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Ibuprofen and the mouse model of Parkinson's disease.

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Migraine with Aura. A Risk Factor for
Unprovoked Seizures in Children?
Christian Wöber, MD,1 and Çiçek Wöber-Bingöl, MD2
Ludvigsson and colleagues1 point out that children with migraine with aura (MA) have a substantially increased risk for
development of subsequent epilepsy. However, the methods
used raise considerable concern about the validity of this
conclusion. In a nationwide surveillance in Iceland, the authors identified children with a first unprovoked seizure and
newly diagnosed epilepsy.
A structured interview was used to assess headache characteristics in 94 patients and 188 control subjects. The interval between the interview and the first seizure is not given.
The authors do not provide data on the time of onset of
migraine. Accordingly, the conclusion that MA patients are
at increased risk for development of subsequent epilepsy is
unfounded. It remains unclear whether the children, the parents, or both were interviewed, an essential point for the validity of data on childhood headache.2 Reducing the minimum number of attacks for diagnosing migraine without
aura from five, as required in the criteria of the International
Headache Society,3 to two may have caused an overestimation of migraine without aura. The authors justify this reduction with an adult study, thereby ignoring age-associated
differences of migraine4; they use the incorrect argument of a
low diagnostic value of five lifetime attacks, and they cite the
wrong references. In addition, a recall bias, as Bille5 demonstrates, cannot be excluded. Patients with a seizure (or their
parents) may recall lifetime headache or aura more likely
than healthy control subjects.
Another matter of concern is the way MA was diagnosed.
It remains unclear whether the authors strictly followed the
International Headache Society criteria. By including “blurry
vision” they definitely did not follow these criteria, because
isolated “blurry vision” is not an accepted symptom of aura.3
Thus, MA probably was overestimated. The authors do not
mention whether they used specific International Headache
Society diagnoses such as typical aura with migraine or nonmigraine headache or typical aura without headache before
classifying all as MA.
Finally, further details on the relation among headaches,
visual symptoms, and seizures are missing. What about headache attributed to epileptic seizure, seizures with visual symptoms, and childhood epilepsy with occipital paroxysms?
In summary, the unclear temporal relation between the
onset of migraine and the occurrence of the first seizure, the
possible overestimation of migraine without aura and MA,
the possible recall bias for lifetime headache and aura, and
the lack of information about the relation among headaches,
visual symptoms, and seizures reduce considerably the validity of Ludvigsson and colleagues’1 article.
Departments of 1Neurology and 2Neuropsychiatry of Childhood
and Adolescence, Medical University of Vienna, Vienna,
1. Ludvigsson P, Hesdorffer D, Olafsson E, et al. Migraine with
aura is a risk factor for unprovoked seizures in children. Ann
Neurol 2006;59:210 –213.
2. Wöber-Bingöl Ç, Wöber C, Karwautz A, et al. Diagnosis of
headache in childhood and adolescence: a study in 437 patients.
Cephalalgia 1995;15:13–21.
3. Headache Classification Subcommittee of the International
Headache Society. The International Classification of Headache
Disorders. 2nd edition. Cephalalgia 2004;24(suppl 1):1–160.
4. Wöber-Bingöl Ç, Wöber C, Karwautz A, et al. Clinical features
of migraine: a cross-sectional study in patients aged three to
sixty-nine. Cephalalgia 2004;24:12–17.
5. Bille B. A 40-year follow-up of school children with migraine.
Cephalalgia 1997;17:488 – 491.
DOI: 10.1002/ana.20842
Ibuprofen and the Mouse Model of Parkinson’s
Iwona Kurkowska-Jastrze˛bska, MD, PhD,1
Andrzej Członkowski, MD, PhD,2
and Anna Członkowska, MD, PhD1,2
Ibuprofen recently has been shown to diminish the risk for
Parkinson’s disease (PD). The mechanism of this effect,
however, remains obscure, because other antiinflammatory
agents do not share this action. In the animal models of PD,
such as the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine
(MPTP) mouse model, ibuprofen has a clear protective effect
similar to other nonsteroidal antiinflammatory drugs
(NSAIDs), but is not toxic to dopaminergic neurons. The
safety for dopaminergic system may be the most important
feature of ibuprofen.
In their recent article, Chen and colleagues1 showed that
the risk for PD is diminished in users of ibuprofen but not
other NSAIDs. Chen and colleagues’1 study was a prospective, long-lasting observation of more than 80,000 men and
more than 90,000 women, which makes us strongly believe
that the presented trend is true.
The use of NSAIDs in neurodegeneration was supported
by the evidence of inflammatory reaction in the place of neurodegeneration and by animal studies showing that NSAIDS
are capable of protecting neurons from various kinds of damage. In the mouse model of PD induced by MPTP intraperitoneal administration, indomethacine2 and rofecoxib3 treatment saved neurons from injury. However, indomethacine
appeared to be toxic in high doses, and rofecoxib failed to
keep its protective properties when used in the prolonged
In our series of experiments,5 ibuprofen also diminished
the decline of dopamine content in striatum in the MPTP
mouse model of PD in a dose-dependent manner and was
not toxic to the dopaminergic system (Fig). The content of
dopamine in striatum showed significant less decrease after
MPTP intoxication in ibuprofen-treated animals compared
with control and nonibuprofen-treated animals. The differences between these groups did not exceed 15% of naive
control level (in dose of 30mg/kg on day 7), indicating only
partial protective effect of the drug. The important observation was that ibuprofen alone did no harm to the dopaminergic system (ie, did not diminish dopamine content in the
striatum) and presented itself as a safe drug for dopaminergic
neurons. Because ibuprofen showed a similar effect as indomethacine,3 the antiinflammatory action may be one of the
possible protective mechanisms.
© 2006 American Neurological Association
Published by Wiley-Liss, Inc., through Wiley Subscription Services
Fig. Dopamine content in striatum in MPTP and ibuprofen (IBF) treated mice. MPTP (60mg/kg) was given in 4 equal doses at
one hour intervals. Ibuprofen treatment (10 or 30 mg/kg) was started one hour before MPTP and continued daily for 7 days. Bars
show mean value ⫾ SD of 6 –10 animals per group. Significant differences (Mann⫺Whitney U test) are indicated by (*) comparing groups to control (p ⬍ 0.001), (#) comparing groups to MPTP group on the same day (p ⬍ 0.01), (f) comparing groups
treated with different doses of IBF on the same day (p ⬍ 0.05).
On the other hand, the difference between ibuprofen and
other NSAIDS effects in PD indicates that some particular
properties of the drug are involved. The diverse effects of
ibuprofen in various models of neurodegeneration (6-OHDA
vs MPP⫹ model of PD in rat6 vs MPTP model in mouse)
confirm the antiinflammatory action. This possible mechanism needs further research, however, because the difficulties
in establishing a predictable model of chronic degeneration
with the proinflammatory profile of glial reaction as seen in
PD may limit progress.
Institute of Psychiatry and Neurology, and 2Department of
Clinical and Experimental Pharmacology, Medical University
of Warsaw, Warsaw, Poland
1. Chen H, Jacobs E, Schwarzschild MA, et al. Nonsteroidal antiinflammatory drugs use and the risk of Parkinson’s disease. Ann
Neurol 2005;58:963–967.
2. Kurkowska-Jastrze˛bska I, Babiuch M, Joniec I, et al. Indomethacin protects against neurodegeneration caused by MPTP intoxication in mice. Int Immunopharmacol 2002;2:1213–1218.
3. Teismann P, Tieu K, Choi D-K, et al. Cyclooxygenase-2 is instrumental in Parkinson’s disease neurodegeneration. Proc Natl
Acad Sci U S A 2003;100:5473–5478.
4. Przybyłkowski A, Przybyłkowski A, Kurkowska-Jastrze˛bska I, et
al. Cyclooxygenases mRNA and protein expression in striata in
the experimental mouse model of Parkinson’s disease induced by
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine administration to
mouse. Brain Res 2004;1019:144 –151.
5. Kurkowska-Jastrzebska I, Przybyłkowski A, Joniec I, et al. Ibuprofen has a protective effect in neurodegeneration caused by intoxication with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine
(MPTP) in mouse. Eur J Neurol 2002;9(suppl 2):203.
6. Carrasco E, Casper D, Werner P. Dopamienrgic neurotoxicity
by 6-OHDA and MPP⫹: differential recruitment for neuronal
cyclooxygenase activity. J Neurosci Res 2005;81:121–131.
Reply: GDNF Poses Troubling Questions for
Doctors, Drug Maker.
John T. Slevin, MD,2,4,6 Greg A. Gerhardt, PhD,1,2,4
Charles D. Smith, MD,2,4,5 Don M. Gash, PhD,1,4,5 and
A. Byron Young, MD3,4
We are writing regarding the recent “NerveCenter” article,
“GDNF Poses Troubling Questions for Doctors, Drug
Maker”.1 We are investigators in one of the unblinded trials2
of glial cell–derived nerve factor (GDNF) alluded to and referenced in the article. We agree with the general proposition
that clinical investigators must be experienced with the disease under study. This article implies that physicians in our
and another small unblinded trial were well meaning in their
intent, but too close to their patients, and thereby clouded in
their clinical judgment. The article further implies that the
investigators in these two trials might have been inexperienced in Parkinson’s disease (PD), and thus unable to appreciate variability in the expression of the disease or the
strength of placebo effects. These issues were raised perhaps
to explain the positive results in both trials. It should be
noted that with 10 treated GDNF patients, our Movement
Disorder Center has arguably the greatest direct clinical experience with intraputamenally delivered GDNF of any center in North America. Our Movement Disorder Center has
participated in clinical trials of PD for more than a decade, is
actively recruiting patients to three multicenter trials, and is
a participant in four trials. Two of our faculty are members
of the Parkinson Study Group, three are “certified” to administer the Unified Parkinson’s Disease Rating Scale, and
the director has participated in the development of PD clinical trial protocols.
Potential toxicity issues were legitimately raised regarding
the infusion of GDNF, but unnamed persons were speculated to be “pretending” that there were no such issues. We
certainly consider the toxicity issues of paramount importance and met with the US Food and Drug Administration
to discuss conditions under which trial participants might
resume extended treatment.3 There was an opportunity for
Annals of Neurology
Vol 59
No 6
June 2006
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ibuprofen, mode, mouse, disease, parkinson
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