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Article from the March 1995 VRP Nutritional Newsletter


ACETYL-L-CARNITINE
The King of Carnitines


Acetyl-L-Carnitine (ALCAR) is the acetyl ester of carnitine, the carrier 
of fatty acids across mitochondrial membranes.  Like carnitine, ALCAR is 
naturally produced in the body and found in small amounts in some foods.

The reversible formation of ALCAR in the body modulates cellular 
concentrations of free coenzyme A and acetyl-coenzyme A, compounds 
integrally involved in numerous cellular functions including energy 
production.  By exchanging across sub-cellular membranes, ALCAR serves 
as a pool of acetyl groups to regenerate acetyl-CoA from free coenzyme 
A.  While this natural role for ALCAR in cellular metabolism has been 
well established for decades, research in recent years has hoisted ALCAR 
from its somewhat mundane role in energy production to nutritional 
cognitive enhancer and neuroprotective agent extraordinaire.  Indeed, 
taken in its entirety, ALCAR has become one of the premiere "anti-aging" 
compounds under scientific investigation, especially in relation to 
brain and nervous system deterioration.

ALCAR is found in various concentrations in the brain, and its levels 
are significantly reduced with aging.(1)  In numerous studies in animal 
models, ALCAR administration has been shown to have the remarkable 
ability of improving not only cognitive changes, but also morphological 
(structural) and neurochemical changes.  Initially, these effects were 
thought to stem from ALCAR's ability to donate its acetyl group to help 
form acetylcholine, or its ability to mimic acetylcholine, a 
neurotransmitter known to have an important role in memory and related 
cognitive functions.

In fact, it is now known that ALCAR has varied effects on cholinergic 
activity, including promoting the release(2) and synthesis(3) of 
acetylcholine.  Additionally, ALCAR promotes high affinity uptake of 
choline, which declines significantly with age.(4)  While these 
cholinergic effects were first described almost a quarter of a century 
ago,(5) it now appears that this is only the tip of the ALCAR iceberg.  
In recent years research on the neurological and other effects of ALCAR 
has exploded, primarily due to pharmaceutical interest in this 
fascinating compound.  This large volume of research has expanded ALCAR 
from acetylcholine mimic to a safe and naturally occurring compound with 
varied effects on numerous age-related degenerative changes in the 
brain.

The discovery that ALCAR has effects on brain systems other than the 
cholinergic system complicated the scientific picture of ALCAR.  This is 
because it was generally believed that ALCAR functioned simply as an 
enhancer of cholinergic activity by promoting the production, or 
mimicking the effect, of acetylcholine.  Before we examine these varied 
effects, however, let's examine what is now known about ALCAR's effects 
on the cholinergic system.  The cholinergic system has been extensively 
researched because of its central role in memory, as well as the 
evidence that cholinergic dysfunction plays a large role in age-related 
memory loss.  This is most evident in Alzheimer's disease, which effects 
primarily cholinergic function.  As mentioned earlier, ALCAR effects 
both acetylcholine synthesis and release.  Additionally, long-term ALCAR 
treatment has shown the ability to restore the decrease in cholinergic 
receptors in some brain areas.  One study found that the functioning of 
the cholinergic synapse was disturbed due to altered properties of the 
neuronal membrane, resulting in the functional impairment of cholinergic 
receptors.  Old rats treated with ALCAR were found to have improved 
acetylcholine release due to a preservation of the neuronal membrane 
structure and the functioning of the receptors embedded within the 
membrane.(6)  Indeed, these varied effects have shown that long-term 
ALCAR treatment reduces the significant age-related difference in 
receptor-mediated acetylcholine release.  This has not gone unnoticed, 
and ALCAR has been studied in Alzheimer's disease patients with 
promising results.

While ALCAR's cholinergic-enhancing properties are exciting, it now 
appears that ALCAR possesses broader neuroprotective and neuroenhancing 
properties than previously thought.  For instance, it is now known that 
ALCAR has effects on the dopaminergic system.(7)  The decline of this 
neurotransmission system is most evident in Parkinson's disease 
patients.  ALCAR has shown the ability to improve age-related changes of 
dopamine receptors, including improved release and binding of dopamine.  
Additionally, ALCAR can prevent dopaminergic neuron death by the 
neurotoxin MPTP.(8)  MPTP causes neurological symptoms similar to 
Parkinson's disease by selectively killing dopaminergic neurons.  Thus, 
it appears that ALCAR can have numerous beneficial effects on 
dopaminergic neurons.  

One of the most important receptor systems involved with cognitive 
function and memory is the NMDA receptor system.  NMDA (N-Methyl-D-
Aspartic acid) receptors are widely distributed in the brain, and their 
effects are mediated by excitatory amino acids like glutamate.  These 
receptors are unique because receptor function is mediated not only by 
the interaction between receptor and excitatory amino acid, but is 
dependent on the membrane potential.  Thus, activation of these 
receptors requires additional synaptic inputs.  While this may sound 
confusing, the point is that NMDA receptors have a "conditional" nature 
to their activation, which is highly unusual.  This underlies the 
central role that NMDA receptors are now believed to play in the 
synaptic plasticity associated with learning and memory.  Indeed, a 
rapidly growing body of evidence suggests that excitatory amino acids, 
through their interaction with NMDA receptors, are involved many aspects 
of neuronal activity.  It has been established that the density of NMDA 
receptors declines with age and that treatment with ALCAR restores to a 
significant degree these receptor numbers.(9)  In fact, even a single 
dose of ALCAR can significantly increase the number of available NMDA 
receptors.

One of the most important, and often overlooked, receptor system is that 
of glucocorticoids.  The hippocampus in the brain is the site of 
negative feedback between the pituitary and adrenal gland, and this 
helps to regulate the production of glucocorticoids by the adrenals.  
The number of glucocorticoid receptors in the hippocampus declines 
significantly with age,(10) and this is thought to result in 
perturbations in the hypothalamus-pituitary-adrenal (HPA) axis.  ALCAR 
treatment has been shown to prevent this age-related decline in receptor 
number.(11)  Because these receptors are central to neuroendocrine 
aging, and their decrease is considered a consistent marker for aging, 
it appears that ALCAR may have substantial potential for helping to slow 
down neuroendocrine aging.  

One of the most exciting areas of brain research has been into the 
functions of Nerve Growth Factor (NGF).  NGF mediates much of its 
effects through a receptor system (NGF receptor system).  Unfortunately, 
aging is associated with a significant drop in the number of NGF 
receptors in certain brain regions, as well as a decrease in the amount 
of NGF produced.  ALCAR has shown the ability to partially reverse both 
of these changes, and has even been shown to have independent 
stimulatory effects on neuronal survival and growth.(12)  Because NGF is 
important for the growth and continued maintenance of neurons, the age-
related decline in NGF function is thought to be directly involved in 
brain aging.  The administration of NGF's are under investigation for 
the treatment of brain injury and damage, and ALCAR's ability to enhance 
NGF effects may have tremendous potential in many diseases and 
conditions affecting the brain and nervous system.  

Taken as a whole, ALCAR represents a novel supplement with tremendous 
potential.  Because it also increases tissue levels of carnitine, as 
well as providing many benefits not found with carnitine 
supplementation, ALCAR represents an alternative to carnitine with 
enhanced properties and benefits.  

Most human studies examining ALCAR have utilized doses from 500-2500 
milligrams daily in divided doses.  Younger, healthy persons would 
probably want to take 500-1000 milligrams daily, while those with 
cognitive deficit due to aging or injury may wish to take 1500-2500 
milligrams daily. While no serious side effects have been noted in 
animal or human studies, ALCAR may cause symptoms of over-stimulation or 
headache in some sensitive individuals.  However, these symptoms are not 
common and are usually caused by beginning with a high dose.  One last 
consideration is ALCAR's stability.  Unlike carnitine, it is recommended 
that ALCAR be kept refrigerated to ensure potency.  Thus, while ALCAR 
can be shipped without refrigeration, manufacturers must be sure to 
refrigerate raw material and finished product during storage to prevent 
premature degradation of the product.  Customers, to further protect 
their investment, should preferably refrigerate ALCAR after receipt.

ALCAR truly represents one of the most promising and well researched 
cognitive-enhancing compounds available today.  The fact that its non-
toxic, occurs naturally in the body, and positively affects so many 
different neurological functions makes its potential both exciting and 
amazing.

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References:
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1).  F.  Maccari, A. Arseni, P. Chiodi, et al, Exp Geront  1990; 25: 
127-134.
2).  A. Imperato, M.T. Ramacci, L. Angelucci, et al, Neurosci Lett  
1989; 107: 251-255.
3).  V. Dolezal and S. Tucek, J Neurochem  1981; 36: 1323-1330.
4).  D. Curti, F. Dagani, M.R. Galmozzi, et al, Mech Ageing Dev  1989; 
47: 39-45.
5).  K. Blum, E. Seifter, J. Seifter, J Pharmacol Exp Ther  1971; 178: 
331-338.
6).  A. Impeerato, M.G. Scrocco, O. Ghirardi, et al, Annals of the NY 
Acad Sci  1991; 621: 90-97.
7).  H. Sershen, L.G. Harsing, M. Banay-Schwartz, et al, J Neurosci Res  
1991; 30: 555-559.
8).  I. Bodis-Wollner, E. Chung, M.F. Ghilardi, et al, J Neural Transm 
Park Dis Diment Sci 1991;  3:  63-72.
9).  L. Fiore and L. Rampello, Acta Neurol  1989; 11: 346-350.
10). R.M. Sapolsky, L.C. Krey, and B.S. McEwen, J Neurosci  1985; 5: 
1222-1227.
11).  F.R. Patacchioli, F. Amenta, M.T. Ramacci, et al, J Neurosci Res  
1989; 23: 462-466.
12).  G. Taglialetela, L. Angelucci, M.T. Ramacci, et al, Brain Res Dev 
Brain Res 1991;  59:  221-230.

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DISCLAIMER:
No information in this article should be taken as a recommendation.  If 
you have any questions about the relationship between ALCAR and your 
health, seek the advice of a qualified physician.
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