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

Multiple sclerosis: the rational basis for treatment with colchicine and evening primrose oil.

Medical Hypotheses MULTIPLE D.F. PRIMROSE Horrobin, HZW THE SCLEROSIS: EVENING lR7, 365-378, 5: 1979 BAS IS RATIONAL FOR TREATMENT WI...
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