Medical
Hypotheses
MULTIPLE
D.F.
PRIMROSE
Horrobin,
HZW
THE
SCLEROSIS:
EVENING
lR7,
365-378,
5:
1979
BAS IS
RATIONAL
FOR TREATMENT
WITH
COLCHIC
Avenue
West,
INE
AND
OIL. Clinical
Research
i tute,
lnst
110
Pine
Montreal
Canada. ABSTRACT
Multip and a
le of
reac
to
sclerosis
its tion
to
consider
new sclerosis
approach
is
tific
approaches
In
lymphocyte cause
the
in
It
lymphocyte
inflammatory vitro
regulation
of
mittent
is
cytoplasmic
fever)
it
has
been
oil
and
has
shown
been
to
results
colchicine
and
in
(Behget’s prevent
may
be
two to
that
of
reduce
considerable
the
compatible
cyto-
with by
inter-
Mediterranean
severity
therapy
in may
associated
into
familial
the
of
dietary be
characterised
and
combined
by may
actions
This
abnormality
calcium
diseases
syndrome or
suggest
improved
have
treat
scien-
abnormality
be of
fail
to
basic evidence
acid
entry
to
made
is
demyelination
with
this As
and
an
fatty
may
the
and
of
colchicine.
fundamental there
the
both
that and
calcium
found
that
episodes
episodes
Preliminary
rose
and evidence
colchicine
inflammatory
sodes.
also
in
view
concepts.
been
with
metabolism
that
new
sceptical
and
sclerosis acid
apparent
abnormality
with
In
multiple
any have
acids
grounded
fatty
now
by
attempts
fatty
In
treatment.
excessively
Recent
with is
known
attracted
sometimes
firmly
essential
There
plasm.
is
patients
manipulation. recurrent
are
and
function.
no
are
polyunsaturated
arbitrary
abnormality
with
patients seriously.
with
not
disease
ologists
neu
concepts. an
a
nature
this
multiple
both
is
(MS
distressing
of
with
such
epi-
evening
prim-
value.
INTRODUCTION Multiple are
sclerosis
no
have
been
a
approaches. neurologists thoroughly
in
known
about that the
one
treating
of
the
Understandably,
Because
such
approaches
tend
become
to take
an
blase
polyunsaturated are the these
rationale
not
ongoing
negative
fats arbitrary
disease proposals behind
and
and
of
proposals in
may the
have
sound be
with so new
taken
365
many who
MS,
and
ideas,
all
diseases.
different are
are
regularly
often eager
fail
highly to
proved to
There
proposals try
intell any
new
disappointing,
to
investigate
them
attitude. colchicine but
experimental
approach.
of
though
research
about
unduly
distressing
even
patients in
to
most it
interest
These
order ail
of
is of
great
and
uses MS.
methods
made.
take
i gent,
The
(MS)
accepted
seriously
have
have a
recently
firm
been
basis
in
laboratory
science.
this
sets
paper
proposed
what out
is In in
det-
THE DEFECT
IN ESSENTIAL
FATTY ACID
METABOLISM
A great deal has been written about this. The idea arose from epidemiological studies which suggested that MS was less common in communities with a high intake of essential fatty acids (EFAs) and from basic laboratory evidence that these acids play a critical role in cell membranes (1,2). This led Swank to embark on a long term programme in which his patients were encouraged to follow a diet low in saturated fats and carbohydrates and high in polyunsaturated fats and other foods generally considered by nutritionists to be highly desirable (3). The diet is a sound one which is similar to the best available diets recommended to the obese and to those anxious to avoid myocardial infarction and other cardiovascular disasters. The diet lowers cholesterol, reduces the stickiness of platelets and leads to weight loss. Over two decades Swank’s patients seemed to do substantially better than other The study is of course uncontrolled and the good results patients with MS (2). have been attributed to luck, to enthusiasm or to the effect of the diet on genera1 well being. The approach has not therefore received wide acceptance by neurologists and many, perhaps most do not recommend it to their patients. In some ways this is difficult to understand since the diet is so desirable Patients have nothing to lose by adopting it and in general health terms. Swank’s results suggest that there may be benefits. The EFA concept has now received a good deal more support. Thompson and his colleagues demonstrated that the commonest EFA, linoleic acid,tended to be low in the blood and other tissues of MS patients and that levels tended to They suggested that this indicated the fall further during relapses (4,5). While on the existence of some metabolic abnormality of EFA metabolism in MS. whole this work has been accepted some have failed to observe the linoleic acid deficit indicating that this deficit is not a necessary part of the MS syndrome (6). What the variability may indicate is that in MS patients there may be reduced entry of linoleic acid into the plasma pool, perhaps because of the Alternatively it may indicate increased recently described malabsorption (7). In either case one would expect removal of linoleic acid from the plasma. those who had a high linoleic For example, variabi 1 i ty in the abnormal i ty. acid intake might be able to compensate for reduced absorption and increased loss and so end up with normal plasma linoleic acid levels. The epidemiological and biochemical evidence for a reduced being important in the disease has led to several controlled The linoleic effect of an increased linoleic acid intake. The results the form of vegetable oils, usually sunflower. Of three reasonably well designed trials whose results are a reduced incidence of relapses and reduced relapse severity, in incidence and reduced relapse severity but no reduction No trial claimed any very obvious effect at all (8,9,io).
linoleic acid level trials of the acid is taken in have been variable. known, one showed one showed one showed no results.
These trials indicate that the increased oil intake does no harm and may perIt is therefore worth trying to find ways of enhancing this haps be of value. One such way follows from the finding that linoleic acid possible effect. which lack the enzyme necessary for In cats, itself is biologically inert. linoleic acid is ineffective as converting it to gamma-linolenic acid (GLA), an EFA. EFA activity depends entirely on conversion of linoleic acid to GLA The importance of this finding lies in a series of papers by Brenner (11,12). have demonstrated that the conversion of (13,14,15) - Brenner and co-workers
366
particularly in the presence of linoleic acid to GLA may be very inefficient, a high saturated fat or carbohydrate intake or in diabetics (Fig. 1). Thus, on a typical North American diet it is possible to be EFA defifor example, Part of the reporcient even if linoleic acid intake is apparently adequate. ted success of the Swank diet may be related to its reduction of fat and refined carbohydrate intake so allowinq utilization of 1 inoleic acid to be more efficient. Because of the potential block in linoleic acid metabol i sm it makes sense to primrose oi 1 has been by-pass it by giving GLA directly. This is why evening acid (722 Ily rich in linoleic This oil is exceptiona proposed for use in MS. Two controlled tria Is of it but is unique in containing 9% of GLA as well. have been carried out using relatively small doses (about 3 ml/day as opposed to the 30 ml/day of sunflower oil used), one in severe chronic MS patients and one in a less severe relapsing group (lO,I6). Both were negative. One possible reason for negative results is the dosage used. Another, and in my is that in these two trials the oil was unfortunaopinion more likely reason, tely packaged in capsules coloured with the dyes, tartrazine and ponceau R. My group has shown that both the dyes are able to block conversion of EFAs to The effect of tartrazine has also been reported by prostaglandins (PGs). The importance of this is that it now appears that the main others (17). EFA-like molecules function of the EFAs is to act as precursors for the PGs. which are similar in physico-chemical properties but which cannot be converted to PGs are without EFA activity (18). This is most strikingly shown in cats where even linoleic acid has no EFA activity because it cannot he converted to GLA and then on to PGs (11,12). An outline of the EFA-PG metabolic pathway is shown in Fig. 1. GLA is very efficiently converted to DGLA which is the precursor of the PGs of the 1 series. DGLA can be converted to arachidonic acid (AA) although this reaction may be less efficient than the previous one. AA is found in a number of foods need not al 1 be formed from other EFAs. including meat and seaweed and AA is There are several PGs of each sort and the precursor of the 2 series PGs. each one seems to have a different and characteristic pattern of act.ivity. There is therefore reason to believe that evening primrose been given an adequate test, a conclusion that is supported both humans and animals described later in the paper. THE DEFECT
IN THE
oil has not by results
yet in
IMMUNE SYSTEM
Perhaps the most popular MS concept at the moment is that it is caused by This may lead to one of two problems or perhaps a defect in the immune system. both together. It may lead to a susceptibility to CNS viral infection with an inability to eliminate such infections rapidly. The abnormality may also lead to an auto-immune response in which the immune system fails to recognize CNS myelin as “self” attacks it and causes demyelination. These concepts have been extensively discussed in a wide variety of papers and will only be summarized very briefly here (19). The main pieces of evidence in favour of an immune problem are: 1. MS patients seem more susceptible to infections than normal even before the disease apparently begins. 2. The histology of developing MS lesions in the CNS is compatible with an auto-immune reaction. 3. In animals a demyelinating disease with some of the characteristics of MS (experimental allergic encephalomyelitis, EAE) can be initiated by injection 367
DIETARY _FREE -
ESTERlFlED LA
LINOLEIC
J
LINOLEIC ACID (LA)
I-
GAMMA-LINOLENIC
ESTERIRED DGLA
ESTEf?lFIED AA
Figure I. essential to convert
-
w -
ACIO
ABSENT
ACID (GLA)
DIHOMO - GAMMA LINOLENIC ACID (DGLA) 1 ARACHIDONIC
IN .CATS
-
-
ABSENT ACID _
(AA)
An outline of the metabolic fatty acids and prostaglandins. LA to GLA or DGLA to AA.
368
I SERIES PGS IN CATS 2 SERIES PGs
pathways Cats
relating are unable
of
fractions
own
CNS
various sor
of
CNS
myelin tests
that
The
in
evidence
whether
existing
damage
be
a
one
clear of
whose
involvement is
close
link
of
a
to
in
the
animal’s
abnormally
defect
modulate
in
B
MS patients
in T
suppres-
lymphocyte
seems
resp-
different
(22).
of
the
immune is
a
system
“prime
MS
is
mover”
or
simply
in
possibility
I am interested
between
damages
behave
particular
is
antigens
abnormality
disputed.
response
MS patients
functions
HLA
population
this
immune
from
evidence
of
normal
for
although may
is
distribution the
resulting
Lymphocytes
there (211,
5. The
from
4.
and
lymphocytes
onses.
the
myelin:
(20).
the
defect
in
EFA
in the
metabolism
now
widely
accepted
aggravates
pre-
that
and
in
there
the
immune
system. For a
reasons
which
deficiency
1 series
PGs
reason
may
precursor The
is
in
the
there
may
be
is of
EFA
deficiency
PGEl so
1 series
to
affected
AA,would of
AA
its
these is
2
a
rise
in
to
an
increase
but
fall
when
one
possibility
of
this
AA
from
(25).
PGs
1 series
of
(23).
dietary
may
series
of
loss
the
series
DGLA
mobilisation
of
synthesis
and
2
on
PGs
that of
of
the
DGLA
unknown
the
to
part
of
lead
of
lead
apparent
deficiency
precursor
actually
formation
a
least
stores for
inhibit
the
to
At
the
mechanism
able
reduce
of
PGs. large
may
become
leads
very
production The
EFAs,which
recently
GLA
dependent
the
is
to
stores
of
phocytes
in T
can
also
be
T
is
which
seems
necessary
animals
the
first
PGs
inhibitory
formation
4.
of
2
series
PGs
depletion
and
of
Lithium
1.
The
imitated
and dietary
ions
is
cause
is
remarkable
lithium
has
a
second
seems This
Zinc
seems
(33)
can
be
converted
atrophy
of
the in
the a disease
synthesis
effect
st i-
messenger
rapidly
potent
in
deficiency (29,3O).
animals
lym-
Prolactin
enteropathica,
in
GLA
in
T
of
2.
zinc
PGEl
PGEl and
hormone
(26).
depressed
for
deficiency whose
thymic
(31,32).
DGLA
1 series
that
regulation
its
(25)
affect
lymphocytes
PGEl
with
absorption
zinc oil,
of by
acrodermatitis
stored
T
PGEl
effects
function
to evidence
of
for
be
humans
zinc of
primrose
function
evidence
in
of
likely
mounting
to
be