Fondazione Mondino - Clinica
Neurologica dell'Università di Pavia
HIGH
PROBABILITY REFUTATION IN DOWN'S SYNDROME SUBJECTS.
(Italian translation /
versione in italiano)
Summary
The
reduced inactivation of oxygen's free radicals is one of the hypotheses put
forward to account for the onset of Alzheiaer's dementia. However scarce
conclusive experimental data may be to
support this theory regarding human species, its refutation has not been
established with any certaity either.
For
this reason Down subjects, who are less prone to cerebral palsy from
prematurity and low birthweight (Cocchi, 1987; Cocchi and Branchesi, 1988), should
also show a retardation in the onset of
dementia, conpared to normal individuals. This is not however the case as on
the contrary it is regularly found that Down subjects anticipate by an average
of 15 years roughiy the onset of an Alzheimer type of dementia.
The metabolic use of oxygen, by organic
tissues in mammals, provokes normally an initial production of the radical
anion superoxide (O2°) which, if in excess, can alone damage the cellular DNA,
oxidize the thiolic groups of the proteins and cause other toxic events such as
lipidic peroxidation [1-2].
This transformation comes about through two metabolic reactions.
First, the divalent reduction of O2°, catalysed by enzymes such as urate- and
D-amino-oxidase; and second by spontaneous or enzymatic dismutation in the
presence of the enzime superoxide-dismutase (SOD) [3-4].
lf for any reason,
usually contingent and acute, and prevalently anoxic-ischaemic [6-10], this
inactivation system becomes inadequate, either the combination of anion
superoxide and hydrogen peroxide derived from the dismutation, or Fenton-type
reactions by the hydrogen peroxide in the presence of copper or iron salts can
produce the hydroxilic radical (OH°) which is extremely reactive with, in effect, any type of organic molecole, so
as to cause irreversible cellular danage [3-4].
The hypothesis of an increase in free radicals as
being the causai factor in dementia.
One theory on ageing attatches great
importance to continuous and chronic cellular damage produced by oxygen free
radicals [11-14], and tends to support this point of view by the report oi
lipofuscins build up, brought about by decay of the cellular membranes. This
build up depends on oxygen and is age-related [5; 15-18].
The accumulation
of lipofuscins, which takes place particularly in the mitochondria, is a
process brought on by ageing and is not specific to Alzheimer's disease [21].
However much aldehydes and ketones produced by the action of free radicals play
their part in the beginning of this process, in actual fact the formation of
lipofuscins in an individual is a metabolic chain not yet fully understood
[16]. It seems that malondialdehyde has a role in the formation of proteins and
lipids, constituents of lipofuscins[16].
On the other hand,
CNS neurons also possess catalase, glutathione-peroxidase and
superoxide-dismutase, being the scavengers against the action of the free
radicals [16].
Data opposing the free radicai hypothesis as cause of
dementia.
However interesting the hypothesis may be that
the cytotoxic action of free radicals is the cause of dementia, it is based on
questionable premises.
It is quite true
that a whole series of illnesses presenting an accumulation of lipofuscins
(from neural ceroid lipofuscinoses to vitamin E deficiency and the effects of
certain chronic intoxications) are also accompanied by mental deterioration
[16] but this is something common to all
pathological thesaurismoses. It is sure however that in Alzheimer's disease,
the most common form of dementia, an accumulation of lipofuscins in the
mitochondria is present, but the same is true for non-demential ageing [21].
Research has been carried out to support this
hypothesis. No difference has been found between normal individuals and those
with Alzheimer's type of dementia, regarding the activity of their brain SOD
[22].
No significant
differences in blood levels of 12 vitamins were found in a group of Alzheimer's
disease patients and a control group of healthy, depressed or
other-type-demented subjects [24].
No changes
suggestive of senile dementia were noted [25].
There is however
one important naturai experiment which is able to question the hypothesis of
the cytotoxic action of oxygen's free radicals as being the cause of dementia.
As well as this,
an adaptive increase of 30% has been revealed in the enzymatic activity of the
GSHPx [35-38]. The increased presence of these two scavengers seems to be
responsible for the reduced incidence of CP from prematurity and low birthwight
[39-40], the main risk factors for it.
These two
conditions are quite frequent also in Down newborns [39-40] and usually can
lead to cerebral lesions by means oi anoxic-ischemic mechanisms.
The fact that this
is not the case, but on the contrary, there is an anticipation and increase in
the onset of demential evolutions, must be taken as a high probability
disproval of the theory that advances the chronic toxic action of the free
radicals as the cause of Alzheimer's disease, at least for Down subjects.
As regards normal individuals there should not
be any difference, but being rather over-cautious we intend the above
explanation to be taken only as a strong indication and as further confirmation
of the experiments which we have cited [22-28].
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Presented at the 1st Congress of the Eur. Neurol. Society, Nice, June
1988.
Printed on It. J. Intellect. Impair. 1988. 1:
127-132
Author's address: dr Renato COCCHI, via Rabbeno, 3
42100 Reggio Emilia (Italy).
renatococchi@libero.it
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