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Mechanism of Action; Acetyl-L-Carnitine

"Your body is made up of millions of tiny cells. Think of each cell like a miniature city. Inside each city, you'll find the power stations of the cell. They're called mitochondria. Of the oxygen consumed by an average cell, the mitochondria use most of it to help turn food into energy."
Bruce Ames, professor of biochemistry at the University of California at Berkeley
http://lpi.oregonstate.edu/staff/hagenbio.html


The functions of L-carnitine include transport of long-chain fatty acids across the mitochondrial membranes into the mitochondria (wherein their metabolism produces bioenergy) and transport of small-chain and medium-chain fatty acids out of the mitochondria in order to, among other things, maintain normal coenzyme A levels in these organelles. It may also have antioxidant activity.

Acetyl-L-carnitine is a delivery form for L-carnitine and acetyl groups. The acetyl component of acetyl-L-carnitine provides for the formation of the neurotransmitter acetylcholine. Abnormal acetylcholine metabolism in the brain, leading to acetylcholine deficits in certain brain regions, is thought to be associated with age-related dementias, including Alzheimer's disease.

http://www.pdrhealth.com/drug_info/nmdrugprofiles/nutsupdrugs/ace_0013.shtml

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The exact mechanisms of action of acetyl-L-carnitine are unknown, but current research indicates they may be related to both ALC’s cholinergic neural transmission activity and its ability to enhance neuronal metabolism in the mitochondria. Purpura et al have attributed the cholinergic effects of ALC to the blocking of post-synaptic inhibition potentials,6 while others have suggested it is due to direct stimulation of the synapses.7 As to enhanced cellular energetics in the mitochondria, human studies have shown ALC has the ability to stabilize cell membrane fluidity via regulation of sphingomyelin levels, and also provides a substrate reservoir for cellular energy production, thereby preventing excessive neuronal cell death. Acetyl-L-carnitine has also been shown to increase hippocampal binding of glucocorticoids and of nerve growth factor.8


6. Purpura DP, Girado M, Smith TG, et al. Structure activity determinants of pharmacological effects of amino acids and related compounds on central synapses. J Neurochem 1959;3:238. 7. Hayashi K. Action of carnitine on excitable tissues of vertebrates. In: Peeters H ed. Protides of the Biological Fluids. Amsterdam: Elsevier;1960:371-381. 8. Perez Polo JR, Werrbach-Perez K, Ramacci MT, et al. Role of nerve growth factors in neurological disease. In: Agnoli A, Cahn J, Lassen N, et al. eds. Senile dementias. 2nd International Symposium. Paris: Libby;1988:15-25.
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Synthesis and Function

L-Carnitine is synthesized in mammalian liver, kidney and brain tissue with lysine, methionine and vitamin C among the required substrates and co-factors. The main body stores are in skeletal and cardiac muscle. Acetyl-L-Carnitine is one of the esters of carnitine and is found along with free plasma carnitine and other acyl esters of varying chain length.1

The formation of ALC originates with cytoplasmic thiokinase which forms acylcoenzyme A from free-fatty acids, ATP and Coenzyme A (CoA). This substance is combined with carnitine to form acylcarnitine via carnitine palmitoyltransferase I. Entry into the mitochondrial matrix occurs through an exchange system of acylcarnitine/carnitine via carnitine-acylcarnitine translocase. For each acylcarnitine molecule traversing the inner mitochondrial membrane, a molecule of carnitine is shuttled out. On the inner mitochondrial membrane, carnitine palmitoyltransferase II converts acylcarnitine to carnitine, liberating acylCoA. Finally, the production of ALC and CoA from carnitine and acetylCoA (obtained via a oxidation of acyl CoA) occurs via carnitine acetyltransferase present in the mitochondrial matrix.2

Carnitine and its esters prevent toxic accumulations of fatty acids and acyl CoA (in the cytoplasm and mitochondria, respectively) while providing acetyl CoA for energy generation in the mitochondria. ALC's enzymatic formation in the mitochondrial matrix is reversible, providing free Coenzyme A and acetyl CoA which can readily be exchanged across membranes, thus providing metabolic energy to intracellular organelles.3 Carnitine acetyltransferase is a reversible enzyme system which appears to be linked with choline acetyltransferase (ChAT), thereby supplying intracellular acetylcholine while the opposite reaction liberates acetylCoA.

This mechanism can explain the improved cholinergic neurotransmission and enhanced intracellular energetics observed in ALC research.


Acetyl-L-Carnitine: Metabolism and Applications in Clinical Practice
John H. Furlong N.D.
http://www.thorne.com/altmedrev/fulltext/alc1-2.html


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