med 2007;3:349 –356.
4. Baumann CR, Stocker R, Imhof HG, et al. Hypocretin-1
(orexin A) deficiency in acute traumatic brain injury. Neurology
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5. España RA, Scammell TE. Sleep neurobiology for the clinician.
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early onset narcolepsy and a generalized absence of hypocretin
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loss of dynorphin, NARP, and orexin in narcolepsy. Neurology
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Brainstem 1H Nuclear
Magnetic Resonance (NMR)
Spectroscopy: Marker of
Demyelination and Repair
in Spinal Cord
Aleksandar Denic, MD,1 Allan Bieber, PhD,1
Arthur Warrington, PhD,1 Prasanna K. Mishra, PhD,2
Slobodan Macura, PhD,2 and Moses Rodriguez, MD1
Measuring in vivo spinal cord injury and repair remains elusive. Using magnetic resonance spectroscopy (MRS) we examined brainstem N-acetyl-aspartate (NAA) as a surrogate
for spinal cord injury in two mouse strains with different
reparative phenotypes following virus-induced demyelination. Swiss Jim Lambert (SJL) and Friend Virus B (FVB)
mice progressively demyelinate with axonal loss. FVB mice
demyelinate similarly but eventually remyelinate coincident
with functional recovery. Brainstem NAA levels drop in both
but recover in FVB mice. Chronically infected SJL mice lost
30.5% of spinal cord axons compared to FVB mice (7.3%).
In remyelination-enhancing or axon-preserving clinical trials,
brainstem MRS may be a viable endpoint to represent overall
spinal cord dysfunction.
Ann Neurol 2009;66:559 –564
New, noninvasive technologies to evaluate spinal cord
injury and repair are needed. Proton magnetic resonance spectroscopy (1H-MRS) is one ideal method;
however, because the spinal cord is small and surrounded by bone, direct spectroscopy has been limited.
During retrograde labeling studies of demyelinated spinal cord axons, we observed a reduction in neuron cell
bodies in the brainstem labeled with fluorescent markers indicating death or dysfunction.1 This led to the
concept that neuron health measured at the brainstem
with MRS may reflect the integrity of many ascending
and descending spinal cord pathways. By following
virus-induced spinal cord disease in two strains of
From the Departments of 1Neurology and 2Biochemistry, Mayo
Clinic College of Medicine, Rochester, MN.
Address correspondence to Dr Moses Rodriguez, Department of Neurology, Mayo Medical School, Guggenheim 442B, 200 First Street,
SW, Rochester, MN 55905. E-mail: rodriguez.moses@mayo.edu
Additional Supporting Information may be found in the online version of this article.
Potential conflict of interest: Nothing to report.
Received Feb 12, 2009, and in revised form Apr 29. Accepted for
publication May 18, 2009. Published online in Wiley InterScience
(www.interscience.wiley.com). DOI: 10.1002/ana.21758
© 2009 American Neurological Association
559
mice, we show that chronic demyelination with axonal
loss and remyelination with axonal preservation result
in different brainstem MRS signatures. This provides
proof in principle that assessment of brainstem MRS in
humans may serve as a surrogate marker of spinal cord
axonal health or injury.
Theiler’s murine encephalomyelitis virus (TMEV) infection in susceptible strains of mice results in immunemediated chronic central nervous system (CNS) demy-
elination and is an excellent model for multiple sclerosis
(MS).2 Histopathology includes focal demyelinated lesions, inflammation, axonal damage, glial scars, and
rarely remyelination. Infection of Swiss Jim Lambert
(SJL) mice results in chronic demyelination with very
little remyelination, whereas infection of Friend Virus B
(FVB) mice results in similar extent of demyelination
followed by almost complete remyelination (Fig 1). Retrograde labeling demonstrated significant injury to axons
and their corresponding neurons in the brainstem in SJL
mice but only limited injury in FVB mice.3
1
H-MRS is a noninvasive method that enables in vivo
quantification of metabolites in the brainstem. Important MRS peaks in nervous tissue are N-acetyl aspartate
(NAA), myo-inositol, creatine/phosphocreatine (Cr),
and choline-containing compounds (Cho). NAA is the
most abundant free amino acid in nervous tissue.4 NAA
concentration is considered to reflect primarily neuronal
and axonal integrity because NAA is almost exclusively
restricted to neurons. The MR spectral profile of purified CNS cells indicates that NAA signal amplitude is
predominant in neurons. NAA signal amplitude in purified cultures of oligodendrocytes or astrocytes was 5%
and 10% of the neuron signal, respectively.5 In the
MRS spectrum, the dominant NAA peak occurs at
2.02ppm, originating from three N-acetyl methyl group
protons.4 The area under the MRS peak is proportional
to the number of spins in the group and can be converted into molar concentration, after proton number
normalization.6 NAA decreases in neurons after injury
and is a marker of integrity. A decrease of NAA concentration occurs early in disease in normal-appearing white
matter of MS patients.7–10 Of importance, the relative
NAA concentration correlates with the neurologic disability in MS patients.11 In this study, we used brainstem MRS as a surrogate marker for spinal cord neuronal integrity in strains of mice with different phenotypes
of virus-induced demyelinating disease.
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Annals of Neurology
Vol 66
No 4
October 2009
Fig 1. SJL and FVB mouse strains differ in the extent of remyelination in the chronic stages of TMEV-induced demyelinating
disease. Is this based on a difference in axon preservation and
can MRS at the brainstem be used in a correlative study? (A)
Example of a demyelinated lesion in an SJL mouse at 270 days
postinfection. (B) Example of a remyelinated lesion in a FVB
mouse at 270 days postinfection (Scale ⫽ 100␮m). (C) Positioning of the region of interest (ROI) voxel over a mouse
brainstem. A very short tripilot MRI scan was used to obtain
images in three orthogonal planes in order to position the
(2.5 ⫻ 2.5 ⫻2.5mm3) voxel according to anatomic landmarks.
(D) A 300MHz, 1H overlapping spectra collected at the mouse
brainstem. Red-colored spectrum is from a healthy, uninfected
mouse and black is from an infected mouse. Choline (Cho),
creatine (Cr), and N-acetyl-aspartate (NAA) are the dominant
peaks. The spectra are referenced to the residual water peak at
4.7ppm and normalized to the creatine peak.
Fig 2. NAA concentrations detected at the brainstem by MRS used to follow the spinal cord demyelinating disease progression in a virusmediated mouse model of multiple sclerosis. (A, C) MRS cross-sectional study was used to compare groups of eight to 10 infected and uninfected SJL and FVB mice. The NAA concentration was significantly decreased in both SJL and FVB mice at 90 days postinfection compared to uninfected mice of the same strains (p ⬍ 0.0001). Bars represent the means of absolute NAA concentrations of the group with
standard error of the mean. At this time both strains present with an equivalent extent of spinal cord demyelination. At 270 days postinfection, NAA concentrations in SJL mice remained low, while in FVB mice the NAA concentration recovered to normal. At this time FVB
mice are completely remyelinated and neurologic deficits are reversed. We interpret this study to show that MRS at the brainstem is detecting a difference in axon preservation that correlates with disability. (B, D) Longitudinal time course study was used to better define the
temporal changes in brainstem NAA levels. Individuals from groups of 15 SJL and FVB mice were monitored prior to TMEV infection
and repeatedly as disease progressed out to 270 days postinfection. Bars represent the means of NAA concentrations of the group with standard error of the mean. Changes in NAA concentration were consistent with those recorded in the previous study (A, C). In both mouse
strains NAA concentration decreased through 180 days postinfection. NAA concentrations remained low in infested SJL mice, but recovered
in FVB mice at the 270-day time point to a level comparable to that prior to infection. Comparison of NAA concentrations for SJL (day
0 vs. day 21 through day 270, p ⬍ 0.001) and for FVB (day 0 vs. day 90, p ⬍ 0.001; day 0 vs. day 270, p ⫽ 0.071; day 90 vs. day
270, p ⬍ 0.001). We interpret this study to indicate that more axons are preserved in FVB mice so that a larger population is available
as a substrate for remyelination. Remyelinated axons regain function and reversed NAA concentrations in the brainstem.
Materials and Methods
Mice
begin 3 months after infection, correlating with neurologic
dysfunction.12
SJL/J and FVB/NJ mice (Jackson Laboratories, Bar Harbor,
ME) were housed and bred in the Mayo Clinic’s animal care
facility. Animal protocols were approved by the Mayo Clinic
Institutional Animal Care and Use Committee.
MRS
Theiler’s Virus Model of Demyelination
Demyelinating disease was induced in 6- to 8-week-old mice
by intracerebral injection of TMEV. See Supporting Methods for more details on virus infection. Axon injury and loss
MRS was performed using a Bruker Avance 300MHz (7T)
vertical bore nuclear magnetic resonance (NMR) spectrometer
(Bruker Biospin, Billerica, MA) equipped with mini- and microimaging accessories. During data acquisition, animal core
temperature was maintained at 37°C by a flow of warm air.
Inhalational isoflurane anesthesia 1.5% to 2.5% in oxygen was
delivered via nose cone. MRS data were obtained from a
Denic et al: Brainstem MRS Spinal Cord Marker
561
2.5 ⫻ 2.5 ⫻ 2.5mm3 voxel, placed over the brainstem (Fig
1C) and a 3 ⫻ 3 ⫻ 3.5mm3 voxel placed over the striatum as
a control (Supporting Fig 1A). Spectra were processed and analyzed with TOPSPIN, Bruker Biospin’s proprietary software.
NAA was quantified by comparing the areas under NAA peaks
from the brainstem with the area under the same peak in a test
phantom standard with known concentration, recorded under
identical conditions, as explained in detail in the Supporting
Methods. Overlapping spectra from a healthy and infected
mouse are shown (Fig 1D).
An Olympus Provis AX70 microscope that was fitted with a
DP70 digital camera and a 60⫻ oil-immersion objective was
used to capture six sample areas of normal-appearing white
matter containing a relative absence of demyelination from
each cross-section, according to the sampling scheme in Fig
3A. Approximately 400,000␮m2 of white matter was sampled from each mouse. Absolute myelinated axon numbers
were calculated as previously reported.13 Methods for brain
pathology scores are described in the Supporting Information.
Spinal Cord Pathology and Axonal Counts
Statistics
Mice were perfused and spinal cords embedded in araldite
plastic (see Supporting Methods for details on morphology).
Data were compared by Student’s t test if normally distributed or by Mann-Whitney Rank sum test if nonnormally
distributed. More than two groups were compared by analysis of variance (ANOVA); p ⬍ 0.05 was considered significant.
Results
Cross-Sectional Mouse Strain Comparison
MRS was collected from three groups of SJL and
FVB mice (n ⫽ 8 –10): normal uninfected, 90 days
postinfection and 270 days postinfection. At 90 days
postinfection brainstem NAA concentrations decreased in both strains compared to uninfected controls (Fig 2A, C). At 270 days postinfection, NAA
concentrations in SJL mice remained low, while NAA
levels recovered in FVB mice. This is consistent with
histopathology and disease phenotype—SJL mice developed axon loss following demyelination12 whereas
FVB mice repaired.1
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Annals of Neurology
Vol 66
No 4
October 2009
Fig 3. The absolute number of myelinated axons at the T6
level of the spinal cord is greater in chronically TMEV-infected
FVB mice compared to infected SJL mice. (A) Demonstration of
the sampling scheme used to collect images to calculate number
of myelinated axons from a mid-thoracic section of each animal.
Images of six sample areas of normal-appearing white matter
containing a relative absence of demyelination were collected
from a cross-section, converted to black and white, and complete
circular objects counted using a macro written in Matlab (The
Mathworks, Natick, MA). Approximately 400,000␮m2 of
white matter was sampled from each mouse. Axons were
counted in the normal-appearing white matter because this provided a global representation of the axon loss from multiple,
randomly distributed demyelinated lesions throughout the spinal
cord. (B) The absolute number of axons in uninfected and 90day and 270-day postinfected SJL and FVB mice. Bars represent the means of the group with standard error of the mean.
In SJL mice there were fewer axons present at 270 days postinfection compared to uninfected age-matched controls (p ⬍
0.001). In FVB mice axons present at 270 days postinfection
were no different than in uninfected controls (p ⫽ 0.134). (C,
D) Positive correlation between brainstem NAA concentrations
and number of axons in chronically infected SJL mice (C) and
FVB mice (D).
Longitudinal Changes in Brainstem NAA
To characterize the temporal changes in NAA concentrations through disease in individual mice, MRS was
performed in groups of SJL and FVB mice (n ⫽ 15)
prior to TMEV infection and at 21, 45, 90, 180, and
270 days after infection (Fig 2). Confirming our first
study, NAA concentrations fell in both strains at 90 days
after infection and remained low 90 days later. Again, at
270 days postinfection, NAA levels recovered close to
baseline in FVB mice but remained low in SJL mice
(Fig 2B, D). In a separate cohort of SJL and FVB mice
at 0, 90, and 270dpi, MRS was performed over the striatum as a control for the brainstem values. No differences were found in NAA concentrations in the striatum
(Supporting Fig 1B). In the same cohort of infected
mice, hemispheric and brainstem MRI was performed,
showing no lesions (Supporting Fig 2A–H). Brain pathology assessment did not reveal significant difference between the two strains ( p ⫽ 0.216) (Supporting Fig 2I, J).
Axon Loss in Chronically Diseased Mice
At the end of the longitudinal study, axons were
counted in the normal-appearing spinal cord white matter at T6 in each mouse (Fig 3B). There were 30.5%
fewer axons in SJL mice at 270dpi compared to agematched uninfected controls ( p ⬍ 0.001). In contrast,
there were 7.3% fewer axons in FVB mice at 270dpi,
which was not different from uninfected controls ( p ⫽
0.134). We found positive correlation between brainstem NAA concentrations and axon counts in both
mouse strains (Fig 3C, D). For SJL mice, r ⫽ 0.823
( p ⫽ 0.012) and for FVB mice r ⫽ 0.775 ( p ⫽ 0.005).
Discussion
Infection of susceptible strains of mice with TMEV induces inflammatory demyelination in the spinal cord.3
In SJL mice, demyelination begins several weeks after
infection with minimal remyelination and progressive
neurologic deficits. FVB mice are similar in ancestry to
SJL mice14 but differ at the MHC H-2 locus. By 3
months after infection, spinal cord demyelination is
equivalent in the two strains. However, 3 months
postinfection, the disease progression diverges. SJL remain demyelinated, whereas FVB mice completely remyelinate and recover neurologic function.3
Retrograde labeling at the T6 level of the spinal cord
with the fluorescent tracer Fluoro-Gold1 shows that demyelination in SJL mice is accompanied by axonal loss,
detected as a decrease of fluorescent brainstem neurons.
Most lesions occur at the cervical and thoracic level.
Therefore, a reduction in the number of labeled brainstem
cells occurs because of disturbed retrograde transport or
axonal degeneration.12 When compared to uninfected
controls, chronically infected SJL mice show ⬎70% reduction in retrograde-labeled brainstem cells. At 270 days
after infection, the brainstem is not demyelinated by elec-
tron microscopy; thus, the changes in MRS in brainstem
are a result of retrograde injury from the spinal cord.
MRS is widely used in models of neurologic disease.
To our knowledge, this is the first study using MRS at
the brainstem as a surrogate marker for axonal injury
and demyelination throughout the spinal cord.
Two possible explanations for the recovery of NAA
levels in FVB mice are: (1) brainstem neurons are only
injured—not destroyed—during demyelination and
regain function as repair progresses; or (2) brainstem
neurons are lost, but later replaced by precursor cells.
Because disability in human MS patients is often determined primarily by spinal cord lesion load, MRS at the
brainstem may predict disease progression. MRS at the
brainstem may also be a viable endpoint in clinical trials
designed to preserve or protect axons in the spinal cord.
This work was supported by grants from the National Institutes of
Health (NIH) (NS R01 24180, NS R0132129, NS048357); National Multiple Sclerosis Society (RG 3172, CA 1011A8); Applebaum Foundation; and Hilton Foundation.
We appreciate the editorial assistance of Lea Dacy.
References
1. Ure D, Rodriguez M. Extensive injury of descending neurons
demonstrated by retrograde labeling in a virus-induced murine
model of chronic inflammatory demyelination. J Neuropathol
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2. Pirko I, Johnson A, Gamez J, et al. Disappearing “T1 black
holes” in an animal model of multiple sclerosis. Front Biosci
2004;9:1222–1227.
3. Bieber AJ, Ure DR, Rodriguez M. Genetically dominant spinal
cord repair in a murine model of chronic progressive multiple
sclerosis. J Neuropathol Exp Neurol 2005;64:46 –57.
4. Govindaraju V, Young K, Maudsley AA. Proton NMR chemical shifts and coupling constants for brain metabolites. NMR
Biomed 2000;13:129 –153.
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brain. Science 2007;318:980 –985.
6. Drost DJ, Riddle WR, Clarke GD. Proton magnetic resonance
spectroscopy in the brain: report of AAPM MR task group #9.
Med Phys 2002;29:2177–2197.
7. Filippi M, Tortorella C, Bozzali M. Normal-appearing white
matter changes in multiple sclerosis: the contribution of magnetic resonance techniques. Mult Scler 1999;5:273–282.
8. Rooney WD, Goodkin DE, Schuff N et al. 1H MRSI of normal appearing white matter in multiple sclerosis. Mult Scler
1997;3:231–237.
9. Roser W, Hagberg G, Mader I, et al. Proton MRS of gadoliniumenhancing MS plaques and metabolic changes in normal-appearing
white matter. Magn Reson Med 1995;33:811– 817.
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NMR proton spectroscopy of normal appearing white matter in
patients with multiple sclerosis. J Neuroradiol 1996;23:49 –55.
11. De Stefano N, Matthews PM, Fu L, et al. Axonal damage correlates with disability in patients with relapsing-remitting multiple sclerosis. Results of a longitudinal magnetic resonance
spectroscopy study. Brain 1998;121(Pt 8):1469 –1477.
Denic et al: Brainstem MRS Spinal Cord Marker
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BRIEF COMMUNICATION
12. McGavern DB, Murray PD, Rivera-Quinones C, et al. Axonal
loss results in spinal cord atrophy, electrophysiological abnormalities and neurological deficits following demyelination in a
chronic inflammatory model of multiple sclerosis. Brain 2000;
123(Pt 3):519 –531.
13. Howe CL, Adelson JD, Rodriguez M. Absence of perforin expression confers axonal protection despite demyelination. Neurobiol Dis 2007;25:354 –359.
14. Beck JA, Lloyd S, Hafezparast M, et al. Genealogies of mouse
inbred strains. Nat Genet 2000;24:23–25.
Androgenic Suppression of
Spreading Depression in
Familial Hemiplegic Migraine
Type 1 Mutant Mice
Katharina Eikermann-Haerter, MD,1
Michael J. Baum, PhD,2 Michel D. Ferrari, MD,3
Arn M.J.M. van den Maagdenberg, PhD,3,4
Michael A. Moskowitz, MD,1 and Cenk Ayata, MD1,5
Familial hemiplegic migraine type 1 (FHM1), a severe migraine
with aura variant, is caused by mutations in the CACNA1A
gene. Mutant mice carrying the FHM1 R192Q mutation exhibit increased propensity for cortical spreading depression
(CSD), a propagating wave of neuroglial depolarization implicated in migraine aura. The CSD phenotype is stronger in female R192Q mutants and diminishes after ovariectomy. Here,
we show that orchiectomy reciprocally increases CSD susceptibility in R192Q mutant mice. Chronic testosterone replacement
restores CSD susceptibility by an androgen receptor-dependent
mechanism. Hence, androgens modulate genetically-enhanced
CSD susceptibility and may provide a novel prophylactic target
for migraine.
Ann Neurol 2009;66:564 –568
Familial hemiplegic migraine (FHM) is an autosomal
dominant subtype of migraine with aura associated
with transient hemiparesis. Aura and headache features
From the Stroke and Neurovascular Regulation Laboratory, Departments of 1Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, 2Department of Biology, Boston University, Boston, MA; Departments of 3Neurology and Human
Genetics, Leiden University Medical Centre, Leiden, The Netherlands, 4Stroke Service and Neuroscience Intensive Care Unit, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA.
Address correspondence to Dr. Cenk Ayata, MD, Stroke and Neurovascular Regulation Laboratory, Massachusetts General Hospital,
149 13th Street, Room 6403, Charlestown, MA 02129. E-mail:
cayata@partners.org
are otherwise identical to those in common forms of
migraine.1 FHM1 is caused by missense mutations in
the CACNA1A gene, which encodes the pore-forming
␣1A-subunit of neuronal Cav2.1 voltage-gated Ca2⫹
channels (VGCC).2 When expressed in transfected cultured neurons, FHM1 mutations shift channel opening
toward more negative membrane potentials and delay
channel inactivation. Channels open with smaller depolarization and stay open longer, allowing more Ca2⫹
to enter presynaptic terminals.3,4 Increased action
potential-evoked Ca2⫹ influx has been shown to enhance excitatory neurotransmission at pyramidal cell
synapses of FHM1 mutant mice.5 Accordingly, mutant
mice carrying the FHM1 R192Q mutation show enhanced susceptibility to cortical spreading depression
(CSD), the electrophysiological correlate of migraine
aura, and a possible trigger of migraine headache
mechanisms.4,6 – 8 CSD is characterized by an intense
depolarization of neuronal and glial membranes propagating at a rate of ⬃3mm/minute. Evoked when extracellular K⫹ concentrations exceed a critical threshold, CSD is associated with massive K⫹ and glutamate
efflux, depolarizing adjacent neurons and glia and facilitate CSD spread.
Gonadal hormones are important modulators of migraine and cortical excitability.9,10 Incidence of common types of migraine both with or without aura is
three-fold higher in females (25%) than in males
(8%).11 A female preponderance has also been described for familial (5:2) and sporadic (4.25:1) hemiplegic migraine.1,12
Brennan et al.13 recently reported that KCl and electrical stimulation thresholds for CSD induction are
both reduced by approximately 50% in wild-type
(WT) female mice compared to males. We found a
similar increase in CSD susceptibility in female FHM1
knockin mice compared to males; the sex difference
was abrogated by ovariectomy and partly restored by
estradiol replacement, suggesting that estrogens modulate CSD susceptibility.7 Although the female preponderance of migraine has been largely attributed to ovarian sex steroids, anecdotal evidence suggests a role for
testosterone and its synthetic derivatives in suppressing
migraine in both men and women.14 –16 Here, we provide in vivo experimental evidence for androgenic suppression of CSD susceptibility, as a surrogate model for
migraine aura. The data suggest that male and female
gonadal hormones exert reciprocal effects on CSD susceptibility, and that androgens may contribute to the
lower prevalence of FHM and common types of migraine in males.
Potential conflict of interest: Nothing to report.
Materials and Methods
Received Feb 19, 2009, and in revised form Jun 7. Accepted for
publication Jun 8, 2009. Published online in Wiley InterScience
(www.interscience.wiley.com). DOI: 10.1002/ana.21779
Experimental groups and the number of mice in each group
are shown in the Table (n ⫽ 106). Adult (4 – 8 months) or
senescent (11–13 months) male FHM1 knockin mice, ho-
564
© 2009 American Neurological Association
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