THE SPECIAL ROLE OF GLUTAMINE
AS ANTISTRESS AGENT
AND CELL-MEDATED IMMUNITY FUEL
By
Renato COCCHI , MD, neurologist and medical psychologist
Summary
L-glutamine
has benefitted of a great novel interest in '90 years. Its immuno 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. L-glutamine is the unique donor of the N atoms 3 and
9 of the purine ring, the base of the nucleogenesis, and so of RNA and DNA. Its
activity in promoting leucocytes production did reach large evidence.
Its
antistress effect did not find punctual research till now Perhaps this happened
because the role of glutamine as the precursor of brain GABA, via l-glutamic
acid, on any kind of external or internal stresses has not yet got further
clarification.
In
situations of stress, the brain can drain glutamine from peripheral storage
departments, skeletal muscles, liver and kidneys, but the main drainage acts on
skeletal muscles where ATP is forced to produce more glutamine. This drives to
reduced availability of ATP for muscle contractions, and the symptom of which
is asthenia.
Key
words: Stress; Glutamine; Immunity; Glutamate; GABA.
Drug
modulation of stress reactions
Immunity
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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.
Immuno-modulatory
properties of l-glutamine
The use of glutamine in depressed children
led me to the chance discovery of the immuno-modulatory 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 via 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.
Of course, in that long time 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 7 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
immuno-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.
As I said, in the Bonn session on Immuno
Modulatory Effects of Amino Acids, glutamine played a primary role.
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 per se 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 reported there my long-lasting clinical experience in humans.
This immune-protective effect in Down
children appears early before the age-related decreasing of easiness to upper
respiratory tract infections (Cocchi 1997, 1998a).
Profound forms of URTI easiness stop at the
8-10 years' interval in drug-treated Ss, but at the 14-16 years' interval in
non treated Ss. Severe forms are again 10% in non-treated subjects, while they
are only 5% in drug-treated Ss, at more than 16 years.
L-glutamine is directly involved in the
nucleogenesis of rapid proliferating cells (Gismondo et al., 1998). Namely it
is the donor of the N atoms 3 and 9 of the purinic ring (Stryer, 1988). By this
way it contributes to a better production of leukocytes (Heberer et al., 1996;
Newsholme & Calder 1997; Yoo, et al., 1997).
Anti-stress
properties of l-glutamine
As a matter of fact I did not use
l-glutamine alone, but I prescribed it as a part of an antistress regimen.
To clarify what kind of stress, I shall
refer to Down’ syndrome, with over 560 subjects seen for consultation. In Down
Ss, a metabolic stress could relate to the so-called "dosage effect"
of the third chromosome 21 (Cocchi 1994). This last follows on 50% increasing
of all the metabolisms having their controling genes on the chromosoma 21.
Research showed that stress undermines host resistance to infections through
neurendocrine mediated changes in immune competence (Boyce et al., 1995). It is
the same for every kind of stress of external or internal origin or both.
As for surgical stress, I did a comparison
beetwen previously treated and non treated Down children who undervent
open-heart interventions. Antistress drugs treated Ss significantly spent less
time in intensive care unit. (Cocchi, 1990).
Because the immune-suppressive action of
stress via the GABA impairment (Horger and Roth, 1995) and subsequent cortisol
hyper-incretion or hyper-activity (Dhabhar et al., 1996; Haessig et al., 1996;
Dantzer, 1997; Friedman and Irwin, 1997), the rationale of the treatment to
counteract this URTI easiness by drugs has its explanation as it follows.
The basic treatment uses Gabaergic drugs
like l-glutamine as the precursor of GABA via l-glutamic acid (Laake et al.,
1995; Shupliakov et al., 1997). Pyridoxine is the cofactor of all
decarboxylases, GAD inclusive (Baxter, 1976). Finally, a benzodiazepine is the
sensitizer of type A Gabaergic receptors and a powerful anti-stress agent
(Bruni et al., 1980; Viukari, 1983; Schoch et al., 1985).
In 1-14 years children we can prescribe the
following:
- glutamine: 125-500 mg daily (not later
than 2 PM);
- pyridoxine 75-150 mg daily;
- diazepam 1-3mg in the evening (in
small children better oxazepam 5-8 mg, always in the evening).
This 3-drugs' prescription works in a
synergistic way and can restore the glutamic-GABA pathway impaired by the
stress itself. The use of a benzodiazepine aims to resensitize type A Gabaergic
receptors, the first metabolic point where stress applies itself. Without doing
it we could induce only the increasing of the glutamate with hazardous effects.
This evening use of a benzodiazepine is the best way to restore sleep (
Viukari, 1983) often impaired by excess adrenergic stimulation due to the
stress itself. Moreover, it can avoid side-effects like daily drowsiness and
muscle relaxation.
Since this approach is non-specific, every
kind of stress can so treated. Other genetic illness can benefit of such an
approach that works favouring the host resistance to metabolic stress. I have
experience in Tuberous sclerosis (Crivelli, Donati and Cocchi, 1999), in a case
of Smith and Magenis syndrome, in a case of William’s syndrome, in a case of
neuro-axonal distrophy.
A multiple personal anecdotal experience
(non yet published) strongly suggests also the use of this antistress therapy
in HIV+ Ss. It can lead to increase the leucocytes production both by reducing
the metabolic stress due to the illness itself and by favouring the
nucleogenesis. It is possible to check this effect in a short time, namely
after on month of therapy by a simple blood white cells’ count.
Finally we can remember that In situations
of stress, the brain can drain glutamine from peripheral storage departments,
skeletal muscles, liver and kidneys, but the main drainage acts on skeletal
muscles where ATP is forced to produce more glutamine. This drives to reduced
availability of ATP for muscle contractions, and the symptom of which is asthenia.
This fact explains the recent non-medical use of glutamine in some athletes or
in body builders going by it to stop ATP depretion
Conclusions
L-glutamine has benefitted of a great novel interest
since the last decade. Its immuno modulatory effect has found many
confirmations long time after the pioneering clinical study of Cocchi, 1981.
Its antistress effect did not had yet punctual research . Despite my personal
clinical efforts, perhaps this happened because the role of glutamine on any
kind of external or internal stress did not get worthy consideration till now.
Since every body illness is always a mobile
compromise between an attack and a resistance, modulation of stress responses
is one way to improve resistance, and in many illnesses, the only way we can
use now.
Medecine seems to develop itself into two
mainstreams: one is the genetic therapy, another is stress therapy. Glutamine
could have a valuable role in this second option.
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Paper presented at the 3rd World Congress on Stress, Dublin 24-27
September 2000.
Author's address : Renato COCCHI MD, via
Rabbeno, 3
42100 Reggio Emilia (Italy).
renatococchi@libero.it
Drug modulation of stress reactions
Immunity
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