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Deficiency of glutamate dehydrogenase in postmortem brain samples from parkinsonian putamen.

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JME patients as affected on the basis of nonspecific EEG
abnormalities such as “diffuse paroxysmal theta rhythms . . .
occasionally with spikes andor sharp waves” {3]. The only
exception we can accept is the generalized “spike-multiple
spike slow wave discharge” because that pattern may be associated with clinically subtle absence seizures [ 1J. The authors
cited above [3] have reported that 17.1% of unaffected sibs
of JME patients showed “this EEG trait of JME’-mainly
paroxysmal theta rhythms. Therefore, 28 of the unaffected
sibs in our data would be expected to show these EEG abnormalities. If these 28 healthy sibs were considered as “affected,” which is the practice of Greenberg’s group [3, 41,
our estimated segregation ratio would be greater than that
reported in our paper {2]. This would affect the estimated
segregation ratio much more than any of the other arguments raised in their letter.
It is certain that the genetics of JME will soon be elucidated and provide a better understanding of the epilepsies.
The families we identified [Z) are ideal for these genetic
studies.
strategy will require appropriate controlled release of DA. We
prepared the polymers to release a very large amount of DA;
this was confirmed by analysis of in vivo striatal dialysates.
The implantation of the polymer device did not result in any
overt neuropathological changes other than a mild and localized gliosis. It is, however, conceivable that striatal implants delivering the amounts of DA achieved in our study
may have untoward effects, including downregulation of postsynaptic DA receptors. Perhaps more importantly, the very
high levels of DA achieved in our study may conceivably
result in loss of surviving dopaminergic afferents to the striat u n , via the generation of hydrogen peroxide and hydroxyl
radicals {3); we are currently investigating this possibility.
In light of the potential neurotoxicity to DA neurons of
very high levels of DA, it will be necessary to determine
carefully both the appropriate rate and total amount of DA
release from polymeric implants. Therefore, we agree with
Lang on the importance of the phrase ”potentialbenefit” to
Parkinson’s disease.
+Departmentsof Psychiatry and Phamzacology
?Department of Neurosurgety
Yale University School of Medicine
New Haven, CT
+Departmentof Clinical Neuropbysiology and Epilepsy
S t Thomas’ Hospital
London, U K
?Division of Neurology
King Khalid University Hospital
Riyadh, Saudi Arabia
References
References
1. Panayiotopoulos CP, Obeid T, Waheed G. Absences in juvenile
myoclonic epilepsy: a clinical and video-electroencephalographic
study. Ann Nekrol 1989;25:391-397
2. Panayiotopoulos CP, Obeid T. Juvenile myoclonic epilepsy: an
autosornal recessive disease. Ann Neurol 1989;25:440-443
3. Greenberg DA, Delgado-EscuetaAV, Maldonado H, Widelitz H.
Segregation analysis of juvenile rnyoclonic epilepsy. Genetic
Epidemiology 1989;5:81-94
4. Greenberg DA, Delgado-EscuecaAV, Widelitz H, et al. Juvenile
myoclonic epilepsy may be linked to the BF and HLA loci on
human chromosome 6. Am J Med Genet 1988;31:185-192
A Cautionary Note on the
Potential Benefits of
Striatal Dopamine Implants
1. Lang AE. Potential benefits of dopamine striatal implant. Ann
Neurol 1990;27:109-110
2. During MJ, Freese A, Sabel BA, et a]. Controlled release of
dopamine from a polymeric brain implant: in vivo characteriza-
tion. Ann Neurol 1989;25:351-356
3. Spina MB, Cohen G. Dopamine turnover and glutathione oxidation: implications for Parhnson’s disease. Proc Natl Acid Sci
USA 1989;86:1398-1400
Deficiency of Glutamate
Dehydrogenase in
Postmortem Brain Samples
from Parkinsonian
Putamen
Ariel Y.Deutch, PhD,’ and Matthew J. During, MD?
Jesse M. Cedarbaum, MD,’ K.-F. R. Sheu, PhD,t
Bradford J. Harding,? John P. Blass, MD, PhDt
France Javoy-Agid, PhD,§ and Yves Agid, MD$
We were pleased to note the letter of Lang El], discussing
our recent paper documenting the release of dopamine (DA)
from striatal polymeric implants {a]. We agree with his comments that this method represents a potential advantage in
the treatment of Parkinson’s disease in that DA delivery can
be restricted to the site at which the transmitter is deficient in
Parkinson’s disease (such as the putamen), and thus avoid the
psychiatric side effects (presumably occurring in cortical sites
or the caudate nucleus) associated with systemic DA replacement therapy using L-dopdcarbidopa or direct DA agonists.
We would like to caution, however, that the use of this
German and associates [I) proposed that the metabolic insult
inciting degeneration of dopamine neurons in Parkinson’s
disease (PD) OCCLKS in the terminal fields in the striatum
rather than at the level of the cell body. Mitochondrial dysfunction has been proposed to be the fundamental pathophysiological mechanism in P D {2). We now suggest a mechanism by which a discrete abnormality in mitochondrial
function might initiate cellular degeneration in PD.
We assayed activities of the mitochondrial enzymes glutamate dehydrogenase (GDH) [ 3 ] , fumarase (FUM) 141, and
the pyruvate dehydrogenase complex (PDHC) [ S } in sam-
Copyright 0 1990 by the American Neurological Association
111
Activities of Mitochondria1 Enzymes in Putamen of Autopsied Brainsa
Controls
PD
PSP
No.
Age
GDH
20
78.8 2 1.9
72.3 k 1.6
67.9 ? 2.3
325.6
285.2
* 10.7
* 11.7b
334.6
i 17.7
31
10
Fumarase
PDHC
128.8 & 10.5
143.0 2 5.2
149.1 ? 7.0
19.1 2 1.0
19.3 2 0.8
18.1 f 0.9
"All values are mean f SEM. Enzyme activities are expressed as nM producdmidmg protein.
bSignificantly different from controls, p < 0.02.
GDH-glutamate dehydrogenase, PDHC = pyruvate dehydrogenase complex, PD
palsy.
ples of putamen obtained at autopsy from the brains of 31
PD patients, 10 patients with progressive supranuclear palsy
(PSP), and 20 control subjects. Eighty-one percent of PD
and 70% of PSP patients (chi square = 5.024; p = NS)
were taking levodopa or dopamine agonists up to the time of
death. There was a small but significant diminution in activity
of GDH, but not FUM or PDHC, in PD brains (Table).
There was no correlation between age or postmortem delay
and GDH activity within groups or in the sample population
as a whole.
Schapira and colleagues [2] demonstrated reduced activity
of Complex I of the mitochondria1 respiratory chain in the
region of the substantia nigra in PD brains. Bindhoff and
associates [6} demonstrated deficiencies in complexes I1 and
IV in muscle biopsy specimens from PD patients [6}. Parker
and colleagues [ 7 ] found reductions in complex I activity in
platelets of PD patients. MPP', the active metabolite of
MPTP, inhibits Complex I 181, perhaps simulating the lesion
in idiopathic PD. Since complex I is the point of entry for
reducing equivalents (as NADH) to the respiratory chain, a
decrease in Complex I activity might result in feedback endproduct inhibition of GDH.
GDH is selectively enriched in glia, particularly in brain
areas that receive a strong glutamatergic input [y}, and is
responsible in part for terminating the action of the neurotransmitter glutamate [ 10). Decreased levels of GDH, by
increasing local glutamate concentrations, might exert an excitotoxic effect via NMDA receptors on striatal dopamine
nerve terminals [l l}, leading to dying-back of dopaminergic
neurons. It is interesting to note that the NMDA-receptor
antagonist MK-801 reduces methamphetamine and, to a
lesser extent, MPTP-induced degeneration of dopamine
neurons in the mouse [12}. Reduction in GDH activity consequent to Complex I deficiency might thus contribute to
cellular degeneration in PD.
"Parkinson and Movement Disorders Sewice
I-Will Roger3 Institute
Altshul Dementia Research Laboratories
The Burke Rebubilitation Center
Cowell University Medical College
White Plains, N Y
Q'LaboratoireMedecine Experimentale
Mipital de (a Salpetriere
Puris. France
112 Annals of Neurology Vol 28 No 1 July 1990
=
Parkinson's disease, PSP = progressive supranuclear
Refv-ences
1. German DC, Manaye K, Smith WK, et al. Midbrain dopaminergic cell loss in Parkinson's disease: computer visualization.
Ann Neurol 1989;26:507-5 14
2. Schapira AHV, Cooper JM, Dexter D, et al. Mitochondrial
complex I deficiency in Parkinson's disease. Lancet 1089;1:1269
3. Sheu K-FR, Blass JP, Cedarbaum JM, et al. Mitochondrial enzymes in hereditary ataxia. Metab Brain Disease 1988;3:151-
160
4. Sheu K-FR, Lai JCK, Blass JP. Properties and regional distribution of pyruvate dehydrogenase kinase in rat brain. J
Neurochem 1984;42:230-236
5. Racker E. Spectrophotometric measurements of the enzymatic
formation of fumaric acid and cis-aconice acid. Biochem Biophys
Acta 1960;7:211-224
6. Bindhoff LA, Birch-Macllin M, Cartlidge NEF, et al. iMitochondrial dysfunction in Parkinson's disease. Lancet 1989;2:49
7. Parker WD, Boyson SJ, Parks JK. Abnormalities of the electron
transport chain in idiopathic Parkinson's disease. Ann Neurol
1989;26:719-723
8. Nicklas WJ, Vyas I, Heikkila RE. Inhibition of NAOH-linked
oxidation in brain mitochondria by 1-methyl 4-phenylpyridine,
a metabolite of- the neurotoxin l-methyl-4phenyl-1,2,3,6tetrachyropyridine. Life Sci 1985;36:2503-2508
9. Aoki C, Milner TA, Sheu K-FR, et al. Regional distribution of
astrocytes with intense immunoreactivity for glutamate dehydrogenase in rat brain: implications for neuronal glia interactions
in glutamate transmission. J Neurosci 1987;7:2214-223 1
10. Hack S , Grass F, Hortnag LH. The glutamate analog aaminoadipic acid is taken up by astrocytes before exerting its
gliotoxic effect in vitro. J Neurosci 1%4;4:2650-265 1
11. Clow DW, Jhamandas KJ. Characterization of Lglutamate action on the release of endogenous dopamine from the rat caudate-putamen. J Pharmacol Exp Ther 1989;248:722-728
12. Sonsalla PK, Nicklas, WJ, Heikkila RE. Role for excitatory
amino acids in methamphetamine-induced riigrostriatal dopaminergic toxicity. Science 1989;244:398-400
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postmortem, putamen, deficiency, dehydrogenase, samples, brain, glutamate, parkinsonism
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