1_ Ophthalmologica. 2003 SepOct;217(5):3517.
Mitotropic compounds for the treatment of agerelated macular degeneration.
The metabolic approach and a pilot study.
Feher J, Papale A, Mannino G, Gualdi L, Balacco Gabrieli C.
Ophthalmic Neuroscience Program, Institute of Ophthalmology, University
of Rome La Sapienza, Rome, Italy. j.feher@agora.it
Recent histopathologic studies have shown that mitochondria and peroxisomes
of the retinal pigment epithelium may play a central role in the pathophysiology
of agerelated macular degeneration (AMD). We supposed that compounds which
improve mitochondrial functions (mitotropic compounds) may show beneficial
effects in preventing AMD. Fourteen patients affected by early AMD were
treated with a mixture containing Acetyl-L-Carnitine (ALC), polyunsaturated
fatty acids (PUFAs), coenzyme Q10 (CoQ10) and vitamin E, while an equal
number of age and sexmatched patients affected by early AMD were treated
with vitamin E only. Recovery time after macular photostress, foveal sensitivity
and mean defect in the visual field as well as blood lipid levels were
recorded at the beginning and after 3, 6, 9, 12 and 24 months of followup.
In the treated group, all the visual functions showed slight improvement
which was evident after 3 months of treatment and remained nearly stationary
by the end of 24 months. The same tests in the control group showed slow
worsening. The divergence between treated and control groups became more
marked with time, but the difference was not significant at any time of
the followup. These findings suggest that the blend of ALC, PUFA, CoQ10
and vitamin E may improve retinal functions in early AMD. Copyright 2003
S. Karger AG, Basel
2_ Int J Tissue React. 2002;24(3):8996.
Longterm ethanol administration enhances agedependent modulation of redox
state in brain and peripheral organs of rat: protection by acetyl carnitine.
Scapagnini G, Ravagna A, Bella R, Colombrita C, Pennisi G, Calvani M,
Alkon D, Calabrese V.
Blanchette Rockefeller Neurosciences Institute, West Virginia University,
Rockville, USA.
Evidence is accumulating that intermediates of oxygen reduction may be
associated with the development of alcoholic disease. Free radicalinduced
perturbation of the oxidant/antioxidant balance in the cell is widely
recognized as the main causative factor of agerelated disorders. In the
present study we investigated the effects of 20 months of ethanol consumption
on the antioxidant defense system in different rat organs compared with
normal aging in the absence and presence of treatment with Lacetyl carnitine.
We demonstrate that aged rats underwent significant perturbation of the
antioxidant defense system, as indicated by depletion of reduced glutathione
(GSH) content, increased oxidized GSH, free radicalinduced luminescence
associated with increased hydroxynonenal content and decreased GSH reductase
activity. These modifications, observed particularly in brain and liver
compared with other organs, were enhanced by longterm alcohol exposure
and, interestingly, were significantly reduced with acetyl carnitine supplements.
Our results indicate that decreased GSH reductase activity and thiol depletion
are important factors in effecting a pathogenic role for oxidative stress
in aging and in all situations in which agecorrelated and oxidantinduced
changes occur, such as in alcoholism. Administration of acetyl carnitine
greatly reduces these metabolic abnormalities. Our findings support its
pharmacological potential in the management of alcoholic disturbances.
3_ Brain Res. 2002 Dec 13;957(2):22330.
Reversal of biochemical and behavioral parameters of brain aging by melatonin
and acetyl Lcarnitine.
Sharman EH, Vaziri ND, Ni Z, Sharman KG, Bondy SC.
Center for Occupational and Environmental Health, Department of Community
and Environmental Medicine, University of California Irvine, Irvine, CA
926971825, USA.
The potential utility of dietary supplementation in order to prevent
some of the oxidative and inflammatory changes occurring in the brain
with age, has been studied. The cerebral cortex of 27monthold male B6C3F1
mice had elevated levels of nitric oxide synthase 1 (EC 1.14.13.39) (nNOS)
and peptide nitrotyrosine relative to cortices of younger (4monthold)
animals. After 25monthold mice received basal diet together with 300 mg/l
acetyl Lcarnitine in the drinking water for 8 weeks, these levels were
fully restored to those found in younger animals. A partial restoration
was found when old animals received basal diet supplemented with 200 ppm
melatonin in the diet. Levels of mRNA (messenger RNA) for nNOS were unchanged
following these treatments implying translational regulation of nNOS activity.
Behavioral indices indicative of exploratory behavior were also depressed
in aged animals. Dietary supplementation with melatonin or acetyl Lcarnitine
partially reversed these changes. These findings suggest that dietary
supplementation cannot merely arrest but indeed reverse some agerelated
increases in markers of oxidative and inflammatory events occurring with
the cortex.
4_ Ann N Y Acad Sci. 2002 Apr;959:491507.
Mitochondrial decay in the aging rat heart: evidence for improvement by
dietary supplementation with Acetyl-L-Carnitine and/or lipoic acid.
Hagen TM, Moreau R, Suh JH, Visioli F.
Department of Biochemistry and Biophysics, Linus Pauling Institute, Oregon
State University, Corvallis, Oregon 97331, USA. tory.hagen@orst.edu
Mitochondrial decay has been postulated to be a significant underlying
part of the aging process. Decline in mitochondrial function may lead
to cellular energy deficits, especially in times of greater energy demand,
and compromise vital ATPdependent cellular operations, including detoxification,
repair systems, DNA replication, and osmotic balance. Mitochondrial decay
may also lead to enhanced oxidant production and thus render the cell
more prone to oxidative insult. In particular, the heart may be especially
susceptible to mitochondrial dysfunction due to myocardial dependency
on betaoxidation of fatty acids for energy and the postmitotic nature
of cardiac myocytes, which would allow for greater accumulation of mitochondrial
mutations and deletions. Thus, maintenance of mitochondrial function may
be important to maintain overall myocardial function. Herein, we review
the major agerelated changes that occur to mitochondria in the aging heart
and the evidence that two such supplements, Acetyl-L-Carnitine (ALCAR)
and (R)alphalipoic acid, may improve myocardial bioenergetics and lower
the increased oxidative stress associated with aging. We and others have
shown that feeding old rats ALCAR reverses the agerelated decline in carnitine
levels and improves mitochondrial betaoxidation in a number of tissues
studied. However, ALCAR supplementation does not appear to reverse the
agerelated decline in cardiac antioxidant status and thus may not substantially
alter indices of oxidative stress. Lipoic acid, a potent thiol antioxidant
and mitochondrial metabolite, appears to increase low molecular weight
antioxidant status and thereby decreases age-associated oxidative insult.
Thus, ALCAR along with lipoic acid may be effective supplemental regimens
to maintain myocardial function.
5_ Proc Natl Acad Sci U S A. 2002 Feb 19;99(4):187681.
Age-associated mitochondrial oxidative decay: improvement of carnitine
acetyltransferase substratebinding affinity and activity in brain by feeding
old rats acetylL carnitine and/or Ralpha lipoic acid.
Liu J, Killilea DW, Ames BN.
Division of Biochemistry and Molecular Biology, University of California,
Berkeley, CA 94720, USA.
We test whether the dysfunction with age of carnitine acetyltransferase
(CAT), a key mitochondrial enzyme for fuel utilization, is due to decreased
binding affinity for substrate and whether this substrate, fed to old
rats, restores CAT activity. The kinetics of CAT were analyzed by using
the brains of young and old rats and of old rats supplemented for 7 weeks
with the CAT substrate Acetyl-L-Carnitine (ALCAR) and/or the mitochondrial
antioxidant precursor Ralphalipoic acid (LA). Old rats, compared with
young rats, showed a decrease in CAT activity and in CATbinding affinity
for both substrates, ALCAR and CoA. Feeding ALCAR or ALCAR plus LA to
old rats significantly restored CATbinding affinity for ALCAR and CoA,
and CAT activity. To explore the underlying mechanism, lipid peroxidation
and total iron and copper levels were assayed; all increased in old rats.
Feeding old rats LA or LA plus ALCAR inhibited lipid peroxidation but
did not decrease iron and copper levels. Ex vivo oxidation of youngrat
brain with Fe(II) caused loss of CAT activity and binding affinity. In
vitro oxidation of purified CAT with Fe(II) inactivated the enzyme but
did not alter binding affinity. However, in vitro treatment of CAT with
the lipid peroxidation products malondialdehyde or 4hydroxynonenal caused
a decrease in CATbinding affinity and activity, thus mimicking agerelated
change. Preincubation of CAT with ALCAR or CoA prevented malondialdehydeinduced
dysfunction. Thus, feeding old rats high levels of key mitochondrial metabolites
can ameliorate oxidative damage, enzyme activity, substratebinding affinity,
and mitochondrial dysfunction.
6_ Proc Natl Acad Sci U S A. 2002 Feb 19;99(4):18705.
Feeding Acetyl-L-Carnitine and lipoic acid to old rats significantly improves
metabolic function while decreasing oxidative stress.
Hagen TM, Liu J, Lykkesfeldt J, Wehr CM, Ingersoll RT, Vinarsky V, Bartholomew
JC, Ames BN.
Department of Biochemistry and Biophysics, Linus Pauling Institute, Oregon
State University, Corvallis, OR 97331, USA.
Mitochondrialsupported bioenergetics decline and oxidative stress increases
during aging. To address whether the dietary addition of Acetyl-L-Carnitine
[ALCAR, 1.5% (wt/vol) in the drinking water] and/or (R)alphalipoic acid
[LA, 0.5% (wt/wt) in the chow] improved these endpoints, young (24 mo)
and old (2428 mo) F344 rats were supplemented for up to 1 mo before death
and hepatocyte isolation. ALCAR+LA partially reversed the agerelated decline
in average mitochondrial membrane potential and significantly increased
(P = 0.02) hepatocellular O(2) consumption, indicating that mitochondrialsupported
cellular metabolism was markedly improved by this feeding regimen. ALCAR+LA
also increased ambulatory activity in both young and old rats; moreover,
the improvement was significantly greater (P = 0.03) in old versus young
animals and also greater when compared with old rats fed ALCAR or LA alone.
To determine whether ALCAR+LA also affected indices of oxidative stress,
ascorbic acid and markers of lipid peroxidation (malondialdehyde) were
monitored. The hepatocellular ascorbate level markedly declined with age
(P = 0.003) but was restored to the level seen in young rats when ALCAR+LA
was given. The level of malondialdehyde, which was significantly higher
(P = 0.0001) in old versus young rats, also declined after ALCAR+LA supplementation
and was not significantly different from that of young unsupplemented
rats. Feeding ALCAR in combination with LA increased metabolism and lowered
oxidative stress more than either compound alone.
7_ Neurochem Res. 2000 Mar;25(3):3959.
Effect of longterm feeding with Acetyl-L-Carnitine on the agerelated changes
in rat brain lipid composition: a study by 31P NMR spectroscopy.
Aureli T, Di Cocco ME, Capuani G, Ricciolini R, Manetti C, Miccheli A,
Conti F.
Department of Biochemistry, SigmaTau Labs, Pomezia, Italy.
Changes in brain lipid composition have been determined in 24 monthsold
Fischer rats with respect to 6 monthsold ones. The cerebral levels of
sphingomyelin and cholesterol were found to be significantly increased
in aged rats, whereas the amount of phosphatidylcholine, phosphatidylethanolamine,
phosphatidylserine, phosphatidylinositol, and phosphatidic acid appear
to be unaffected by aging. Longterm feeding with Acetyl-L-Carnitine was
able to reduce the agedependent increase of both sphingomyelin and cholesterol
cerebral levels with no effect on the other measured phospholipids. These
findings shown that changes in membrane lipid metabolism and/or composition
represent one of the alterations occurring in rat brain with aging, and
that longterm feeding with Acetyl-L-Carnitine can be useful in normalizing
these agedependent disturbances.
8_ Am J Otol. 2000 Mar;21(2):1617.
Biologic activity of mitochondrial metabolites on aging and agerelated
hearing loss.
Seidman MD, Khan MJ, Bai U, Shirwany N, Quirk WS.
Department of Otolaryngology Head & Neck Surgery, Henry Ford Health
System, Detroit, Michigan 48323, USA.
HYPOTHESIS: Compounds that upregulate mitochondrial function in an aging
model will improve hearing and reduce some of the effects of aging. BACKGROUND:
Reactive oxygen metabolites (ROM) are known products of oxidative metabolism
and are continuously generated in vivo. More than 100 human clinical conditions
have been associated with ROM, including atherosclerosis, arthritis, autoimmune
diseases, cancers, heart disease, cerebrovascular accidents, and aging.
The ROM are extremely reactive and cause extensive DNA, cellular, and
tissue damage. Specific deletions within the mitochondrial DNA (mtDNA)
occur with increasing frequency in age and presbyacusis. These deletions
are the result of chronic exposure to ROM. When enough mtDNA damage accrues,
the cell becomes bioenergetically deficient. This mechanism is the basis
of the mitochondrial clock theory of aging, also known as the membrane
hypothesis of aging. Nutritional compounds have been identified that enhance
mitochondrial function and reverse several agerelated processes. It is
the purpose of this article to describe the effects of two mitochondrial
metabolites, alphalipoic acid and acetyl Lcarnitine, on the preservation
of agerelated hearing loss. METHODS: Twentyone Fischer rats, aged 24 months,
were divided into three groups: acetyl1carnitine, alphalipoic acid, and
control. The subjects were orally supplemented with either a placebo or
one of the two nutritional compounds for 6 weeks. Auditory brainstem response
testing was used to obtain baseline and posttreatment hearing thresholds.
Cochlear, brain, and skeletal muscle tissues were obtained to assess for
mtDNA mutations. RESULTS: The control group demonstrated an expected age-associated
threshold deterioration of 3 to 7 dB in the 6week study. The treated subjects
experienced a delay in progression of hearing loss. Acetyl1carnitine improved
auditory thresholds during the same time period (p<0.05). The mtDNA
deletions associated with aging and presbyacusis were reduced in the treated
groups in comparison with controls. CONCLUSIONS: These results indicate
that in the proposed decline in mitochondrial function with age, senescence
may be delayed by treatment with mitochondrial metabolites. Acetyl1carnitine
and alphalipoic acid reduce age-associated deterioration in auditory sensitivity
and improve cochlear function. This effect appears to be related to the
mitochondrial metabolite ability to protect and repair ageinduced cochlear
mtDNA damage, thereby upregulating mitochondrial function and improving
energyproducing capabilities.
9_ FEBS Lett. 1999 Jul 9;454(3):2079.
The effect of aging and Acetyl-L-Carnitine on the pyruvate transport and
oxidation in rat heart mitochondria.
Paradies G, Petrosillo G, Gadaleta MN, Ruggiero FM.
Department of Biochemistry and Molecular Biology, University of Bari,
Italy. g.paradies@biologia.uniba.it
The effect of aging and acute treatment with Acetyl-L-Carnitine on the
pyruvate transport and oxidation in rat heart mitochondria was studied.
The activity of the pyruvate carrier as well as the rates of pyruvatesupported
respiration were both depressed (around 40%) in heart mitochondria from
aged rats, the major decrease occurring during the second year of life.
Administration of Acetyl-L-Carnitine to aged rats almost completely restored
the rates of these metabolic functions to the level of young control rats.
This effect of Acetyl-L-Carnitine was not due to changes in the content
of pyruvate carrier molecules. The heart mitochondrial content of cardiolipin,
a key phospholipid necessary for mitochondrial substrate transport, was
markedly reduced (approximately 40%) in aged rats. Treatment of aged rats
with Acetyl-L-Carnitine reversed the age-associated decline in cardiolipin
content. As the changes in cardiolipin content were correlated with changes
in rates of pyruvate transport and oxidation, it is suggested that Acetyl-L-Carnitine
reverses the agerelated decrement in the mitochondrial pyruvate metabolism
by restoring the normal cardiolipin content.
10_ Altern Med Rev. 1999 Jun;4(3):14461.
A review of nutrients and botanicals in the integrative management of
cognitive dysfunction.
Kidd PM.
Dementias and other severe cognitive dysfunction states pose a daunting
challenge to existing medical management strategies. An integrative, early
intervention approach seems warranted. Whereas, allopathic treatment options
are highly limited, nutritional and botanical therapies are available
which have proven degrees of efficacy and generally favorable benefittorisk
profiles. This review covers five such therapies: phosphatidylserine (PS),
Acetyl-L-Carnitine (ALC), vinpocetine, Ginkgo biloba extract (GbE), and
Bacopa monniera (Bacopa). PS is a phospholipid enriched in the brain,
validated through doubleblind trials for improving memory, learning, concentration,
word recall, and mood in middleaged and elderly subjects with dementia
or agerelated cognitive decline. PS has an excellent benefittorisk profile.
ALC is an energizer and metabolic cofactor which also benefits various
cognitive functions in the middleaged and elderly, but with a slightly
less favorable benefittorisk profile. Vinpocetine, found in the lesser
periwinkle Vinca minor, is an excellent vasodilator and cerebral metabolic
enhancer with proven benefits for vascularbased cognitive dysfunction.
Two metaanalyses of GbE demonstrate the best preparations offer limited
benefits for vascular insufficiencies and even more limited benefits for
Alzheimer's, while "commodity" GbE products offer little benefit,
if any at all. GbE (and probably also vinpocetine) is incompatible with
bloodthinning drugs. Bacopa is an Ayurvedic botanical with apparent antianxiety,
antifatigue, and memorystrengthening effects. These five substances offer
interesting contributions to a personalized approach for restoring cognitive
function, perhaps eventually in conjunction with the judicious application
of growth factors.
11_ Mech Ageing Dev. 1995 Nov 3;85(1):3753.
Age and traumadependent modifications of neuromuscular junction and skeletal
muscle structure in the rat. Effects of longterm treatment with Acetyl-L-Carnitine.
De Angelis C, Scarfo C, Falcinelli M, Perna E, Ramacci MT, Angelucci L.
Department of Morphometry and Histology, Institute for Research on Senescence,
Rome, Italy.
The influence of ageing and crushing of the sciatic nerve on the morphology
of the neuromuscular junction (NMJ) and on the muscle fiber composition
were studied in the rat soleus muscle using histochemical techniques associated
with image analysis. The influence of a 6month treatment with Acetyl-L-Carnitine
(ALCAR, 150 mg/kg/day) on the age and crushingdependent changes of the
NMJ and on agerelated modifications of the muscle fiber composition was
assessed as well. In control old and injured young rats a loss of complexity
of the NMJ was observed. Treatment with ALCAR resulted in an increased
endplate complexity both in old rats and in young rats injured by crushing,
in comparison with respective controls. The structure of the rat soleus
muscle changes with increasing age. Modification mainly consists in a
type II fiber atrophy, and in the alteration of the peculiar mosaic organization
of the soleus muscle fibers. In ALCARtreated old rats, the morphology
of the soleus muscle fibers was similar to that observed in adult animals.
These findings suggest that treatment with ALCAR has a beneficial effect
on NMJ and on muscle fiber structure in ageing or after nerve crushing.
The possible mechanism of action of this 'trophic' effect of ALCARtreatment
is discussed.
12_ Mech Ageing Dev. 1995 Oct 13;84(2):10312.
Carnitineacylcarnitine translocase activity in cardiac mitochondria from
aged rats: the effect of Acetyl-L-Carnitine.
Paradies G, Ruggiero FM, Petrosillo G, Gadaleta MN, Quagliariello E.
Department of Biochemistry and Molecular Biology, University of Bari,
Italy.
Agerelated changes in mitochondrial fatty acids metabolism may underlie
the progressive decline in cardiac function. The effect of aging and acute
treatment with Acetyl-L-Carnitine on fatty acids oxidation and on carnitineacylcarnitine
translocase activity in rat heart mitochondria was studied. Rates of palmitoylcarnitine
supported respiration as well as carnitinecarnitine and carnitinepalmitoylcarnitine
exchange reactions were all depressed (approx. 35%) in heart mitochondria
from aged rats. These effects were almost completely reversed following
treatment of aged rats with Acetyl-L-Carnitine. Heart mitochondrial cardiolipin
content was significantly reduced (approx. 38%) in aged rats. Treatment
of aged rats with Acetyl-L-Carnitine restored the level of cardiolipin
to that of young rats. It is suggested that Acetyl-L-Carnitine is able
to reverse agerelated decrement in mitochondrial carnitineacylcarnitine
exchange activity by restoring the normal cardiolipin content.
13_ J Gerontol A Biol Sci Med Sci. 1995 Jul;50(4):B23236.
Acetyl-L-Carnitine: chronic treatment improves spatial acquisition in
a new environment in aged rats.
Caprioli A, Markowska AL, Olton DS.
Institute for Research on Senescence, Sigma Tau, Rome, Italy.
Chronic Acetyl-L-Carnitine (ALCAR) treatment prevents some agerelated
memory impairment. The present experiment examined the effects of aging
and ALCAR in Fischer 344 rats on retention of spatial discrimination test
in a familiar environment (FE), and on the acquisition of a spatial discrimination
in a novel environment (NE). Rats 18 months or 3 months old were trained
with a new procedure to assess spatial discrimination in the Morris water
maze. Performance during acquisition in FE was used to assign each old
rat to one of two classes: Good Performers (GP) and Poor Performers (PP)
based on their swim time to reach the platform. The old rats displayed
heterogeneous performance and a spatial discrimination deficit. Chronic
ALCAR treatment enhanced spatial acquisition in the NE of rats with agerelated
behavioral impairments and had a slight effect on retention of the spatial
discrimination in the FE.
14_ Neurochem Res. 1994 Jul;19(7):7958.
Age-dependent loss of NMDA receptors in hippocampus, striatum, and frontal
cortex of the rat: prevention by Acetyl-L-Carnitine. Castornia M, Ambrosini
AM, Pacific L, Ramacci MT, Angelucci L. Institute for Research on Senescence,
Sigma Tau S.p.A., Pomezia, Italy.
Acute i.p. administration of Acetyl-L-Carnitine (ALCAR), a component
of several biological systems, has been found to modify spontaneous and
evoked electrocortical activity in young rats, and, in the old rats, to
improve learning ability and to increase the number of NMDA receptors
in the whole brain. The present study was aimed at ascertaining the effect
of chronic treatment with ALCAR added to drinking water on agerelated
changes in the different brain areas of rats. In twentyfourmonthold rats,
ALCAR treatment for six months significantly impeded the decline in the
number of NMDA receptors within the hippocampus, the frontal cortex and
the striatum compared to the adult animal. This finding thus confirms
the previously reported positive effect of ALCAR on the brain NMDA receptor
system.
15_ Ann N Y Acad Sci. 1993 Sep 24;695:3246. Acetyl-L-Carnitine and Alzheimer's
disease: pharmacological considerations beyond the cholinergic sphere.
Carta A, Calvani M, Bravi D, Bhuachalla SN. SigmaTau Pharmaceuticals,
Department of Scientific Affairs, Gaithersburg, Maryland 20878.
Since ALCAR and Lcarnitine are "shuttles" of long chain fatty
acids between the cytosol and the mitochondria to undergo betaoxidation,
they play an essential role in energy production and in clearing toxic
accumulations of fatty acids in the mitochondria. ALCAR has been considered
of potential use in senile dementia of the Alzheimer type (SDAT) because
of its ability to serve as a precursor for acetylcholine. However, pharmacological
studies with ALCAR in animals have demonstrated its facility to maximize
energy production and promote cellular membrane stability, particularly
its ability to restore membranal changes that are agerelated. Since recent
investigations have implicated abnormal energy processing leading to cell
death, and severitydependent membrane disruption in the pathology of Alzheimer's
disease, we speculate that the beneficial effects associated with ALCAR
administration in Alzheimer patients are due not only to its cholinergic
properties, but also to its ability to support physiological cellular
functioning at the mitochondrial level. This hypothetical mechanism of
action is discussed with respect to compelling supportive animal studies
and recent observations of significant decrease of carnitine acetyltransferase
(the catalyst of Lcarnitine acylation to Acetyl-L-Carnitine) in autopsied
Alzheimer brains.
16_ Physiol Behav. 1992 Jul;52(1):1857.
Active avoidance learning in old rats chronically treated with levocarnitine
acetyl.
Ghirardi O, Caprioli A, Milano S, Giuliani A, Ramacci MT, Angelucci L.
Institute for Research on Senescence, Sigma Tau S.p.A., Pomezia, Rome,
Italy.
The aging laboratory animal is recognized as a suitable experimental
model for the investigation on drugs potentially able to retard the agedependent
decline in cognitive functions. There is robust evidence that levocarnitine
acetyl (ALCAR), the acetyl derivative of carnitine, when administered
chronically, prevents some agerelated deficits of the central nervous
system, mainly at the hippocampal level. On the basis of this evidence
and because learning of active avoidance was demonstrated to become impaired
with age, we decided to investigate the effect of ALCAR in rats. For statistical
evaluation of results, the Cluster Analysis technique was chosen. This
procedure pointed out the great heterogeneity of the old population and
allowed the classification of the animals into homogeneous groups according
to their response pattern. The effect of ALCAR was evident in the higher
number of treated old animals yielding escape responses, indicating that
ALCAR can preserve, at least partially, learning and memory from the natural
decay occurring with age.
17_ Int J Clin Pharmacol Res. 1992;12(56):25362.
Morphological and electrophysiological changes of peripheral nervemuscle
unit in the aged rat prevented by levocarnitine acetyl.
Scarfo C, Falcinelli M, Pacifici L, Bellucci A, Reda E, De Angelis C,
Ramacci MT, Angelucci L.
Institute for Research on Senescence, Sigma Tau S.p.A. Pomezia, Rome,
Italy.
The effects of levocarnitine acetyl on structure and function of the
sciatic nerve and neuromuscular junctions of the soleus and extensor digitorum
longus muscles were studied in the aged rat. To that end, neuromuscular
conduction velocity (NMCV) was measured in vivo and morphological and
morphometric evaluations were performed. Treatment with levocarnitine
acetyl, 150 mg/kg day for six months, restored NMCV values to the levels
measured in the young rat; significantly reduced the number of degenerating
elements; and increased the number of myelinated fibres having normal
structural features. In the soleus and extensor digitorum longus muscles,
levocarnitine acetyl increased the complexity of neuromuscular junctions.
These experimental findings suggest a neurotrophic action of levocarnitine
acetyl on the peripheral nervous system that might have therapeutical
applications in agerelated peripheral nerve changes.
18_ J Neurosci Res. 1991 Nov;30(3):5559.
Effect of Acetyl-L-Carnitine on the dopaminergic system in aging brain.
Sershen H, Harsing LG Jr, BanaySchwartz M, Hashim A, Ramacci MT, Lajtha
A. Center for Neurochemistry, Nathan S.
Kline Institute for Psychiatric Research, Orangeburg, New York 10962.
We studied the effect of Acetyl-L-Carnitine (ALCAR) on dopamine release
and the effect of longterm Acetyl-L-Carnitine treatment on agerelated
changes in striatal dopamine receptors and brain amino acid levels. In
striatal tissue that had been incubated with [3H]dopamine, Acetyl-L-Carnitine
increased the release of [3H]dopamine evoked by electrical stimulation.
In striatal tissue from aged mice administered Acetyl-L-Carnitine for
3 months, the release of [3H]dopamine evoked by electrical stimulation
was higher than that of its aged control; the release after a second stimulation
was similar in the two groups. There was a significant decline in the
number of D1 striatal dopamine receptors with age. The Bmax was 51% lower
in 1.5yearold mice than in 4monthold animals. Administration of Acetyl-L-Carnitine
for 3 months diminished the reduction in the binding of [3H]SCH23390.
[3H]Spiperone binding to D2 receptors was not decreased with age and was
not affected by Acetyl-L-Carnitine treatment. Agerelated decreases in
levels of several amino acids were observed in several brain regions.
Acetyl-L-Carnitine lessened the reduction in the level of taurine only
in the striatum. The findings confirm the multiple effects of Acetyl-L-Carnitine
in brain, and suggest that its administration can have a positive effect
on agerelated changes in the dopaminergic system.
19_ Brain Res Dev Brain Res. 1991 Apr 24;59(2):22130.
Acetyl-L-Carnitine enhances the response of PC12 cells to nerve growth
factor.
Taglialatela G, Angelucci L, Ramacci MT, WerrbachPerez K, Jackson GR,
PerezPolo JR.
Department of Human Biological Chemistry and Genetics, University of Texas
Medical Branch, Galveston 77550.
We have demonstrated that treatment of rat pheochromocytoma (PC12) cells
with Acetyl-L-Carnitine (ALCAR) stimulates the synthesis of nerve growth
factor receptors (NGFR). ALCAR has also been reported to prevent some
agerelated impairments of the central nervous system (CNS). In particular,
ALCAR reduces the loss of NGFR in the hippocampus and basal forebrain
of aged rodents. On these bases, a study on the effect of NGF on the PC12
cells was carried out to ascertain whether ALCAR induction of NGFR resulted
in an enhancement of NGF action. Treatment of PC12 cells for 6 days with
ALCAR (10 mM) stimulated [125I]NGF PC12 cell uptake, consistent with increased
NGFR levels. Also, neurite outgrowth elicited in PC12 cells by NGF (100
ng/ml) was greatly augmented by ALCAR pretreatment. When PC12 cells were
treated with 10 mM ALCAR and then exposed to NGF (1 ng/ml), an NGF concentration
that is insufficient to elicit neurite outgrowth under these conditions,
there was an ALCAR effect on neurite outgrowth. The concentration of NGF
necessary for survival of serumdeprived PC12 cells was 100fold lower for
ALCARtreated cells as compared to controls. The minimal effective dose
of ALCAR here was between 0.1 and 0.5 mM. This is similar to the reported
minimal concentration of ALCAR that stimulates the synthesis of NGFR in
these cells. The data here presented indicate that one mechanism by which
ALCAR rescues aged neurons may be by increasing their responsiveness to
neuronotrophic factors in the CNS.
20_ Neurobiol Aging. 1990 SepOct;11(5):4918.
Acetyl-L-carnitine. 1: Effects on mortality, pathology and sensorymotor
performance in aging rats.
Markowska AL, Ingram DK, Barnes CA, Spangler EL, Lemken VJ, Kametani H,
Yee W, Olton DS.
Department of Psychology, University of Colorado, Boulder 80309.
Three different test sites assessed the effects of acetyl1carnitine (AC)
on agerelated changes in general health, sensorymotor skills, learning,
and memory. Two groups of rats began the experiments at 16 months of age.
One group (OLDAC) was given AC, 75 mg/kg/day, beginning at 16 months.
The other group (OLDCON) was treated identically except it was not given
the drug. Beginning at 22 months of age, these rats and a group of young
(34 months old) rats (YGCON) were given a series of sensorymotor tasks.
AC decreased mortality, and had no reliable effect on body weight, fluid
intake, or the general health of the rats. These data indicate that a
chronic dose of AC does not interfere with food and water intake, and
may increase longevity. An agerelated decline of performance occurred
in most of the sensorymotor tasks; locomotor activity was reduced in a
novel environment and in a runwheel, and the ability to prevent falling
was reduced in tests on a taut wire, rotorod, inclined screen, and several
types of elevated bridges. An agerelated decline of performance did not
occur in grooming, or in the latency to initiate several different behaviors.
AC had no effect on performance in any sensorymotor task. These data indicate
that the improvements produced by AC in some tests of spatial memory may
be due to the effects of AC on cognitive abilities rather than on sensorymotor
skills.
21_ Neurochem Res. 1990 Jun;15(6):597601.
Acetyl-L-Carnitine as a precursor of acetylcholine.
White HL, Scates PW.
Division of Pharmacology, Wellcome Research Laboratories, Research Triangle
Park, North Carolina 27709.
Synthesis of [3H]acetylcholine from [3H]Acetyl-L-Carnitine was demonstrated
in vitro by coupling the enzyme systems choline acetyltransferase and
carnitine acetyltransferase. Likewise, both [3H] and [14C] labeled acetylcholine
were produced when [3H]Acetyl-L-Carnitine and D[U14C] glucose were incubated
with synaptosomal membrane preparations from rat brain. Transfer of the
acetyl moiety from Acetyl-L-Carnitine to acetylcholine was dependent on
concentration of Acetyl-L-Carnitine and required the presence of coenzyme
A, which is normally produced as an inhibitory product of choline acetyltransferase.
These results provide further evidence for a role of mitochondrial carnitine
acetyltransferase in facilitating transfer of acetyl groups across mitochondrial
membranes, thus regulating the availability in the cytoplasm of acetylCoA,
a substrate of choline acetyltransferase. They are also consistent with
a possible utility of Acetyl-L-Carnitine in the treatment of agerelated
cholinergic deficits.
22_ Int J Clin Pharmacol Res. 1990;10(12):658.
Dietary Acetyl-L-Carnitine improves spatial behaviour of old rats.
Markowska AL, Olton DS.
Department of Psychology, Johns Hopkins University, Baltimore, Maryland.
Acetyl-L-Carnitine was given to aging rats to determine the extent to
which it changed agerelated impairments in several different behaviours.
One group of rats was given Acetyl-L-Carnitine, 80 mg/day, beginning at
16 months of age. A second group of rats was housed and treated identically,
except that no drug was administered. At 22 months of age, both groups
of rats began a series of behavioural tests, along with a group of young
rats, four months of age. The tests included: place learning on a circular
platform, probe reversal of place learning on a circular platform, two
choice simultaneous spatial discrimination in the stem of a Tmaze spatial
alternation in the arms of a Tmaze, and sensorymotor behaviour (initiation
of walking, turning in an alley, walking on a square, round, and rectangular
bridge, turning on an inclined grid, holding on to a wire, lightdark preference).
The tasks varied in their sensitivity to agerelated impairments. These
data indicate that longterm therapy with Acetyl-L-Carnitine attenuates
certain agerelated cognitive deficits and may have a beneficial effect
on longevity.
23_ Int J Clin Pharmacol Res. 1990;10(12):4951.
Peroxidative stress and cerebral aging.
Fariello RG.
Department Neurological Sciences, RushPresbyterian St. Lukes Medical Center,
Chicago, Illinois.
In order to test the hypothesis that cerebral nuclei showing agerelated
neuronal depletion would also show signs of vulnerability in their free
radical scavenger systems and accumulation of the compounds resulting
from peroxidation, the regional levels of a number of compounds were measured
in mouse brains. With the exception of the tocopherols all the antioxidants
had lower concentrations in the Substantia nigra which showed the most
severe neuronal depletion with age. Acetyl-L-Carnitine is being investigated
as a determinant of neuronal longevity.
24_ J Neurosci Res. 1989 Aug;23(4):4626.
Acetyl-L-Carnitine reduces the agedependent loss of glucocorticoid receptors
in the rat hippocampus: an autoradiographic study.
Patacchioli FR, Amenta F, Ramacci MT, Taglialatela G, Maccari S, Angelucci
L.
Institute of Pharmacology II, Medical Faculty, University of Rome, La
Sapienza, Italy.
Brain autoradiography in adrenalectomized rats injected with 3Hcorticosterone
2 hr before sacrifice was used to study the effect of aging and longterm
Acetyl-L-Carnitine treatment on the hippocampal glucocorticoid receptor.
Densitometric analysis of silver grains in individual nerve cells of the
hippocampus showed that pyramidal neurones of the CA1 field and granular
cells of the dentate gyrus are richest in 3Hcorticosterone binding sites,
whereas pyramidal neurons of the CA3 field have the lowest number of binding
sites. There was a significant decline in the number of glucocorticoid
receptors within the various hippocampal areas, both as the total number
of 3Hcorticosterone binding sites and as the number per single pyramidal
or granule neuron associated with aging and perhaps due to loss of adrenocorticoidcompetent
neurons. The dentate gyrus and the CA1 region were mostly affected by
the agedependent decrease in glucocorticoid receptors of the hippocampus.
Twentyeightmonthold rats, treated with Acetyl-L-Carnitine for 7 months,
showed a significantly higher number of 3Hcorticosterone binding sites
within the various hippocampal regions examined than did agematched controls.
The CA1 and the dentate gyrus were the regions most susceptible to amelioration
by Acetyl-L-Carnitine treatment. These findings suggest a positive effect
of Acetyl-L-Carnitine treatment on agerelated changes which occur in the
hippocampus.
25_ Neurochem Res. 1988 Oct;13(10):90916.
Action of Lacetylcarnitine on agedependent modifications of mitochondrial
membrane proteins from rat cerebellum.
Villa RF, Turpeenoja L, Benzi G, Giuffrida Stella AM.
Institute of Pharmacology, Faculty of Science, University of Pavia, Italy.
Protein patterns of mitochondrial outer membrane, inner membrane, and
matrix from nonsynaptic (free) mitochondria from rat cerebellum at different
ages (4, 8, 12, 16, 20, and 24 months) were analyzed by gel electrophoresis.
Acute Lacetylcarnitine treatment was performed by a single i.p. injection
(100 mg/kg body weight) of the substance 60 min before the sacrifice of
the animals. Different agedependent changes were obtained for the proteins
of the three fractions. The amount of some protein subunits increased
and/or decreased after drug treatment. In particular, protein composition
of the inner mitochondrial membrane showed significant agerelated modifications.
This result probably indicates differences in protein synthesis and/or
turnover rates in the various mitochondrial compartments during aging.
Acute Lacetylcarnitine treatment caused: a high increase in the amount
of one inner membrane protein with Mw 16 kDa, at all the ages studied;
a decrease in the amount of many other inner membrane proteins; modifications
of some matrix proteins. Our results show that in vivo administration
of Lacetylcarnitine affects mainly the inner membrane protein composition
of cerebellar mitochondria.
26_ J Neurosci Res. 1988 Aug;20(4):4916.
Nerve growth factor binding in aged rat central nervous system: effect
of Acetyl-L-Carnitine.
Angelucci L, Ramacci MT, Taglialatela G, Hulsebosch C, Morgan B, WerrbachPerez
K, PerezPolo R.
Department of Pharmacology, University of Rome, Italy.
The nerve growth factor protein (NGF) has been demonstrated to affect
neuronal development and maintenance of the differentiated state in certain
neurons of the peripheral and central nervous system (CNS) of mammals.
In the CNS, NGF has sparing effects on cholinergic neurons of the rodent
basal forebrain (BF) following lesions where it selectively induces choline
acetyltransferase (ChAT). NGF also induces ChAT in the areas to which
BF provides afferents. In aged rats, there is a reduction in the NGFbinding
capacity of sympathetic ganglia. Here, we wish to report that there is
a decrease in the NGFbinding capacity of the hippocampus and basal forebrain
of aged (26monthold) rats as compared to 4monthold controls but no change
in NGF binding in cerebellum. In all instances, equilibrium binding dissociation
constants did not differ significantly. Treatment of rats with Acetyl-L-Carnitine,
reported to improve cognitive performance of aged rats, ameliorates these
agerelated deficits.
27_
28_ Exp Brain Res. 2002 Jul;145(2):1829. Epub 2002 May 04.
Systemic Acetyl-L-Carnitine eliminates sensory neuronal loss after peripheral
axotomy: a new clinical approach in the management of peripheral nerve
trauma.
Hart AM, Wiberg M, Youle M, Terenghi G.
University Department of Surgery, BlondMcIndoe Centre, Royal Free &
University College Medical School, London, UK.
Several hundred thousand peripheral nerve injuries occur each year in
Europe alone. Largely due to the death of around 40% of primary sensory
neurons, sensory outcome remains disappointingly poor despite considerable
advances in surgical technique; yet no clinical therapies currently exist
to prevent this neuronal death. Acetyl Lcarnitine (ALCAR) is a physiological
peptide with roles in mitochondrial bioenergetic function, which may also
increase binding of nerve growth factor by sensory neurons. Following
unilateral sciatic nerve transection, adult rats received either one of
two doses of ALCAR or sham, or no treatment. Either 2 weeks or 2 months
later, L4 and L5 dorsal root ganglia were harvested bilaterally, in accordance
with the Animal (Scientific Procedures) Act 1986. Neuronal death was quantified
with a combination of TUNEL [TdT (terminal deoxyribonucleotidyl transferase)
uptake nick end labelling] and neuron counts obtained using the optical
disector technique. Sham treatment had no effect upon neuronal death.
ALCAR treatment caused a large reduction in the number of TUNELpositive
neurons 2 weeks after axotomy (sham treatment 33/group; lowdose ALCAR
6/group, P=0.132; highdose ALCAR 3/group, P<0.05), and almost eliminated
neuron loss (sham treatment 21%; lowdose ALCAR 0%, P=0.007; highdose ALCAR
2%, P<0.013). Two months after axotomy the neuroprotective effect of
highdose ALCAR treatment was preserved for both TUNEL counts (no treatment
five/group; highdose ALCAR one/group) and neuron loss (no treatment 35%;
highdose ALCAR 4%, P<0.001). These results provide further evidence
for the role of mitochondrial bioenergetic dysfunction in posttraumatic
sensory neuronal death, and also suggest that acetyl Lcarnitine may be
the first agent suitable for clinical use in the prevention of neuronal
death after peripheral nerve trauma.
29_ Drug Saf. 1998 Dec;19(6):48194.
Peripheral neuropathy with nucleoside antiretrovirals: risk factors, incidence
and management.
Moyle GJ, Sadler M.
Kobler Clinic, Chelsea and Westminster Hospital, London, England.
Distal symmetrical peripheral neuropathy is a common adverse experience
in persons with HIV infection. This condition, which presents as a pain,
numbness. burning and/or dysaethesia initially in the feet, is often multifactorial
in its origin. Nucleoside analogue reverse transcriptase inhibitors represent
an important contributor to peripheral neuropathy. Specifically, around
10% of patients receiving stavudine or zalcitabine and 1 to 2% of didanosine
recipients may have to discontinue therapy with these agents due to neuropathy.
Prompt withdrawal of these therapies enables gradual resolution of signs
and symptoms in most patients, although a period of symptom intensification
may occur shortly after withdrawal. Risk factors for developing peripheral
neuropathy during nucleoside analogue therapy include low CD4+ cell count
(<100 cells/mm3), a prior history of an AIDS defining illness or neoplasm,
a history of peripheral neuropathy, use of other neurotoxic agents including
high alcohol (ethanol) consumption and nutritional deficiencies such as
low serum hydroxocobalamin levels. Thus, patients at increased risk of
peripheral neuropathy should potentially avoid the use of the neurotoxic
nucleoside analogues or be more carefully monitored during therapy. Management
of this problem includes patient education. prompt withdrawal of the likely
causative agent (giving consideration not to leave the patient on a suboptimal
therapy regimen) and simple analgesia. with augmentation with tricyclic
antidepressants or anticonvulsant agents when pain is severe. New agents
that may assist in managing this condition include levacecarnine (Acetyl-L-Carnitine)
and nerve growth factors such as recombinant human nerve growth factor.
30_ Exp Gerontol. 1996 SepOct;31(5):57787.
Spatial memory and NGF levels in aged rats: natural variability and effects
of Acetyl-L-Carnitine treatment.
Taglialatela G, Caprioli A, Giuliani A, Ghirardi O.
Institute for Research on Senescence, Sigma Tau S.p.A., Pomezia, Rome,
Italy.
The natural variability of behavioral performance of aged rats was used
to evaluate the effect of Acetyl-L-Carnitine (ALCAR) on spatial learning
and NGF levels in different brain areas. We used a cluster analysis procedure
to subdivide the aged animals into three classes of performance (good,
intermediate, and poor). These three classes were equally subdivided into
controls and ALCARtreated animals in order to investigate its effect on
spatial retention. The stratification of animals prior to treatment allowed
us to highlight the state dependency of the action of ALCAR. The effect
of the molecule in improving spatial retention was evident only in the
intermediate performance group. Furthermore, the drug reduced the NGF
levels in the basal forebrain of treated animals, especially in the intermediate
performance group. These results suggest a performancedependent effect
of ALCAR and a nonlinear relationship between NGF levels and learning
ability in aged rats.
31_ Neurochem Res. 1997 Mar;22(3):25765.
Acetyl-L-Carnitine arginine amide prevents beta 2535induced neurotoxicity
in cerebellar granule cells.
Scorziello A, Meucci O, Calvani M, Schettini G.
Institute of Pharmacology, School of Medicine, University of Genova, Italia.
Cerebellar granule cells (CGC) at different stages of maturation in vitro
(1 or 6 DIV), were treated with beta 2535 and Acetyl-L-Carnitine arginine
amide (ST857) in presence of 25 mM KCl in the culture medium, and neuronal
viability was assessed. Three days of treatment slightly modified the
survival of 1 DIVtreated cells, which degenerate and die five days later
betaamyloid matching. Similarly, a significative neurotoxic effect was
observed on 6 DIV treatedcells after 5 days of exposure to the peptide,
while the death occurred within 8 days. ST857 coincubated with beta 2535
was able to rescue neurons from beta 2535induced neurotoxicity. We also
studied the changes in Ca2+ homeostasis following glutamate stimulation,
in control and betaamyloid treated single cells, either in presence or
in absence of ST857. beta 2535 did not affect basal [Ca2+]i, while modified
glutamateinduced [Ca2+]i increase, causing a sustained plateau phase of
[Ca2+]i, that persisted after the removal of the agonist. ST857 pretreatment
completely reverted this effect suggesting that, in CGC chronically treated
with beta 2535, ST857 could protect the cells by neurotoxic insults of
the peptide likely interfering with the cellular mechanisms involved in
the control of Ca2+ homeostasis.
32_ Prog Neuropsychopharmacol Biol Psychiatry. 1995 Jan;19(1):11733.
Effects of Acetyl-L-Carnitine treatment and stress exposure on the nerve
growth factor receptor (p75NGFR) mRNA level in the central nervous system
of aged rats.
Foreman PJ, PerezPolo JR, Angelucci L, Ramacci MT, Taglialatela G.
Institute for Research on Senescence Sigma Tau, Pomezia, Italy.
1. There is growing evidence that the nerve growth factor protein (NGF),
a neurotrophic factor for peripheral and central nervous system (CNS)
neurons, may play a role in the modulation of the hypothalamopituitaryadrenocortical
axis (HPAA). While NGF binding is decreased in rodent CNS after stress
exposure, this reduction is prevented by treatment with Acetyl-L-Carnitine
(ALCAR), a chemical substance able to prevent some degenerative events
associated with aging. 2. The authors studied the effect of cold stress
on the lowaffinity NGF receptor (p75NGFR) mRNA levels in the basal forebrain
and cerebellum of aged rats chronically treated with ALCAR. 3. The present
results show that ALCAR abolished the age-associated reduction of p75NGFR
mRNA levels in the basal forebrain of old animals, but did not affect
the response to stress stimuli. 4. Also, treatment with ALCAR maintained
p75NGFR mRNA levels in the cerebellum of old animals at levels almost
identical to those observed in young control animals. 5. These results
suggest a neuroprotective effect for ALCAR on central cholinergic neurons
exerted at the level of transcription of p75NGFR. The restoration of p75NGFR
levels could increase trophic support by NGF of these CNS cholinergic
neurons which are implicated in degenerative events associated with aging.
33_ Neurochem Res. 1995 Jan;20(1):19.
Neurite outgrowth in PC12 cells stimulated by Acetyl-L-Carnitine arginine
amide.
Taglialatela G, Navarra D, Olivi A, Ramacci MT, WerrbachPerez K, PerezPolo
JR, Angelucci L.
Institute for Research on Senescence SigmaTau, Pomezia, Italy.
Senescence of the central nervous system is characterized by a progressive
loss of neurons that can result in physiological and behavioral impairments.
Reduction in the levels of central neurotrophic factors or of neurotrophin
receptors may be one of the causes of the onset of these degenerative
events. Thus, a proper therapeutic approach would be to increase support
to degenerating neurons with trophic factors or to stimulate endogenous
neurotrophic activity. Here we report that Acetyl-L-Carnitine arginine
amide (ST857) is able to stimulate neurite outgrowth in rat pheochromocytoma
PC12 cells in a manner similar to that elicited by nerve growth factor
(NGF). Neurite induction by ST857 requires de novo mRNA synthesis and
is independent of the action of several common trophic factors. The integrity
of the molecular structure of ST857 is essential for its activity, as
the single moieties of the molecule have no effect on PC12 cells, whether
they are tested separately or together. Also, minor chemical modifications
of ST857, such as the presence of the arginine moiety at a position other
than the amino one, completely abolish its neuritogenic effect. Lastly,
the presence of ST857 in the culture medium competes with the high affinity
NGF binding in a dose dependent fashion. These results, although preliminary,
are suggestive of a possible role for ST857 in the development of therapeutic
strategies to counteract degenerative diseases of the CNS.
34_ Int J Dev Neurosci. 1995 Feb;13(1):139.
Acetyl-L-Carnitine restores choline acetyltransferase activity in the
hippocampus of rats with partial unilateral fimbriafornix transection.
Piovesan P, Quatrini G, Pacifici L, Taglialatela G, Angelucci L.
Institute for Research on Senescence, SigmaTau, Pomezia, Italy.
Transection of the fimbriafornix bundle in adult rats results in degeneration
of the septohippocampal cholinergic pathway, reminiscent of that occurring
in aging as well as Alzheimer disease. We report here a study of the effect
of a treatment with Acetyl-L-Carnitine (ALCAR) in threemonthold Fischer
344 rats bearing a partial unilateral fimbriafornix transection. ALCAR
is known to ameliorate some morphological and functional disturbances
in the aged central nervous system (CNS). We used choline acetyltransferase
(ChAT) and acetyl cholinesterase (AChE) as markers of central cholinergic
function, and nerve growth factor (NGF) levels as indicative of the trophic
regulation of the medioseptal cholinergic system. ChAT and AChE activities
were significantly reduced in the hippocampus (HIPP) ipsilateral to the
lesion as compared to the contralateral one, while no changes were observed
in the septum (SPT), nucleus basalis magnocellularis (NBM) or frontal
cortex (FCX). ALCAR treatment restored ChAT activity in the ipsilateral
HIPP, while AChE levels were not different from those of untreated animals,
and did not affect NGF content in either SPT or HIPP.
35_ Neurol Res. 1995 Oct;17(5):3736.
Effects of levoacetylcarnitine on second motoneuron survival after axotomy.
Fernandez E, Pallini R, Tamburrini G, Lauretti L, Tancredi A, La Marca
F.
Department of Neurosurgery, Catholic University Medical School, Rome,
Italy.
Little is known about factors that regulate the survival of cranial motoneurons
which project to peripheral targets. Various neurotrophic factors of central
and peripheral origin have been isolated. In this study, we examined thirteen
newborn Wistar rats to determine the effects of Acetyl-L-Carnitine treatment
on the survival of motoneurons within the facial nucleus after transection
of the facial nerve. Acetyl-L-Carnitine was administered for 7 days in
seven rats after nerve transection, while saline solution was injected
in 6 rats used as controls. Both the motoneuron number and the motoneuron
diameter were significantly higher in the facial nucleus of the rats treated
with Acetyl-L-Carnitine than in the facial nucleus of the control rats.
The results obtained suggest that Acetyl-L-Carnitine can rescue a substantial
number of facial motoneurons from axotomyinduced cell death. Compared
to neurotrophic factors, because of its simple molecular structure, Acetyl-L-Carnitine
permits a safe oral and parenteral administration. It is suggested that
Acetyl-L-Carnitine could be considered for use as a therapeutic agent
in neurodegenerative disorders.
36_ J Pharmacol Exp Ther. 1995 Jul;274(1):43743.
Developmental deficiency of the cholinergic system in congenitally hyperammonemic
spf mice: effect of Acetyl-L-Carnitine.
Ratnakumari L, Qureshi IA, Maysinger D, Butterworth RF.
Division of Medical Genetics, SainteJustine Hospital, Montreal, Quebec,
Canada.
The sparsefur (spf) mutant mouse has an Xlinked deficiency of hepatic
ornithine transcarbamylase (OTC) and develops hyperammonemia in the postnatal
period similar to that seen in human patients. We studied the effect of
congenital hyperammonemia on the development of cerebral cholinergic parameters
such as choline acetyltransferase (ChAT), acetylcholinesterase (AChE)
and highaffinity choline uptake (HACU) in spf mice. The serum ammonia
levels of spf mutant mice were significantly elevated after weaning compared
with control animals. ChAT activity levels started decreasing in mutant
spf mice from the age of 30 days (i.e., immediately after weaning); it
reached significantly lower levels in the adult animals. HACU was consistently
lower (P < .01) in spf/Y mice compared with controls up to the adult
stage. However, there were no marked changes in the activity of AChE between
control and hyperammonemic spf mice. The levels of betaNGF, which is essential
for cholinergic differentiation and function, were significantly lower
in different brain regions of adult mutant mice compared with normal controls.
A treatment of spf/spf breeding females with Acetyl-L-Carnitine, at a
dose of 1.5 mM in drinking water, starting from day 1 of conception, resulted
in a significant restoration of ChAT activity levels in some brain regions
of the spf/Y offspring. The betaNGF levels were also significantly elevated
after supplementation with ALCAR in mutant mice compared with untreated
mutant mice. These data are suggestive of a neurotrophic property of ALCAR
during cholinergic deficiency caused by congenital hyperammonemia.
37_ Int J Dev Neurosci. 1995 Feb;13(1):139.
Acetyl-L-Carnitine restores choline acetyltransferase activity in the
hippocampus of rats with partial unilateral fimbriafornix transection.
Piovesan P, Quatrini G, Pacifici L, Taglialatela G, Angelucci L.
Institute for Research on Senescence, SigmaTau, Pomezia, Italy.
Transection of the fimbriafornix bundle in adult rats results in degeneration
of the septohippocampal cholinergic pathway, reminiscent of that occurring
in aging as well as Alzheimer disease. We report here a study of the effect
of a treatment with Acetyl-L-Carnitine (ALCAR) in threemonthold Fischer
344 rats bearing a partial unilateral fimbriafornix transection. ALCAR
is known to ameliorate some morphological and functional disturbances
in the aged central nervous system (CNS). We used choline acetyltransferase
(ChAT) and acetyl cholinesterase (AChE) as markers of central cholinergic
function, and nerve growth factor (NGF) levels as indicative of the trophic
regulation of the medioseptal cholinergic system. ChAT and AChE activities
were significantly reduced in the hippocampus (HIPP) ipsilateral to the
lesion as compared to the contralateral one, while no changes were observed
in the septum (SPT), nucleus basalis magnocellularis (NBM) or frontal
cortex (FCX). ALCAR treatment restored ChAT activity in the ipsilateral
HIPP, while AChE levels were not different from those of untreated animals,
and did not affect NGF content in either SPT or HIPP.
38_ Neurochem Res. 1995 Jan;20(1):19.
Neurite outgrowth in PC12 cells stimulated by Acetyl-L-Carnitine arginine
amide.
Taglialatela G, Navarra D, Olivi A, Ramacci MT, WerrbachPerez K, PerezPolo
JR, Angelucci L.
Institute for Research on Senescence SigmaTau, Pomezia, Italy.
Senescence of the central nervous system is characterized by a progressive
loss of neurons that can result in physiological and behavioral impairments.
Reduction in the levels of central neurotrophic factors or of neurotrophin
receptors may be one of the causes of the onset of these degenerative
events. Thus, a proper therapeutic approach would be to increase support
to degenerating neurons with trophic factors or to stimulate endogenous
neurotrophic activity. Here we report that Acetyl-L-Carnitine arginine
amide (ST857) is able to stimulate neurite outgrowth in rat pheochromocytoma
PC12 cells in a manner similar to that elicited by nerve growth factor
(NGF). Neurite induction by ST857 requires de novo mRNA synthesis and
is independent of the action of several common trophic factors. The integrity
of the molecular structure of ST857 is essential for its activity, as
the single moieties of the molecule have no effect on PC12 cells, whether
they are tested separately or together. Also, minor chemical modifications
of ST857, such as the presence of the arginine moiety at a position other
than the amino one, completely abolish its neuritogenic effect. Lastly,
the presence of ST857 in the culture medium competes with the high affinity
NGF binding in a dose dependent fashion. These results, although preliminary,
are suggestive of a possible role for ST857 in the development of therapeutic
strategies to counteract degenerative diseases of the CNS.
39_ Prog Neuropsychopharmacol Biol Psychiatry. 1995 Jan;19(1):11733.
Effects of Acetyl-L-Carnitine treatment and stress exposure on the nerve
growth factor receptor (p75NGFR) mRNA level in the central nervous system
of aged rats.
Foreman PJ, PerezPolo JR, Angelucci L, Ramacci MT, Taglialatela G. 005A
Institute for Research on Senescence Sigma Tau, Pomezia, Italy.
1. There is growing evidence that the nerve growth factor protein (NGF),
a neurotrophic factor for peripheral and central nervous system (CNS)
neurons, may play a role in the modulation of the hypothalamopituitaryadrenocortical
axis (HPAA). While NGF binding is decreased in rodent CNS after stress
exposure, this reduction is prevented by treatment with Acetyl-L-Carnitine
(ALCAR), a chemical substance able to prevent some degenerative events
associated with aging. 2. The authors studied the effect of cold stress
on the lowaffinity NGF receptor (p75NGFR) mRNA levels in the basal forebrain
and cerebellum of aged rats chronically treated with ALCAR. 3. The present
results show that ALCAR abolished the age-associated reduction of p75NGFR
mRNA levels in the basal forebrain of old animals, but did not affect
the response to stress stimuli. 4. Also, treatment with ALCAR maintained
p75NGFR mRNA levels in the cerebellum of old animals at levels almost
identical to those observed in young control animals. 5. These results
suggest a neuroprotective effect for ALCAR on central cholinergic neurons
exerted at the level of transcription of p75NGFR. The restoration of p75NGFR
levels could increase trophic support by NGF of these CNS cholinergic
neurons which are implicated in degenerative events associated with aging.
40_ Neurobiol Aging. 1995 JanFeb;16(1):14.
Clinical and neurochemical effects of Acetyl-L-Carnitine in Alzheimer's
disease.
Pettegrew JW, Klunk WE, Panchalingam K, Kanfer JN, McClure RJ.
Department of Psychiatry, Western Psychiatric Institute and Clinic, University
of Pittsburgh, School of Medicine, PA 15213, USA.
In a doubleblind, placebo study, Acetyl-L-Carnitine was administered
to 7 probable Alzheimer's disease patients who were then compared by clinical
and 31P magnetic resonance spectroscopic measures to 5 placebotreated
probable AD patients and 21 agematched healthy controls over the course
of 1 year. Compared to AD patients on placebo, Acetyl-L-Carnitinetreated
patients showed significantly less deterioration in their MiniMental Status
and Alzheimer's Disease Assessment Scale test scores. Furthermore, the
decrease in phosphomonoester levels observed in both the Acetyl-L-Carnitine
and placebo AD groups at entry was normalized in the Acetyl-L-Carnitinetreated
but not in the placebotreated patients. Similar normalization of highenergy
phosphate levels was observed in the Acetyl-L-Carnitinetreated but not
in the placebotreated patients. This is the first direct in vivo demonstration
of a beneficial effect of a drug on both clinical and CNS neurochemical
parameters in AD.
41_ Brain Res. 1995 Mar 13;674(1):1426.
Spatial discrimination learning and choline acetyltransferase activity
in streptozotocintreated rats: effects of chronic treatment with Acetyl-L-Carnitine.
Prickaerts J, Blokland A, Honig W, Meng F, Jolles J.
Department of Psychiatry and Neuropsychology, University of Limburg, Maastricht,
The Netherlands.
Treatment of rats with i.c.v. injected streptozotocin (STREP) may provide
a relevant model of neurodegeneration that is induced by a decrease in
the central metabolism of glucose. Acetyl-L-Carnitine (ALCAR) enhances
the utilization of alternative energy sources and by such a mechanism
of action ALCAR could antagonize the effects of STREP treatment. In this
study the effects of chronic treatment with ALCAR were evaluated on spatial
discrimination learning in the Morris task and choline acetyltransferase
(ChAT) activity of middleaged STREPtreated rats. Chronic treatment with
ALCAR attenuated both the STREPinduced impairment in spatial bias and
the decrease in hippocampal ChAT activity. These findings indicate that
ALCAR treatment has a neuroprotective effect, although further studies
are needed to characterize the mechanism of action of ALCAR in this model.
42_ Brain Res. 1994 Jan 7;633(12):7782.
Acetyl-L-Carnitine treatment increases choline acetyltransferase activity
and NGF levels in the CNS of adult rats following total fimbriafornix
transection.
Piovesan P, Pacifici L, Taglialatela G, Ramacci MT, Angelucci L.
Institute for Research on Senescence SigmaTau, Pomezia, Italy.
Transection of the fimbriafornix in adult rats is a useful model for
producing impairments of cholinergic activity in the hippocampus (HIPP)
and atrophy of the medial septum cholinergic perikarya, similar to those
observed during senescence, that are possibly due to the lack of nerve
growth factor (NGF) retrogradely transported from the hippocampus. In
our investigation we used choline acetyltransferase (ChAT) as an index
of cholinergic activity in HIPP, frontal cortex (FCX), septum and nucleus
basalis magnocellularis (NBM) along with measurements of NGF levels in
the HIPP. Threemonthold rats with unilateral total fimbria transection
received Acetyl-L-Carnitine (ALCAR) (150 mg/kg/day) in drinking water
for 1 week before and 4 weeks after the lesion). ALCAR is a substance
known to ameliorate some morphological and functional disturbances in
the aging central nervous system (CNS). ChAT activity in septum and FCX,
and NGF levels in HIPP were significantly increased in the treated group,
compared with untreated control groups, while no changes were found in
the NBM. On the other hand, a similar ALCAR treatment in unoperated animals
induced an increase in ChAT activity in FCX but not in septum nor in NBM.
These data are suggestive of a neurotrophic property of ALCAR exerted
on those central cholinergic pathways typically damaged by aging.
43_ Exp Gerontol.
1994 JanFeb;29(1):5566.
Acetyl-L-Carnitine treatment increases nerve growth factor levels and
choline acetyltransferase activity in the central nervous system of aged
rats.
Taglialatela G, Navarra D, Cruciani R, Ramacci MT, Alema GS, Angelucci
L.
Institute for Research on Senescence SigmaTau, Pomezia, Italy.
The hypothesis that some neurodegenerative events associated with ageing
of the central nervous system (CNS) may be due to a lack of neurotrophic
support to neurons is suggestive of a possible reparative pharmacological
strategy intended to enhance the activity of endogenous neurotrophic agents.
Here we report that treatment with Acetyl-L-Carnitine (ALCAR), a substance
which has been shown to prevent some impairments of the aged CNS in experimental
animals as well as in patients, is able to increase the levels and utilization
of nerve growth factor (NGF) in the CNS of old rats. The stimulation of
NGF levels in the CNS can be attained when ALCAR is given either for long
or short periods to senescent animals of various ages, thus indicating
a direct effect of the substance on the NGF system which is independent
of the actual degenerative stage of the neurons. Furthermore, longterm
treatment with ALCAR completely prevents the loss of choline acetyltransferase
(ChAT) activity in the CNS of aged rats, suggesting that ALCAR may rescue
cholinergic pathways from age-associated degeneration due to lack of retrogradely
transported NGF.
44_ Life Sci. 1994;54(17):120514.
Acetyl-L-Carnitine affects aged brain receptorial system in rodents.
Castorina M, Ferraris L. Institute for Research on Senescence, SigmaTau,
Pomezia, Rome, Italy.
Acetyl-L-Carnitine (ALCAR), the acetyl ester of carnitine, is regarded
as a compound of considerable interest because of its capacity to counteract
several physiological and pathological modifications typical of brain
ageing processes. In particular, it has been demonstrated that ALCAR can
counteract the agedependent reduction of several receptors in the central
nervous system of rodents, such as the NMDA receptorial system, the Nerve
Growth Factor (NGF) receptors, those of glucocorticoids, neurotransmitters
and others, thereby enhancing the efficiency of synaptic transmission,
which is considerably slowed down by ageing. The present review thus postulates
the importance of ALCAR administration in preserving and/or facilitating
the functionality of carnitines, the concentrations of which are diminished
in the brain of old animals.
45_ Biochem Pharmacol. 1992 Aug 4;44(3):57785.
Stimulation of nerve growth factor receptors in PC12 by Acetyl-L-Carnitine.
Taglialatela G, Angelucci L, Ramacci MT, WerrbachPerez K, Jackson GR,
PerezPolo JR.
Department of Human Biological Chemistry and Genetics, University of Texas
Medical Branch, Galveston 77550.
Acetyl-L-Carnitine (ALCAR) prevents some deficits associated with aging
in the central nervous system (CNS), such as the agedrelated reduction
of nerve growth factor (NGF) binding. The aim of this study was to ascertain
whether ALCAR could affect the expression of an NGF receptor (p75NGFR).
Treatment of PC12 cells with ALCAR increased equilibrium binding of 125INGF.
ALCAR treatment also increased the amount of immunoprecipitable p75NGFR
from PC12 cells. Lastly, the level of p75NGFR messenger RNA (mRNA) in
PC12 was increased following ALCAR treatment. These results are in agreement
with the hypothesis that there is a direct action of ALCAR on p75NGFR
expression in aged rodent CNS.
46_ Int J Dev Neurosci. 1992 Aug;10(4):3219.
Culture of dorsal root ganglion neurons from aged rats: effects of Acetyl-L-Carnitine
and NGF.
Manfridi A, Forloni GL, ArrigoniMartelli E, Mancia M.
Institute of Human Physiology II, University of Milan, Italy.
In vitro neuronal preparations are used to study the action mechanism
of substances which are active in normal and pathological brain aging.
One major concern with in vitro assays is that the use of embryonic or
adult neurons may hamper an appreciation of the relevance of these substances
on aged nervous tissue. In the present study for the first time cultures
of aged dorsal root ganglia from 24monthsold rats were maintained in vitro
up to 2 weeks. This model was used to investigate the neurotrophic/neuroprotective
action of nerve growth factor and Acetyl-L-Carnitine. A large population
of aged dorsal root ganglia neurons was responsive to nerve growth factor
(100 ng/ml). Nerve growth factor induced an increase of initial rate of
axonal regeneration and influenced the survival time of these neurons.
Acetyl-L-Carnitine (250 microM) did not affect the axonal regeneration
but substantially attenuated the rate of neuronal mortality. A significant
difference was evident between the Acetyl-L-Carnitinetreated and the untreated
neurons from the first cell counting (day 3 in culture). After 2 weeks
the number of aged neurons treated with Acetyl-L-Carnitine was almost
double that of the controls. The effects of Acetyl-L-Carnitine on aged
DRG neurons potentially explain the positive effects in clinical and in
vivo experimental studies.
47_ Brain Res Dev Brain Res. 1991 Apr 24;59(2):22130.
Acetyl-L-Carnitine enhances the response of PC12 cells to nerve growth
factor.
Taglialatela G, Angelucci L, Ramacci MT, WerrbachPerez K, Jackson GR,
PerezPolo JR.
Department of Human Biological Chemistry and Genetics, University of Texas
Medical Branch, Galveston 77550.
We have demonstrated that treatment of rat pheochromocytoma (PC12) cells
with Acetyl-L-Carnitine (ALCAR) stimulates the synthesis of nerve growth
factor receptors (NGFR). ALCAR has also been reported to prevent some
agerelated impairments of the central nervous system (CNS). In particular,
ALCAR reduces the loss of NGFR in the hippocampus and basal forebrain
of aged rodents. On these bases, a study on the effect of NGF on the PC12
cells was carried out to ascertain whether ALCAR induction of NGFR resulted
in an enhancement of NGF action. Treatment of PC12 cells for 6 days with
ALCAR (10 mM) stimulated [125I]NGF PC12 cell uptake, consistent with increased
NGFR levels. Also, neurite outgrowth elicited in PC12 cells by NGF (100
ng/ml) was greatly augmented by ALCAR pretreatment. When PC12 cells were
treated with 10 mM ALCAR and then exposed to NGF (1 ng/ml), an NGF concentration
that is insufficient to elicit neurite outgrowth under these conditions,
there was an ALCAR effect on neurite outgrowth. The concentration of NGF
necessary for survival of serumdeprived PC12 cells was 100fold lower for
ALCARtreated cells as compared to controls. The minimal effective dose
of ALCAR here was between 0.1 and 0.5 mM. This is similar to the reported
minimal concentration of ALCAR that stimulates the synthesis of NGFR in
these cells. The data here presented indicate that one mechanism by which
ALCAR rescues aged neurons may be by increasing their responsiveness to
neuronotrophic factors in the CNS.
48_ Int J Dev Neurosci. 1991;9(1):3946.
Effect of Acetyl-L-Carnitine on forebrain cholinergic neurons of developing
rats.
De Simone R, Ramacci MT, Aloe L.
Institute of Neurobiology, C.N.R., Rome, Italy.
It has been shown that the endogenous compound, Acetyl-L-Carnitine (ALCAR),
acts in the brain as a metabolic cofactor in the synthesis of acetylcholine.
In these studies, ALCAR was injected into the brain of developing rats
every other day for the first three weeks after birth in order to assess
its effect on forebrain cholinergic neurons. The results showed that intracerebroventricular
(icv) administration of ALCAR causes an increase of choline acetyltransferase
(ChAT) activity and of nerve growth factor receptor expression in the
striatum. Biological assays of brain tissues revealed that the level of
nerve growth factor (NGF) in the hippocampus also increases. The ability
of brain cholinergic tissues to respond to exogenous administration of
ALCAR is discussed.
49_ J Neurosci Res. 1990 Mar;25(3):3315.
125Ibetanerve growth factor binding is reduced in rat brain after stress
exposure.
Taglialatela G, Angelucci L, Ramacci MT, Foreman PJ, PerezPolo JR.
Department of Human Biological Chemistry and Genetics, University of Texas
Medical Branch, Galveston 775502777.
In the central nervous system (CNS), the presence of nerve growth factor
(NGF) and its receptor, NGFR, in cholinergic neurons has been demonstrated.
In this study we report that, after exposure to stress, there was a reduction
in total binding of NGF in the hippocampus and basal forebrain of 3.5monthold
rats without significant changes in the frontal cortex or cerebellum.
Chronic treatment with Acetyl-L-Carnitine (ALCAR), that prevents some
agerelated impairments of CNS, for 1.5 months, decreased NGF binding in
hippocampus and basal forebrain but abolished the stressrelated reduction
of NGF binding observed in the hippocampus of untreated rats.
50_ J Neurosci Res. 1988 Aug;20(4):4916.
Nerve growth factor binding in aged rat central nervous system: effect
of Acetyl-L-Carnitine.
Angelucci L, Ramacci MT, Taglialatela G, Hulsebosch C, Morgan B, WerrbachPerez
K, PerezPolo R.
Department of Pharmacology, University of Rome, Italy.
The nerve growth factor protein (NGF) has been demonstrated to affect
neuronal development and maintenance of the differentiated state in certain
neurons of the peripheral and central nervous system (CNS) of mammals.
In the CNS, NGF has sparing effects on cholinergic neurons of the rodent
basal forebrain (BF) following lesions where it selectively induces choline
acetyltransferase (ChAT). NGF also induces ChAT in the areas to which
BF provides afferents. In aged rats, there is a reduction in the NGFbinding
capacity of sympathetic ganglia. Here, we wish to report that there is
a decrease in the NGFbinding capacity of the hippocampus and basal forebrain
of aged (26monthold) rats as compared to 4monthold controls but no change
in NGF binding in cerebellum. In all instances, equilibrium binding dissociation
constants did not differ significantly. Treatment of rats with Acetyl-L-Carnitine,
reported to improve cognitive performance of aged rats, ameliorates these
agerelated deficits. |