Læknablaðið - 15.09.2003, Qupperneq 15

FRÆÐIGREINAR V HRÖRNUNARSJÚKDÓMAR
HEILA
Hrörnunarsjúkdómar í heila
- oxavarnarensím og kopar
Kynning á rannsóknum
Þorkell
Jóhannesson1
PRÓFESSOR EMERÍTUS í
LYFJA- OG EITUREFNAFRÆÐI
Jakob Kristinsson1
LYFJAFRÆÐINGUR, SÉRFRÆÐ-
INGUR í EITUREFNAFRÆÐI
Jón Snædal2
LÆKNIR, SÉRFRÆÐINGUR
í LYF- OG ÖLDRUNAR-
LÆKNINGUM
'Rannsóknastofa í lyfjafræði
og eiturefnafræði, Lyfjafræði-
stofnun HÍ, 2Öldrunarlækn-
ingadeild Landspítala
Landakoti.
Fyrirspurnir og bréfaskipti:
Jón Snædal, Öldrunarlækn-
ingadeild Landspítala
Landakoti v/ Túngötu,
101 Reykjavík,
símar 543 9805 og 824 5518.
Bréfsími 525 1819.
jsnaedal@landspitali. is
Lykilorð: kopar, oxavarnar-
ensím, Alzheimer, Parkinson,
hreyfitaugungahrörnun, Downs
heilkenni, einhverfa, riða.
Ágrip
Inngangur: Hrörnunarsjúkdómar í miðtaugakerfi eiga
langflestir það sameiginlegt að í þeim á sér stað sam-
söfnun og útfelling á próteinum í taugafrumum eða
utan við þær hver sem orsökin kann að vera. Talið er
að efnabreytingar, sem eru undanfari samsöfnunar
og útfellinga, séu skaðvaldurinn fremur en útfelling-
arnar sjálfar. Efnabreytingar þessar leiða að öllum
Iíkindum til myndunar á skaðlegum súrefnisfríhóp-
um. Oxavarnir líkamans, sem bæði taka til sértækra
efna og oxavarnarensíma, vinna gegn þessu ferli og
því hefur þeirri tilgátu verið varpað fram að veiklað-
ar oxavarnir séu sameiginlegur þáttur í meingerð
hrörnunarsjúkdóma í miðtaugakerfi, hvort sem er í
mönnum eða öðrum spendýrum.
Aðferðir: Magn kopars og virkni tveggja oxavarn-
andi ensíma sem innihalda kopar, cerúlóplasmíns og
súperoxíðdísmútasa 1 (SODl), var ákvarðað í blóð-
inu. Gerðar voru tvenndarrannsóknir er tóku til Alz-
heimer sjúkdóms, Parkinson sjúkdóms, hreyfitaug-
ungahrörnunar og sjúklinga með Downs heilkenni
auk sjúklinga með einhverfu. Einnig var gerð rann-
sókn á sauðfé á mismunandi svæðurn með mismun-
andi líkum á riðusmiti. í þeirri rannsókn var að auki
ákvörðuð virkni glútatíonperoxídasa sem er selenríkt
oxavarnarensím og magn mangans ákvarðað í blóð-
inu.
Niðurstöður: Oxunarvirkni cerúlóplasmíns og virkni
SODl var marktækt minni í Alzheimer sjúkdómi án
ENGLISH SUMMARY
Jóhannesson Þ, Kristinsson J, Snædal J
Neurodegenerative diseases, antioxidative
enzymes and copper. A review of experimental
research
Læknablaðið 2003; 89: 659-71
Introduction: In almost all degenerative diseases of the
brain aggregation of proteins inside neurons or extra-
cellulary, is a common pathological phenomenon regard-
less of etiology. It is assumed that the biochemical path-
ways leading to aggregation are more harmful than the
aggregations themselves and most likely imply production
of free oxygen radicals. This oxidative stress is in the body
met by free radical scavengers in the form of specific
chemical substances and antioxidative enzymes. It has
therefore been postulated that defective free radical
defense is a common pathway in most neurodegenerative
diseases in humans as well as in other mammals.
Material and methods: The concentration of copper and
the activity of two antioxidative copper containing enzy-
mes, ceruloplasmin and superoxide dismutase (SOD 1),
was analyzed in the blood. A series of case control studies
were performed in Alzheimer's disease (AD), Parkinson's
disease (PD) and amyotrophic lateral sclerosis (ALS) as
well as in Down's syndrome and autism. Furthermore, a
study in sheep was conducted in different areas with
different risks of infection of scrapie. In that study, in
addition, the activity of the selenium-containing enzyme,
glutathione peroxidase, was determined as well as the
concentratíon of manganese in blood.
Results: The oxidative activity of ceruloplasmin and SOD1
was shown to be significantly lowered in Alzheimer's dis-
ease without any signs of copper deficiency. In Parkinson's
disease, the oxidative activity of ceruloplasmin was also on
the whole shown to be signifcantly lowered, and further-
more, it decreased significantly as well as the SOD1 acti-
vity with duration of the disease. In ALS, the means of all
of the determinations were shown to be the same, but the
equality of variances differed significantly in the patients
compared to their controls. In Down's syndrome past the
age of 40, when Alzheimer's type changes appear in the
brain, the SOD1 activity and the ceruloplasmin specific
oxidative activity (activity in relation to concentration) was
significantly lowered compared with the younger patients.
In autism, a non-degenerative affection of the central
nervous system, there was no difference between patients
and their controls. In the sheep, the results indicated a
relationship between decreased glutathione peroxidase
activity, and possibly also SOD1 activity, and increased
susceptibility to scrapie infection. No connection was
found between ceruloplasmin oxidative activity and sus-
ceptibility to scrapie infection. Susceptibility to scrapie
infection was apparantly not conntected with low levels of
copper or high levels of manganese in blood of the animals.
Discussion: The results indicate that the oxidative
defenses in four neurodegenerative diseases with different
clinical features are defective as the activity of two copper
containing antioxidative enzymes, ceruloplasmin and
SOD1, was found defective in all of them. In a
developmental syndrome (autism), where neither active
degenerative changes nor aggregations are found, no such
changes in enzyme activity were detected. The results thus
support the idea that deranged oxidative defense is a
common denominator in the pathogenesis of these
diseases. As far as sheep is concerned, the results also
indicate, that there is a defect in oxidative defense
connected with increased susceptibility to scrapie infection
in the form of lowered glutathione peroxidase activity.
Key words: copper, antioxidative enzymes, Alzheimer’s
disease, Parkinson’s disease, amyotrophic lateral sclerosis,
Down’s syndrome, autism, scrapie.
Correspondence: Jón Snædal, jsnaedal@landspitali.is
Læknablaðið 2003/89 659