Easing mitochondrial stress
in chronic Chlamydia pneumoniae infections: the use of
dietary supplements
David Wheldon
Introduction
In health a balanced diet provides all the vitamins and antioxidants
necessary to maintain vigour, and supplementation cannot reasonably
be recommended.
In disease states, however, the situation is different. Chronic
persistent infections with Chlamydia pneumoniae are characterized
by high levels of oxidative stress as a result of complex inflammatory
processes. Multiple Sclerosis is no exception. The concentrations
of reactive oxygen and nitrogen species - superoxide, nitric
oxide and peroxynitrite, a toxic metabolite of nitric oxide -
increase dramatically in MS not only because of bacterial activity
but because of the pro-inflammatory immune response to this activity.
The antioxidant buffering capacity within the brain is known
to be limited. Oligodendrocytes seem to be particularly vulnerable
to oxidative stress. Unresolved oxidative stress can damage the
lipids, proteins and nucleic acids of cells and mitochondria;
mitochondrial DNA is particularly vulnerable. [reviewed by Smith KJ, Kapoor R, Felts
PA. Demyelination: the role of reactive oxygen and nitrogen species.
Brain Pathol. 1999 Jan;9(1):69-92.]
Levels of isoprostane are increased in the CSF and brain tissue
in inflammatory states and in MS. [Greco A, Minghetti L, Levi G. Isoprostanes,
novel markers of oxidative injury, help understanding the pathogenesis
of neurodegenerative diseases. Neurochem Res. 2000 Oct;25(9-10):1357-64.]
These authors comment:
'Isoprostanes are prostaglandin-like compounds which are formed
by free radical catalysed peroxidation of arachidonic acid esterified
in membrane phospholipids. They are emerging as a new class of
sensitive, specific and reliable markers of in vivo lipid peroxidation
and oxidative damage.'
There is some evidence that the progression of MS is more severe
in those who have a genetically-determined relative inability
to remove the toxic products of oxidative stress. [Mann CL et al., Glutathione
S-transferase polymorphisms in MS: their relationship to disability.
Neurology. 2000 Feb 8;54(3):552-7.]
Antioxidants are depleted in the serum and CSF of MS patients.
[reviewed
by Besler HT, Comoglu S. Lipoprotein oxidation, plasma total
antioxidant capacity and homocysteine level in patients with
multiple sclerosis. Nutr Neurosci. 2003 Jun;6(3):189-96.] These authors found that, during MS
relapses, there was a significant increase in the levels of autoantibodies
against oxidized low-density lipoproteins, a strong decrease
in plasma total antioxidant capacity and an elevated plasma homocysteine
level. (Elevated homocysteine levels are also found in inflammatory
arterial disease, and are associated with coronary thrombosis.)
There is evidence that damage in MS is not limited to the plaque
areas. The current view is that considerable biochemical alterations
are present in both grey matter and in normal-appearing white
matter. Might an ongoing intracerebral Chl. pneumoniae
infection cause widespread oxygen depletion in the brain? Graumann
and colleagues found up-regulation of genes involved in maintenance
of cellular homeostasis, and in neural protective mechanisms
known to be induced upon ischemic preconditioning in MS. [Graumann U, et al.,
Molecular changes in normal appearing white matter in multiple
sclerosis are characteristic of neuroprotective mechanisms against
hypoxic insult. Brain Pathol. 2003; 13(4): 554-73.] Haemodynamic disorders have been found
in MS, with decreased grey matter and increased white matter
perfusion. [Rashid
W et al., Abnormalities of cerebral perfusion in multiple sclerosis.
J Neurol Neurosurg Psychiatry. 2004; (9): 1288-93.]
The damage caused by free radicals may be multifactorial, synergic
and unexpected. In 1982 Amaducci and co-workers described an
increased incidence of MS in leather workers exposed to organic
solvents. [Amaducci
L et al., Multiple sclerosis among shoe and leather workers:
an epidemiological survey in Florence. Acta Neurol Scand.
1982 Feb;65(2):94-103.]
A raised incidence of MS has also been found in nurse-anaesthetists,
who are exposed to volatile anaesthetic agents. [Flodin U et al., Multiple
sclerosis in nurse anaesthetists. Occup Environ Med. 2003
Jan;60(1):66-8]
Are there any dangers of supplementation? Disappointment follows
undue expectation: the remarkable claims made for vitamin C in
malignancy in the 1970's are now known to have been based on
the comparison of groups of patients whose diagnoses were made
under different circumstances and so were not comparable. [Cameron E, Pauling
L. Supplemental ascorbate in the supportive treatment of cancer:
Prolongation of survival times in terminal human cancer. Proc
Natl Acad Sci USA. 1976 Oct;73(10):3685-9.] This has generated not a little antipathy
amongst physicians; recollection of this punctured bubble has
tended to eclipse the more modest findings that antioxidants
may be of help in slowing the rate of progress of Alzheimer's
disease.
Supplements may not be standardized and may not be present in
the same physiological form in which they are in the body; they
are not necessarily controlled by their manufacturers and are
not assayed by the state. But this is also true of prescription
drugs: in the case of some generics the patient may not receive
what the physician has prescribed. One should go for quality
in both.
There is a theoretical risk, during treatment of malignancies
with radiotherapy or chemotherapy, that antioxidants such as
Vitamins C and E may help protect tumour cells against purposefully-made
free radicals. [reviewed
by D'Andrea G, Use of antioxidants during chemotherapy and radiotherapy
should be avoided. CA Cancer J Clin. 2005 55(5):319-21.] On reading this paper I was left with
the feeling that the author is against antioxidant supplementation
in general; the argumentation is a little disingenuous. Were
it really believed, recommendation of a junk-food diet would
be the next logical step.
The risks of supplementation are present but small. The possible
benefits - by counteracting chronic endotoxicity and unrelenting
inflammatory damage, by restoring a range of depleted antioxidants,
and by preventing mitochondrial degradation before this becomes
irreversible - are very great.
Vitamin C
Humans cannot make Vitamin
C (ascorbic acid) and require a dietary source.
Vitamin C is required for the synthesis of collagen, which is
a component of arterial walls, tendons, ligaments and bronchioles.
Persistent infection with Chlamydia pneumoniae damages
arterial and bronchial walls [Theegarten G et al. The role of chlamydia in
the pathogenesis of pulmonary emphysema. Electron microscopy
and immunofluorescence reveal corresponding findings as in atherosclerosis.
Virchows Arch. 2000 Aug;437(2):190-3.]. Cross-linkages occur in collagen and elastin
with stiffening. These cross-linkages are capable of reversal
[Vaitkevicius
PV et al., A cross-link breaker has sustained effects on arterial
and ventricular properties in older rhesus monkeys. Proc Natl
Acad Sci USA. 2001 Jan 30;98(3):1171-5.]
Vitamin C is also a powerful antioxidant, able to protect proteins,
carbohydrates and nucleic acids (DNA and RNA) against damage
by free radicals and reactive oxygen species that can be generated
during normal cellular metabolism; this damage is increased enormously
on exposure to bacterial endotoxins and ensuing inflammation.
Vitamin C has the capacity to regenerate other antioxidants such
as vitamin E [Chan
AC. Partners in defense, vitamin E and vitamin C. Can J Physiol
Pharmacol. 1993 Sep;71(9):725-31.]
Vitamin C helps make the neurotransmitter noradrenaline (norepinephrine).
Vitamins C and E in combination are particularly active, and,
if taken as supplements, may protect against the onset of certain
diseases; elderly men who took supplements of both vitamin C
and E were found to have an 88% reduction in the frequency of
vascular dementia (but not Alzheimer's dementia) compared with
men who did not take the supplements. The protective effect was
substantially greater in men who reported long-term use of both
vitamins. [Masaki
KH et al., Association of vitamin E and C supplement use with
cognitive function and dementia in elderly men. Neurology.
2000 Mar 28;54(6):1265-72.]
Vitamin B2, B6, B12 and
Folate
Vitamin B2 (Riboflavin), Vitamin
B6 (pyridoxal phosphate), Vitamin B12 (as oral methylcobalamin)
and folate are also important. Low concentrations of these vitamins
are found in persons with excess plasma homocysteine. Homocysteine
is an amino acid whose metabolism is involved with remethylation,
which requires folic acid and B-12, and transsulphuration, which
requires B-6. [Data
from the Framingham studies, reviewed by Selhub, J. J. Nutr.
136:1726S - 1730S] Hyperhomocysteinaemia,
due to interference with the methionine pathway, is also found
in chronic infections with C. pneumoniae [Nabipour I, et al.
Heart Lung Circ. Correlation of hyperhomocysteinaemia
and Chlamydia pneumoniae IgG seropositivity with coronary artery
disease in a general population. 2007 Dec;16(6):416-22.] and is a feature of diseases as diverse
as adult onset asthma, arteriopathy and dementia. Elevated homocysteine
levels are found in the plasma of persons with MS even when the
disease is in remission [Ramsaransing GS, et al. J Neurol Neurosurg
Psychiatry. 2006 Plasma homocysteine levels in multiple sclerosis.
Feb;77(2):189-92. Raised
homocysteine damages proteins, most notably in the endothelium,
and may be responsible for some of the vascular changes seen
in MS [D'haeseleer
M, Lancet Neurol. 2011 Jul;10(7):657-66.]
Supplementation with vitamin
B complex is thus recommended.
Note: There is evidence that
the cellular uptake of Vitamin B12 and folate is greatly improved
by supplementation with low-dose lithium compounds. Lithium orotate
is the preferred form. [Reviewed in depth by Marshall T M, Lithium as
a nutrient. Journal of American Physicians and Surgeons
2015 20 (4) 104-109.]
Bioflavonoids
Bioflavonoids are a large,
heterogenous group of pigmented plant molecules; in evolutionary
terms they may have emerged because of their ability to cope
with the immense free radical load associated with photosynthesis.
They are polyphenols, but beyond that they have a wide structural
diversity. Over 4000 bioflavonoids have been described. They
have been divided into 7 different families according to their
chemical structure. Though they are efficient antioxidants, tissue
and cellular levels may be too low for this to be their prime
benefit. Williams and colleagues suggest that flavonoids, and
their in vivo metabolites, may not act as conventional
hydrogen-donating antioxidants but may exert modulatory actions
in cells through actions at protein kinase and lipid kinase signalling
pathways. [Williams
RJ, Spencer JP, Rice-Evans C. Flavonoids: antioxidants or signalling
molecules? Free Radic Biol Med. 2004;36(7):838-849.]
Quercetin is a ubiquitous bioflavonoid
with powerful activity against the production of proinflammatory
cytokines in macrophages stimulated by lipopolysaccharide. [Cho SY, Park SJ, Kwon
MJ, et al. Quercetin suppresses proinflammatory cytokines production
through MAP kinases andNF-kappaB pathway in lipopolysaccharide-stimulated
macrophage. Mol Cell Biochem. 2003;243(1-2):153-160.]
A mixture of bioflavonoids
from Waltheria indica, a plant used for centuries in India
for inflammatory disorders, was found to significantly and dose-dependently
inhibit the production of the nitric oxide (NO) and the cytokines
tumor necrosis factor-a and interleukin (IL)-12, in lipopolysaccharide
and g interferon activated murine peritoneal macrophages,
without displaying cytotoxicity. The major constituent of extracts
of this were quercetin. [Rao YK, Fang SH, Tzeng YM. Inhibitory effects
of the flavonoids isolated from Waltheria indica on the
production of NO, TNF-a
and IL-12 in activated macrophages. Biol Pharm Bull. 2005
May;28(5):912-5.]
The ability of bioflavonoids
to enter the CNS in man is uncertain, but dietary anthocyanin
from blueberries has been found to enter the CNS of aged rats,
with some evidence that memory was improved. [Andres-Lacueva C, Shukitt-Hale B,
Galli RL, Jauregui O, Lamuela-Raventos RM, Joseph JA. Anthocyanins
in aged blueberry-fed rats are found centrally and may enhance
memory. Nutr Neurosci. 2005 Apr;8(2):111-20.] This is of particular interest, as
the authors found the anthocyanin in several parts of the brain,
including the hippocampus, which is concerned with the processing
of experiences into memories, which are stored elsewhere. The
hippocampus is often the first area to be damaged in Alzheimer's
disease. In another aged rat study, again using blueberries,
short-term but not long-term memory was significantly enhanced.
[Ramirez
MR, Izquierdo I, Raseira MD, Zuanazzi JA, Barros D, Henriques
AT. Effect of lyophilised Vaccinium berries on memory, anxiety
and locomotion in adult rats. Pharmacol Res. 2005 Aug
9. Epub ahead of printing.]
Pomegranate juice appears
to have remarkable properties, with recently reported benefits
in coronary artery disease, [Aviram M et al., Pomegranate juice consumption
for 3 years by patients with carotid artery stenosis reduces
common carotid intima-media thickness, blood pressure and LDL
oxidation. Clin Nutr. 2004 Jun;23(3):423-33.; Sumner MD
et al., Effects of pomegranate juice consumption on myocardial
perfusion in patients with coronary heart disease. Am J Cardiol.
2005 Sep 15;96(6):810-4. ]
hyperlipidaemia in diabetics, [Esmaillzadeh A et al., Concentrated pomegranate
juice improves lipid profiles in diabetic patients with hyperlipidemia.
J Med Food. 2004 Fall;7(3):305-8.]
prostatic cancer [Malik
A et al., Pomegranate fruit juice for chemoprevention and chemotherapy
of prostate cancer. Proc Natl Acad Sci U S A. 2005 Sep
28; [Epub ahead of print] and
hypertension.
[Aviram M, Dornfeld L. Pomegranate juice consumption inhibits
serum angiotensin converting enzyme activity and reduces systolic
blood pressure. Atherosclerosis. 2001 Sep;158(1):195-8.]
This new work is promising.
Vitamin E
The term vitamin E describes
a family of eight antioxidants - four tocopherols and four tocotrienols.
Deficiency is rare, but it is quite possible that relative deficiency
may occur in chronic Chlamydia pneumoniae infection, due
to increased oxidative stress and consequent demand for antioxidants.
a-tocopherol, the commonest E vitamin, is fat
soluble and protects fats from oxidative degeneration. Fats are
an integral part of cell membranes - including myelin - and are
vulnerable to destruction through oxidation by free radicals.
Endotoxin can also bind to them. When a molecule of a-tocopherol
neutralizes a free radical, it is itself neutralized. However,
other antioxidants, such as vitamin C, are capable of regenerating
its antioxidant capacity. [Chan AC. Partners in defense, vitamin E and
vitamin C. Can J Physiol Pharmacol. 1993; 71(9): 725-31.] Deficiency of vitamin E results in
neurological symptoms, notably vertigo, ataxia and peripheral
neuropathy.
Chronic Chlamydia pneumoniae infection has been linked
with Alzheimer's dementia, which is characterised by intracerebral
oxidative damage; one controlled study showed that supplementation
of individuals who had moderate neurological impairment with
2,000 IU of synthetic a-tocopherol daily for two years resulted
in a significant slowing of the progression of Alzheimer's dementia.
[Sano M
et al. N Engl J Med. 1997 Apr 24;336(17):1216-22.] The mechanism for this protection
may be inhibition of the sphingomyelin-ceramide cascade which
results in oxidative stress and cell-death. [Ayasolla K et al., Inflammatory mediator
and beta-amyloid (25-35)-induced ceramide generation and iNOS
expression are inhibited by vitamin E. Free Radic Biol Med.
2004 Aug 1;37(3):325-38.]
This cascade can be initiated by lipopolysaccharides amongst
other agents.
Many commercial preparations calling themselves 'Vitamin E' contain
synthetic a-tocopherol only. There is evidence
that all eight members of the vitamin E family are required in
health. The tocotrienols (which until recently have been largely
ignored) may be particularly important. Abnormal angiogenesis
occurs in chronic C. pneumoniae infection and in other
degenerative diseases (it is a serious component of the pathology
in diabetes mellitus for instance), and the tocotrienols have
been shown in vivo to act against new vessel formation.
[Nakagawa
K, et al., In vivo angiogenesis is suppressed by unsaturated
vitamin E, tocotrienol. J Nutr. 2007 137(8): 1938-43.] Tocotrienols are neuroprotective,
particularly against oxidative stress, possibly more so than
tocopherols [Khanna
S, Roy S, et al., Characterization of the potent neuroprotective
properties of the natural vitamin E alpha-tocotrienol. J Neurochem.
2006 Sep;98(5):1474-86. pdf available]. Sources and properties of the tocotrienols
are discussed in this excellent review [Sen CK, Khanna S, Roy S. Tocotrienols:
Vitamin E beyond tocopherols. Life Sci. 2006 78(18): 2088-98.
pdf available]. Natural
scources of balanced tocopherols and tocotrienols may be preferable
to synthetic sources. Wheat-germ and wheat-germ oil are ideal
sources.
Omega 3 oil
Omega 3 oils are polyunsaturated;
they include a-linolenic acid which is found in plant
oils, particularly flax-seed oil. Fish-derived Omega 3 oils include
eicosapentaenoic (EPA) and docosahexaenoic acids (DHA); EPA and
DHA can also be synthesised in the body from a-linolenic
acid.
Eicosanoids are chemical messengers derived from 20-carbon polyunsaturated
fatty acids. They play critical roles in immune and inflammatory
responses. They are fabricated from EPA. They are also fabricated
from arachidonic acid. Arachidonic acid-derived eicosanoids differ
from EPA-derived eicosanoids in being more potent inducers of
inflammation and clotting. The average Western diet, poor in
oily fish, tends to allow a chronic imbalance of eicosanoids
and creates an unfavourable ratio of arachidonic acid- and EPA-derived
eicosanoids. Oily fish or Omega 3 oils correct this balance and
protect against cardiovascular disease. [Kris-Etherton PM et al. Fish consumption,
fish oil, omega-3 fatty acids, and cardiovascular disease. Circulation.
2002;106(21):2747-2757; Calder PC, Proc Nutr Soc. 2002 Aug;61(3):345-58.] Chlamydia pneumoniae is known
to have an input into cardiovascular disease.
Fish-derived Omega 3 oils inhibit graft-versus-host reactions
in animal studies; the same studies showed an inhibition of the
production of Tumour-Necrosis Factor alpha (TNF-a).
[Grimm,
H et al., Immunoregulation by parenteral lipids: impact of the
n-3 to n-6 fatty acid ratio. J Parenter Enteral Nutr.
1994 Sep-Oct;18(5):417-21.]
TNF-a has a complex pro-inflammatory cytokine; it
is a component of the innate immune response. Raised TNF-a
levels have been found to be associated with fatigue in MS patients.
[Flachenecker
P, et al. Cytokine mRNA expression in patients with multiple
sclerosis and fatigue. Mult Scler. 2004 Apr;10(2):165-9.] TNF-a is produced in large amounts in response
to bacterial endotoxins.
Evening Primrose Oil
Evening primrose oil contains
linoleic acid (LA) and gamma-linoleic acid (GLA). LA is plentiful
in oils derived from nuts and seeds, and, in health, GLA is readily
synthesized from it in the body. Thus GLA supplementation is
unnecessary in health. However, in disorders which have an autoimmune
component - as may be the case with MS - there is some evidence
that the ability to synthesize GLA is impaired. GLA may defend
against endotoxin damage. This has been shown in cell-culture
[Crutchley
DJ, Hydroxyeicosatetraenoic acids and other unsaturated fatty
acids inhibit endotoxin-induced thromboplastin activity in human
monocytes. Biochem Biophys Res Commun. 1985 Oct 15;132(1):67-73.] and in animal studies. [Karlstad MD et al.,
Effect of intravenous lipid emulsions enriched with g-linolenic acid on plasma n-6 fatty
acids and prostaglandin biosynthesis after burn and endotoxin
injury in rats. Crit Care Med. 1993 Nov;21(11):1740-9.]
GLA has been found to increase bone density in the elderly. [Kruger MC et al.,
Calcium, g-linolenic acid and
eicosapentaenoic acid supplementation in senile osteoporosis.
Aging (Milano) 1998 Oct;10(5):385-94.] This may be important, as osteoporosis is often
problematic in MS, where falls can be disastrous.
GLA has a beneficial effect in the treatment of peripheral neuropathy;
[Keen H
et al., Treatment of diabetic neuropathy with g-linolenic acid. The g-Linolenic Acid Multicenter Trial Group. Diabetes
Care. 1993 Jan;16(1):8-15.]
This may be of relevance; peripheral neuropathy is seen in severe
chronic infection with Chlamydia pneumoniae and may well
be caused by endotoxin release. Experimentally, endotoxin has
been shown to cause peripheral neuropathy in an animal model.
[Brown
RF et al., Bacterial lipopolysaccharide induces a conduction
block in the sciatic nerves of rats. Lab Anim Sci. 1999
Feb;49(1):62-9.]
N-acetyl cysteine ~ Selenium
Reduced glutathione (GSH) neutralizes
peroxides in the presence of a peroxidase which has 4 atoms of
selenium (Se) bound as seleno-cysteine moieties. During this
process GSH is oxidized and is then regenerated by a reductase.
Glutathione reductase is increased in the CSF of patients with
MS. [Calabrese
V et al., Changes in cerebrospinal fluid levels of malondialdehyde
and glutathione reductase activity in multiple sclerosis. Int
J Clin Pharmacol Res. 1994; 14(4): 119-23.] By contrast, low levels of glutathione peroxidase
were found in MS patients. [Mai J et al., High dose antioxidant supplementation
to MS patients. Effects on glutathione peroxidase, clinical safety,
and absorption of selenium. Biol Trace Elem Res. 1990
Feb;24(2):109-17.] Taken
together, these data suggest a disordered glutathione metabolism
in MS, which accords with the evidence that oxidative stress
is a part of this disease. Inherited glutathione synthetase deficiency
has been described; it is accompanied by progressive peripheral
and central neurological disorders. [Meister A, Larsson A. GSH synthetase
deficiency and other disorders of the g-glutamyl cycle. In: Scriver CR, et al., eds.
The Metabolic and Molecular Bases of Inherited Disease (Volume
1). New York: McGraw-Hill; 1995;1461-1495 (Chapter 43).]
GSH is a tripeptide composed of glutamate, cysteine and glycine.
It is thought not to be absorbed intact from the gut and must
be made in the body. Glutamate and glycine are well represented
in the diet; cysteine less so. The concentration of this amino
acid is thus the limiting factor in the synthesis of glutathione.
The best form of supplementation is N-acetyl cysteine (NAC) which
is safer than cysteine.
Supplementation of diet with NAC in MS patients elevates levels
of GSH peroxydase. [Mai
J et al., High dose antioxidant supplementation to MS patients.
Effects on glutathione peroxidase, clinical safety, and absorption
of selenium. Biol Trace Elem Res. 1990 Feb;24(2):109-17.] Selenium is required for the synthesis
of GSH peroxydase (see above.) Selenium levels are low in patients
with MS. Mai and colleagues (above) found that supplementation
with selenium normalized the low levels of this element.
N-acetyl cysteine and selenium would seem to be useful supplements
for restoring GSH stores; this is particularly important as GSH
plays a part in the regeneration of other antioxidants.
Acetyl L-carnitine
Carnitine and acetyl L-carnitine (ALC) facilitate the transport
of fatty acids across the mitochondrial membrane. The acetyl
group of ALC is used in the biosynthesis of acetyl-CoA, a key
intermediary in the generation of cellular energy. Depletion
of ALC increases mitochondrial stress. Supplementation with ALC
reduced fatigue in Chronic Fatigue Syndrome [Vermeulen RC, Scholte HR. Exploratory
open label, randomized study of acetyl- and propionylcarnitine
in chronic fatigue syndrome. Psychosom Med. 2004 Mar-Apr;66(2):276-82.] It also alleviated fatigue in MS.
[Tomassini
V et al., Comparison of the effects of acetyl L-carnitine and
amantadine for the treatment of fatigue in multiple sclerosis:
results of a pilot, randomised, double-blind, crossover trial.
J Neurol Sci. 2004 Mar 15;218(1-2):103-8.]
Peroxynitrite is a strong oxidant capable of damaging target
tissues, particularly the brain, which is known to be endowed
with limited antioxidant buffering capacity. Inducible nitric
oxide synthase is upregulated in the CNS in patients with MS.
[Calabrese
V et al., Disruption of thiol homeostasis and nitrosative stress
in the cerebrospinal fluid of patients with active multiple sclerosis:
evidence for a protective role of ALC. Neurochem Res.
2003 Sep;28(9):1321-8.]
These authors comment: 'Western blot analysis showed in MS patients
increased nitrosative stress associated with a significant decrease
of reduced glutathione (GSH). Increased levels of oxidized glutathione
(GSSG) and nitrosothiols were also observed. Interestingly, treatment
of MS patients with ALC resulted in decreased CSF levels of NO
reactive metabolites and protein nitration, as well as increased
content of GSH and GSH/GSSG ratio. Our data sustain the hypothesis
that nitrosative stress is a major consequence of NO produced
in MS-affected CNS and implicate a possible important role for
acetylcarnitine in protecting brain against nitrosative stress,
which may underlie the pathogenesis of MS.'
ALC has many prophylactic properties. It was found to protect
against acoustic damage to the inner ear in an animal model [Kopke R et al., Prevention
of impulse noise-induced hearing loss with antioxidants. Acta
Otolaryngol. 2005 Mar;125(3):235-43.]
Reviewing the literature, Ames and Liu conclude that trials of
ALC in the treatment of mild cognitive impairment and mild Alzheimer's
disease showed significant efficacy vs. placebo. [Ames BN, Liu J. Delaying
the mitochondrial decay of aging with acetylcarnitine. Ann
N Y Acad Sci. 2004 Nov;1033:108-16. Review.]
ALC treatment was found to be efficacious in alleviating symptoms,
particularly pain, and improved nerve fiber regeneration and
vibration perception in patients with established diabetic neuropathy.
[Sima AA
et al., Acetyl-L-carnitine improves pain, nerve regeneration,
and vibratory perception in patients with chronic diabetic neuropathy:
an analysis of two randomized placebo-controlled trials. Diabetes
Care. 2005 Jan;28(1):89-94.]
In a cell culture study ALC was found to protect against damage
caused by beta-amyloid (Abeta), a neurotoxic peptide which accumulates
in the brain in Alzheimer's disease. [Dhitavat S, Ortiz D, Shea TB, Rivera
ER. ALC protects against amyloid-beta neurotoxicity: roles of
oxidative buffering and ATP levels. Neurochem Res. 2002
Jun;27(6):501-5.] These
authors found that ALC attenuated oxidative stress and cell death
induced by beta-amyloid neurotoxicity. They comment: 'Abeta depleted
ATP levels, suggesting Abeta may induce neurotoxicity in part
by compromising neuronal energy. ALC prevented ATP depletion;
therefore, ALC may mediate its protective effect by buffering
oxidative stress and maintaining ATP levels.' This is particularly
interesting when considering chronic Chlamydia pneumoniae
infection; the mechanism of accentuation of oxidative damage
by ATP starvation may be similar. Electron microscopic studies
have shown that replicating chlamydiae are always found in close
proximity to mitochondria; they are obligate energy parasites,
their metabolic function being a reversal of that of mitochondria.
[reviewed
by Stratton CW, The pathogenesis of systemic chlamydial infections:
theoretical considerations of host-cell energy depletion and
its metabolic consequences. Antimicrobics and infectious diseases
newsletter. 1997; 16 (5) 33-38.]
Oxidative damage may be an important factor in neurone-loss associated
with ageing. In an rat model Liu and colleagues demonstrated
that oxidative damage to nucleic acids (8-hydroxyguanosine and
8-hydroxy-2'-deoxyguanosine) increased with age in the hippocampus,
a region of the brain concerned with 'encoding' memory from the
immediate circumstance. Oxidative damage to nucleic acids occurred
predominantly in RNA. Dietary administration of ALC and / or
a-lipoic acid significantly reduced the extent
of oxidized RNA, the combination being the most effective. [Liu J et al., Memory
loss in old rats is associated with brain mitochondrial decay
and RNA/DNA oxidation: partial reversal by feeding acetyl-L-carnitine
and/or R-a -lipoic acid. Proc
Natl Acad Sci U S A. 2002 Feb 19;99(4):2356-61. Erratum in:
Proc Natl Acad Sci U S A 2002 May 14;99(10):7184-5.]
Alpha-Lipoic acid
Alpha lipoic acid (ALA) plays an important role in mitochondrial
energy production. It is also a powerful antioxidant. In health,
sufficient can be synthesized in the body. However, in conditions
of chronic oxidative stress it may become depleted; in depletion
its role as an antioxidant is the first to be impaired. Strong
antioxidant properties are shown by its reduced form, dihydrolipoic
acid (DHLA). [reviewed
by Biewenga GP et al., The pharmacology of the antioxidant lipoic
acid. Gen Pharmacol. 1997 Sep;29(3):315-31]
ALA scavenges hydroxyl radicals, hypochlorous acid, peroxynitrite,
and singlet oxygen. DHLA also scavenges superoxide and peroxyl
radicals and can regenerate thioredoxin, vitamin C, and glutathione,
which in turn can recycle vitamin E. [reviewed by Packer L et al., Molecular
aspects of lipoic acid in the prevention of diabetes complications.
Nutrition. 2001 Oct;17(10):888-95.]
ALA also has the ability to chelate to inorganic mercury and
to increase the biliary excretion of this metal in animal experiments.
[Gregus
Z et al., Effect of lipoic acid on biliary excretion of glutathione
and metals. Toxicol Appl Pharmacol. 1992 May;114(1):88-96.] ALA may also ameliorate oxidative
damage caused by the toxic metal cadmium. [Bludovska M et al., The influence
of a-lipoic acid on the
toxicity of cadmium. Gen Physiol Biophys. 1999 Oct;18
Spec No:28-32] Cadmium
and mercury are intensely toxic in the CNS.
Coenzyme Q10 (Ubiquinone)
Coenzyme Q10 (CoQ10, ubiquinone) is a lipid-soluble molecule
active in the hydrophobic core of the phospholipid bilayer of
the inner membrane of mitochondria where it effects electron
transfer within the electron transport chain.
CoQ10 also serves as an important antioxidant, particularly within
the mitochondrion.
CoQ10 is adequately synthesized in children and adolescents;
however, the ability of the body to synthesize CoC10 begins to
diminish surprisingly early in adult life. [Kalen A et al., Age-related changes
in the lipid compositions of rat and human tissues. Lipids.
1989 Jul;24(7):579-84.]
By mid-life most people are dependent on dietary sources.
Lipid peroxidation, caused by free radical damage, diminishes
CoC10 levels in cells [Forsmark-Andree P et al., Lipid peroxidation
and changes in the ubiquinone content and the respiratory chain
enzymes of submitochondrial particles. Free Radic Biol Med.
1997;22(3):391-400.] When
CoC10 levels become low, a vicious circle of lipid peroxidation
and CoQ10 depletion begins, resulting in mitochondrial damage.
Aejmelaeus and colleagues comment: 'The decline is most significant
in males under 50 years; in older age groups the values remain
stable at a low level. Q10 supplementation doubles the number
of ubiquinol-10-containing low-density lipoprotein (LDL) molecules
and may therefore have an inhibitory effect on LDL oxidation.'
[Aejmelaeus
R et al., Ubiquinol-10 and total peroxyl radical trapping capacity
of LDL lipoproteins during aging: the effects of Q-10 supplementation.
Molecular Aspects of Medicine 18(Suppl.) (1997), s113-s120.]
CoQ10 protected against toxic damage to neurones in animal studies.
[Beal MF
et al., Coenzyme Q10 and nicotinamide block striatal lesions
produced by the mitochondrial toxin malonate. Ann Neurol.
1994 Dec;36(6):882-8] It
also protected against neurological damage caused by endotoxins.
[Chuang
YC et al., Neuroprotective effects of coenzyme Q10 at rostral
ventrolateral medulla against fatality during experimental endotoxemia
in the rat. Shock. 2003 May;19(5):427-32.]
A combination of antioxidants (acetyl L-carnitine, CoQ10 and
n-3 oils) was found to improve and stabilize vision in age-related
macular degeneration (AMD). [Feher J et al., Improvement of visual functions
and fundus alterations in early age-related macular degeneration
treated with a combination of acetyl L-carnitine, n-3 fatty acids,
and coenzyme Q10. Ophthalmologica. 2005 May-Jun;219(3):154-66.] AMD is a condition with a multifactorial
aetiology, one factor being chronic infection with Chlamydia
pneumoniae [Ishida
O et al., Is Chlamydia pneumoniae infection a risk factor
for age related macular degeneration? Br J Ophthalmol.
2003 May;87(5):523-4; Kalayoglu MV et al., Serological association
between Chlamydia pneumoniae infection and age-related
macular degeneration. Arch Ophthalmol. 2003 Apr;121(4):478-82;
Robman L et al., Exposure to Chlamydia pneumoniae Infection
and Progression of Age-related Macular Degeneration. Am J
Epidem 2005 161(11):1013-1019.]
AMD is a disorder characterized by mitochondrial depletion and
damage. [Feher
J et al., Mitochondrial alterations of retinal pigment epithelium
in age-related macular degeneration.Neurobiol Aging. 2005 Jun
22.] AMD may be considered
a paradigm of chronic progressive infections with Chlamydia
pneumoniae and improvement following antioxidant treatment
is significant.
Melatonin
Melatonin (MEL), an indole, was originally described as a hormone
biosynthesized from L-tryptophan within the pineal gland in the
brain; it was found to regulate sleep patterns. Since its discovery,
this remarkable molecule has been found have numerous and diverse
actions in the cell. MEL is a potent antioxidant, protecting
mitochondria from oxidative stress [reviewed by Leon J, Acuna-Castroviejo
D, Sainz RM, Mayo JC, Tan DX, Reiter RJ. melatonin and mitochondrial
function. Life Sci. 2004 Jul 2;75(7):765-90.] MEL also acts directly on the electron
transport chain, increasing ATP synthesis while preventing the
oxidative damage associated with such an increase. [Acuna-Castroviejo
D, Escames G, Leon J, Carazo A, Khaldy H. Mitochondrial regulation
by melatonin and its metabolites. Adv Exp Med Biol. 2003;527:549-57.]
These authors also found
that MEL restored levels of the important antioxidant glutathione.
MEL is a readily diffusible mobile molecule and is able to pass
into any tissue, cell or cell compartment with ease. [reviewed by Hardeland
R, Pandi-Perumal SR. melatonin, a potent agent in antioxidative
defense: Actions as a natural food constituent, gastrointestinal
factor, drug and prodrug. Nutr Metab (Lond). 2005 Sep
10;2(1):22.] These authors
observe that, unusually for a hormone, MEL is a normal dietary
constituent, and is found in yeasts and plants; walnuts are a
particularly rich source. Dietary MEL can markedly influence
blood-levels. [Reiter
RJ, Manchester LC, Tan DX.Melatonin in walnuts: Influence on
levels of melatonin and total antioxidant capacity of blood.
Nutrition. 2005; 21(9): 920-4.] The fact that MEL is a normal dietary constituent
removes some of the hesitation which one may have in using it
for supplementation.
MEL protects against endotoxin-induced lipid peroxidation. [Sewerynek E, Melchiorri
D, Chen L, Reiter RJ. Melatonin reduces both basal and bacterial
lipopolysaccharide-induced lipid peroxidation in vitro. Free
Radic Biol Med. 1995 Dec;19(6):903-9.] This is very important in the CNS, where key
lipids are relatively unprotected by other antioxidants.
Reiter and colleagues, in a comprehensive review, observe: 'Melatonin
reduces oxidative stress by several means. Thus, the indole [melatonin]
is an effective scavenger of both the highly toxic hydroxyl radical,
produced by the 3 electron reduction of oxygen, and the peroxyl
radical, which is generated during the oxidation of unsaturated
lipids and which is sufficiently toxic to propagate lipid peroxidation.
Additionally, melatonin may stimulate some important antioxidative
enzymes, i.e., superoxide dismutase, glutathione peroxidase and
glutathione reductase. In in vivo tests, melatonin in pharmacological
doses has been found effective in reducing macromolecular damage
that is a consequence of a variety of toxic agents, xenobiotics
and experimental paradigms which induce free radical generation.
In these studies, melatonin was found to significantly inhibit
oxidative damage that is a consequence of paraquat toxicity,
potassium cyanide administration, lipopolysaccharide treatment,
kainic acid injection, carcinogen administration, carbon tetrachloride
poisoning, etc., as well as reducing the oxidation of macromolecules
that occurs during strenuous exercise or ischemia-reperfusion.
In experimental models which are used to study neurodegenerative
changes associated with Alzheimer's and Parkinson disease, melatonin
was found to be effective in reducing neuronal damage. Its lack
of toxicity and the ease with which melatonin crosses morphophysiological
barriers and enters subcellular compartments are essential features
of this antioxidant.' [Reiter RJ, Carneiro RC, Oh CS. Melatonin in
relation to cellular antioxidative defense mechanisms. Horm
Metab Res. 1997 Aug;29(8):363-72.]
MEL was found to inhibit the production of endotoxin-induced
Tumour Necrosis Factor alpha. [Sacco S et al., Mechanism of the inhibitory
effect of melatonin on tumor necrosis factor production in vivo
and in vitro. Eur J Pharmacol. 1998 Feb 19;343(2-3):249-55.] and in an animal model was found to
exert immunoregulatory effects via T-helper 2 (Th2) cell products.
Th2 products may modulate the secretion and/or action of inflammatory
cytokines, which play an important role in the development of
septic shock associated with endotoxemia. [Maestroni GJ. melatonin as a therapeutic
agent in experimental endotoxic shock. J Pineal Res. 1996
Mar;20(2):84-9.]
Post-mortem studies showed diminished levels of MEL in the ventricular
CSF of those who had died with Alzheimer's disease (AD) compared
with age-matched controls. However, CSF MEL levels were uniformly
low in those who had died with advanced dementia, irrespective
of their age.
[Liu RY et al., Decreased melatonin levels in postmortem cerebrospinal
fluid in relation to aging, Alzheimer's disease, and apolipoprotein
E-epsilon4/4 genotype. J Clin Endocrinol Metab. 1999 Jan;84(1):323-7.]
MEL depletion was found
to be a very early event in the development of AD. [Zhou JN et al., Early
neuropathological Alzheimer's changes in aged individuals are
accompanied by decreased cerebrospinal fluid melatonin levels.
J Pineal Res. 2003; 35(2): 125-30.] A loss of the diurnal rhythm of MEL levels may
precede the first clinical signs of the disease. [Wu YH et al., Molecular
changes underlying reduced pineal melatonin levels in Alzheimer
disease: alterations in preclinical and clinical stages. J
Clin Endocrinol Metab. 2003 Dec;88 (12): 5898-906.] MEL ameliorated evening agitation and
improved cognitive and non-cognitive functions in patients with
AD in small controlled trials. [Brusco LI et al., Melatonin treatment stabilizes
chronobiologic and cognitive symptoms in Alzheimer's disease.
Neuro Endocrinol Lett. 2000; 21(1): 39-42; Cardinali DP
et al., The use of melatonin in Alzheimer's disease. Neuro
Endocrinol Lett. 2002;23 Suppl 1:20-3; Asayama K, et al.,
Double blind study of melatonin effects on the sleep-wake rhythm,
cognitive and non-cognitive functions in Alzheimer type dementia.
J Nippon Med Sch. 2003; 70(4): 334-41.] Interestingly, it took several weeks for benefits
to appear, suggesting an action other than sedation, which is
immediate. Another, larger, multicentre study detected no benefits
from melatonin in sleep disorders in Alzheimer's dementia. [Singer C, et al.,
Alzheimer's Disease Cooperative Study. A multicenter, placebo
- controlled trial of melatonin for sleep disturbance in Alzheimer's
disease. Sleep. 2003; 26(7): 893-901.] However, actigraphy, used in most studies of
melatonin in sleeping disorders in Alzheimer's disease, does
not give a direct measurement of sleep. Studies using polysomnography,
which does measure sleep directly, but which is intrusive, would
seem to be rare.
Sleep disorders are common in MS, with a flattening of the normal
circadian sleeping/waking rhythm, leading to wakefulness at night
and a tendency to somnolence during the day. [Fleming WE, Pollak CP. Sleep disorders
in multiple sclerosis. Semin Neurol. 2005 Mar;25(1):64-8.
Review.] This may due to
decreased nocturnal biosynthesis of MEL. [Wu YH et al., Molecular changes underlying
reduced pineal melatonin levels in Alzheimer disease: alterations
in preclinical and clinical stages. J Clin Endocrinol Metab.
2003 Dec;88 (12): 5898-906.]
Decreased MEL biosynthesis is associated with pineal calcification.
[Kunz D
et al., A new concept for melatonin deficit: on pineal calcification
and melatonin excretion. Neuropsychopharmacology. 1999
Dec; 21(6):765-72.] Pineal
calcification is common in MS. [Sandyk R, Awerbuch GI. The pineal gland in multiple
sclerosis. Int J Neurosci. 1991 Nov;61(1-2): 61-7.] Indeed, nocturnal MEL levels were
found to be lower than daytime levels in 11 of 25 patients with
MS. [Sandyk
R, Awerbuch GI. Nocturnal plasma melatonin and alpha-melanocyte
stimulating hormone levels during exacerbation of multiple sclerosis.
Int J Neurosci. 1992 Nov-Dec;67(1-4):173-86. Review] MEL is a major antioxidant in the
brain, and chronic depletion would be expected to allow widespread
oxidative damage in the CNS. [Reiter RJ et al., Reactive oxygen intermediates,
molecular damage, and aging. Relation to melatonin. Ann N
Y Acad Sci. 1998 Nov 20;854:410-24. Review.]
MEL may also correct disordered steroid metabolism. The hypothalamic
- pituitary - adrenal (HPA) axis (an ancient pathway which releases
cortisol in response to acute and chronic stress) is known to
be disturbed in MS; activation of corticotropin releasing hormone
(CRH) neurons and increased cortisol has been found in the cerebrospinal
fluid (CSF) of MS patients, indicating activation of the HPA
axis in this disease. [Huitinga I et al., The hypothalamo - pituitary
- adrenal axis in multiple sclerosis. Ann N Y Acad Sci.
2003;992:118-28. Review]
The basal level of cortisol is significantly increased in the
CSF of MS patients. [Erkut
ZA et al., Cortisol is increased in postmortem cerebrospinal
fluid of multiple sclerosis patients: relationship with cytokines
and sepsis. Mult Scler. 2002; 8(3): 229-36.] Chronically elevated cortisol levels due to
activation of CRH neurons can be damaging, particularly to the
hippocampus, the area of the brain where memory is processed.
[Lupien
SJ et al., The Douglas Hospital Longitudinal Study of Normal
and Pathological Aging: summary of findings. J Psychiatry
Neurosci. 2005;30 (5): 328-34.]
In an animal study this atrophy was found to be reversible. [Magarinos AM, Deslandes
A, McEwen BS. Effects of antidepressants and benzodiazepine treatments
on the dendritic structure of CA3 pyramidal neurons after chronic
stress. Eur J Pharmacol. 1999; 371(2-3): 113-22.] However, in another animal study,
dietary MEL reduced hypothalamic CRH. [Konakchieva R et al., Chronic melatonin
treatment and the hypothalamo - pituitary - adrenal axis in the
rat: attenuation of the secretory response to stress and effects
on hypothalamic neuropeptide content and release. Biol Cell.
1997; 89(9):587-96.] These
authors comment 'MEL attenuates the adrenocortical response to
stress and influences the biosynthesis, release and glucocorticoid
responsiveness of hypothalamic ACTH secretagogues.' Depression
is another disorder which can be set in motion by dysregulation
of the HPA axis (perhaps acting in concert with pro-inflammatory
cytokines.) [reviewed
by Schiepers OJ, Wichers MC, Maes M. Cytokines and major depression.
Prog Neuropsychopharmacol Biol Psychiatry. 2005; 29(2):
201-17.]
Melatonin would thus seem a valuable supplement in disease forms
characterized by oxidative stress.
Concluding remarks
Easing mitochondrial stress
by dietary supplementation in chronic infections with intracellular
pathogens such as Chlamydia pneumoniae would seem a very
reasonable and low-risk therapeutic strategy. Chronic release
of endotoxins in an unresolved infection results in a strong
pro-inflammatory immune reaction; this gives rise to a barrage
of free radicals which cause profound oxidative damage and setting
up vicious circles of antioxidant depletion and further free
radical production. It is likely that release of endotoxins continues
long after the organisms have been killed by antibiotics as host
cells are broken down in programmes of cell replacement.
The risks of supplementation are low provided pure agents are
used.
When the infection is resolved, and healing complete, supplementation
may be reduced and an appropriately balanced diet continued.
Caveat
This reviewer is a medical practitioner and a microbiologist
with no especial knowledge of cell-biology, nutrition, or biochemistry;
this page gives only stop-gap information. Chronic infections
quickly become multifactorial, and the demands of effective treatment
transcend traditional medical disciplines.
return to ms-index page
uploaded 2nd October
2005; revised 9th August 2011
|