ANTIDEPRESSANT AND IMMUNE MODULATING ACTIVITY
OF THE L-GLUTAMINE
Renato
COCCHI, neurologist and medical psychologist.
(Italian
translation) // Testo in italiano
Summary
Following
the pioneer articles of about 20 years ago (Cocchi 1976 and 1981 ) a review has
been carried out on antidepressant and immune modulating activities of the
l-glutamine.
L-glutamine
has benefitted of a great novel interest in '90 years. Its immune modulatory
effect on cell-mediated immunity has found whole confirmation, and in Bonn,
1999 Cocchi pointed up its possible use in HIV+ patients, according to his
anecdotal clinical trials.
Its
antidepressant action did not get accurate investigations till now. Perhaps
this happened because the role of the glutamine as precursor of the GABA
through the glutamate on every kind of external or internal stress, did not get
yet any clarification.
Key
words: Stress; Depression; Immunity; Glutamine; Glutamate; GABA.
Drug modulation of stress reactions
.
Immunity
Symptoms
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L-glutamine (GLN), first isolated in 1883
and synthesized in 1933, has now gained renewed interest since the years '90.
Its ubiquity in nature, both in the free state and peptide linkage, strongly
suggests a primary metabolic role as part of various enzymatic transformations.
We know that l-glutamine can easily cross the blood-brain barrier when
introduced intravenously, parenterally or by diet, thus increasing its brain
content.
With glutamic acid, it represents at least
half the amount of nonprotein nitrogen in nervous tissues. Glutamic acid now
accepted as the main excitatory neurotransmitter of the brain, cannot cross the
blood-brain barrier. Nevertheless, it can transform itself into l-glutamine
from which it can again form itself. So diet glutamic acid can also reach the
CNS after its blood transformation into l-glutamine.
Since nearly half a century many clinical
searches reported favourable results from treatments with glutamine. Ravel et
al., 1955 carried over its turnover action on the alcoholic toxicity in
treating chronic alcoholism and delirium tremens. In this field several
researchers reported that the l-glutamine somehow managed a prevention action
against the excess of alcoholic consumption either in men and animals ( Rogers
et al., 1956; Rogers and Pelton 1957a; Tail 1961; De Maio and Madeddu, 1961;
Mouren et al., 1965; Naviau et al., 1966; Garbin and Vartanian, 1968 and 1969).
The glutamine has shown various forms of
epilepsy improved (Benassi and Bortolotti, 1959; De Maio and Madeddu, 1960; Vizioli
and Maccagnani, 1960; Flour and Renson, 1961; Gandini and Gandini-Collodel,
1967).
Later, this result had its explanation,
since the glutamine is the greater precursor of the glutamic acid, which in its
turn is the precursor of the GABA, the whole spread inhibiting brain
neurotransmitter.
Le Beau et al., 1962 they considered of
great interest the effects of the l-glutamine on the conscience in
neurosurgery, and compared them to what obtained through strychnine and
amphetamines, the main substances used for that purpose.
An other meaningful result observed in fewer
recent studies is that to increase cognitive skills in mentally retarded
(Rogers and Pelton, 1957b; Romerio and Chiarabelli, 1959; Farina et al., 1961;
Bigi, 1961; Beley et al., 1964; Invernizzi et al., 1966).
Even in little children with normal IQ the
use of the l-glutamine, compared to the placebo, led to a meaningful increase
of intellectual skills. (Brasseur, 1972).
Antidepressant properties of the l-glutamine.
I have again found the same results on the
intellectual efficiency in mentally retarded and in false-mentally retarded,
but I immediately had some doubts that we were dealing with antidepressant
properties.
At that time I could act on cognitive skills
either with low doses of chlothiapine (Cocchi and Terribili, 1971 and 1975 ) or
with a low dose compound of amitriptyline + perphenazine (Cocchi, 1974 ).
My paper on antidepressant action of the
l-glutamine followed this awareness ( Cocchi, 1976 ). I reported my anecdotal
impressions after clinical trials on 42 adults with various psychiatric
diseases:
"- The glutamine has clear
antidepressant action, and muscle relaxation is its target-symptom;
- it greatly affects some sleep troubles,
anticipating both falling asleep and sleep lasting;
- it increases dreaming, or at least it
eases their recalling;
- it increases appetite and, consequently,
the bodily weigh;
- the antidepressant effect works only on
the bodily symptoms of the depression, not on the psychic symptoms, when there is
a primary psychic cause of them;
- it acts even on the psychic symptoms, only
if they are secondary to the bodily ones;
- it owns an evident disinhibiting effect;
- it has not any sedative effect, even
initially;
- it doesn't produce hypotension, mouth
dryness, drooling, vertigoes, tachycardia and extrapiramidal symptoms.
- it doesn't own muscle relaxing effect, but
on the contrary it increases muscular tone;
- it does not lead to tolerance;
- when this symptom is present, it has
sometimes favourable effects on the constipation;
- its administration is compatible with
phenothiazines, butyrophenons, benzodiazepines, tricyclic antidepressants and
sulpiride;
- in the treatment of anxious depression it
can reduce tricyclics doses (its combination with IMAOs did not still have any
trial);
- in association with the chlorimipramine it
stopped several depressive phases of cyclic psychoses, once causing a sudden
maniac reaction;
- it did not work in a case of endogenous
depression with motor inhibition;
- it seems of notable interest if added to
the maintenance of normal therapy in some psychotic subjects. In these cases it
lead to the reduction of the doses neuroleptic drugs used;
- it has shown extreme interest, by itself
or with benzodiazepinees with poor muscle-relaxing action, in the treatment of
the senile depression;
- in one case out of two I used it with
success in treating the depression, which followed a long-acting neuroleptic
drug regimen. I reported it elsewhere (Cocchi, 1975);
- according to some points of view, its
activity is similar to amphetamines. We think that it induces excitement and
insomnia, when prescribed in increased doses than we used."
After 25 years the continuous use of the
l-glutamine leads me to confirm nearly all the previous "anecdotal
impressions," with some caution. Its effect on sleep seems currently
synergistic with the benzodiazepine that I always prescribe in combination,
with an action on the increase of the GABA and on the sensitization of the
postsynaptic type A GABAergic receptor.
Its activity on dreaming or their recalling
probably comes out from a specific feature of the benzodiazepine. Prescribed
without the support of a low dose benzodiazepine dose, the glutamine caused the
maniacal switch in a depressed child (Cocchi and Viarengo, published only in
1977).
Immune-modulator properties of l-glutamine
The use of glutamine in depressed children
led me to the chance discovery of the immune-modulator properties of this amino
acid (Cocchi, 1981). In that pioneering paper I stated the double action of
l-glutamine.
I envisaged these two biochemical ways. The
first runs as part of an antistress therapy through at least, better GABA
inhibition and the second as an essential donor of atoms for the nucleogenesis.
After that I produced several reports about
the use of GLN to counteract easiness to upper respiratory tract infections,
mainly in Down syndrome children (Cocchi, 1997; Cocchi 1998a and 1998b).
In the recent 6th International Congress on
Amino Acids (Bonn, 1999), l-glutamine had a special emphasis into the session
of Immuno Modulatory Effects of Amino Acids.
Four papers out of five pointed up this
skill of improving non specific immunity to l-glutamine, a fact already
reported by me in 1981. Oehler and Roth (1999) showed that GLN has also
anti-apoptotic properties according to an experiment using human myelocytic
U937 cells. GLN enriched cells at the onset of heat shock reduce apoptosis as
compared with same cells cultured in absence of GLN.
Yaqoob, 1999, asserted GLN as a well-known
preferred fuel of cells of the immune system and able to promote in vitro
lymphocyte proliferation. By summarizing some recent research, Yaqoob suggested
that the increasing of oral availability of GLN could promote immune responses
involving macrophage- or T cell-derived cytokines.
There is in increased consumption of GLN
during inflammatory processes such as infections, because GLN is the main
substrate of stimulated monocytes and macrophages, or hepatocytes in the liver.
These cells release inflammatory mediators
such as interleukin-1, interleukin-6 and tumour necrosis factor alpha, or, as
for the liver, "acute phase proteins."
Lavoinne (1999) tested if GLN in itself may play
a key role both in macrophages and hepatocytes during the acute phase response
and got confirmation of it. Moreover the effect of GLN can be mediated or not
by GLN-induced cell swelling, now regarded as a novel regulatory mechanism.
During this session I summarized my over
20-year clinical experience in using GLN to counteract easiness to upper
respiratory tract infections both in normal and Down's syndrome children
(Cocchi, 1999a, 1999b). While the preceding papers dealt in vitro experiments,
I there reported my long-lasting clinical experience in humans.
Of course, in that long interval, reports on
glutamine and immunity appeared in the world scientific literature. Shabert and
Wilmore, 1996, suggested that glutamine depletion may explain the progression
of tissue wasting during human immuno deficiency virus infection.
Severely ill surgical patients undergo
glutamine depletion and this as been implicated as a cause of immune
dysfunction in vivo. With the introduction of stable dipeptides of glutamine into
total parenteral nutrition regimens, the immune system had a favourable outcome
by a direct glutamine's action on its cells. (O'Riordain, De Beaux and Fearon,
1996).
Athletes undergoing prolonged and strenuous
exercise, are at risk of infections. After various exercises, athletes who took
a drink with glutamine significantly reduced this risk as compared with those
who had a drink with a placebo. This difference had evaluation of the incidence
of infections during the seven days following the exercise (Castell, Poortmans
and Newsholme, 1996).
Patients with excess of thyroid hormones as
it happens in Graves' disease can weakly impair the utilisation of glutamine by
lymphocytes. So they can have troubles in cell mediated immunity,
differentiation of B lymphocytes and the activity of NK cells (Werner, Costa
Rosa, Romaldini and Curi, 1996).
The glutamine supplementation maintains
intramuscular glutamine concentrations and normalizes lymphocyte function in
Escherichia Coli infected weaned pigs (Yoo, Field and McBurney, 1997). White
blood cell counts were significantly greater in GLN supplemented than GLN non
supplemented pigs. That extra GLN supply maintained muscular glutamine
concentrations and normalized lymphocyte function in infected pigs.
Cynober, in 1997, wrote that the
immune-activating effect of glutamine did not have full explanation.
In prednisone treated or burned animals,
dietary supplements of glutamine - alone or with arginine, with or without
dehydroepiandrosterone (a natural endogenous steroid) -, reversed the
susceptibility to infections. (Gennari and Alexander, 1997).
Nwsholme and Calder, 1997, suggested that
the high rate of glutamine utilisation by immune system cells serves to
maintain a high intracellular concentration of intermediates of biosynthetic
pathways. In effects optimal rates of DNA, RNA and protein synthesis can be
maintained.
Conclusions
L-glutamine has benefitted of a great novel
interest since the last decade. Its immuno modulator effect has found many
confirmations long time after the pioneering clinical study of Cocchi, 1981.
Its antidepressant action, pointed out by
Cocchi, 1976, did not get accurate investigations till now. Perhaps this
happened because the role of the glutamine as precursor of the GABA through the
glutamate on every kind of external or internal stress, did not still have any
clarification.
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First published on Internet on June 2002. Copyright by Renato Cocchi,
2002.
Author's address : Dr Renato COCCHI, via Rabbeno, 3
42100 Reggio Emilia (Italy).
renatococchi@libero.it
Italian translation // Testo in italiano
Drug modulation of stress reactions
Immunity
Symptoms
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