11
ALCAR is a quintessential nootropic: an endogenous amino acid already present in the body and brain, it enhances cognition, protects against damage, and prevents or ameliorates many of the undesirable changes to the brain that occur as we age. As such, it is tolerated well by most, and combines nicely with most other nootropics. This review will focus on the effect ALCAR exerts upon the acetylcholine system, as well as more briefly describe other mechanisms of neurological interest.
This research project grew out of a desire to explain an effect I observed in myself: ALCAR fulfilled a very definite requirement for choline supplementation in piracetam usage. Taking even small amounts of ALCAR with alpha GPC resulted in a tension headache (sign of ACh overload), while much larger doses of either did not. This suggested to me that ALCAR had some kind of synergistic (i.e. multiplicative) effect somewhere in the acetylcholine pathway.
This is very much a work in progress; research of this kind generates a torrential cascade of references, and leads into general areas of inquiry in the pursuit of adequate explanation. But enough people have been asking about these mechanisms that I felt it would be helpful to publish a document with the most relevant details, if not a complete explanation. There are several more mechanisms by which ALCAR impacts the acetylcholine system, which are mentioned briefly at the end of the review. These will be fleshed out and referenced as I have time to read more papers, and adjustments will be made to existing explanations as I receive more full texts.
Feel free to post comments here, though I've created a forum thread to announce updates, discuss the research, and collect experience accounts of those who have tried the ALCAR + piracetam combination.
There is some confusion about the cholinergic potential of ALCAR, that results from the terminology we use on the board. We say that piracetam requires a "choline source," when what we more precisely mean is that we need to increase production and release of acetylcholine (ACh) to compensate for the hippocampal ACh depletion that piracetam causes [1-2].
The most common way to achieve this is by exogenous supplementation of choline, or a precursor which is converted into (or already is) one of the forms of choline useful in the brain [41]. Exogenous choline protects against artificial ACh depletion [3] (like piracetam), and increases the rate of resynthesis [3, 42, 49-50]. Improved choline supply may also provide a "backup" pool which may be mobilized for synthesis later [4-5, 43]; and increases the magnitude of ACh production in response to neural [3] or chemical [6-7, 42] stimulation.
But there are some drawbacks to this route. A certain elevated concentration of extracellular brain choline is required to effect an increase in ACh [6]; this is one of the reasons why many studies show no increase of ACh in response to exogenous choline [49-54]. An increase in plasma choline results in a net Ch increase in the brain [44], though by a lesser factor [48]. Most of this is rapidly taken up into cells or phosphorylated, and the surplus removed to the CSF [45, 47]—resulting in a small level of sustained extracellular choline [45-46]. In the absence of neural or chemical stimulation, increasing the amount of choline in the brain will only provide a very small and short-lived spike in basal ACh release in the hippocampus and cortex [6, 25]. The fact that added choline does not result in increased basal ACh shows that there are many systems of regulation—activity dependence, phosphorylation, plasma-brain-CSF exchange, choline uptake transporters, and recycling system—which make choline supplementation alone an inefficient and possibly ineffective means. This is where ALCAR comes in.
This incredibly helpful graphic illustrates the course of the acetyl moieity (group) that ends up in acetyl-choline [8]:
The first enzyme (on the left) is Carnitine Acetyltransferase (CarAT), which transfers the acetyl group from ALCAR to acetyl-Coenzyme A (acetyl-CoA). Then the enzyme Choline Acetyltransferase (ChAT) transfers the acetyl group to choline to yield ACh. (This process has been demonstrated in slices of rat brains [8, 11, 23], and proposed by several others who could not construct the proper experimental system to demonstrate all of the effects [22-23]).
So, how might increasing availability of the acetyl moeity help us? The answer is in the equilibria of the coupled enzyme reaction above. The CarAT reaction has equilibrium near unity [9-10]; this means that it will utilize about half of any added substrates (ALCAR) to synthesize new products (acetyl-CoA). However, the equilibrium of the ChAT reaction is greatly in favor of the products (Keq of 12.3 [26] or 13.3 [27]); the vast majority of an added substrate will be converted into ACh. In other words, provided that CoA and choline are available, ALCAR should have a dose-dependent impact on amount of acetylcholine produced. (see Acetylcholine Release, below)
(It is worth noting that CarAT is able to acetylate choline directly [36], but with a very low affinity. It is speculated that it plays virtually no role in brain ACh biosynthesis [15]. However, it has been shown to account for up to half of ACh production in some muscular models [56-59], so a possible role in the brain cannot be discounted.)
Other enzymes and substrates are also responsible for the synthesis of acetyl-CoA, and are responsible for a greater amount than is contributed by ALCAR [11, 18-21]. The substrate which makes the largest contribution to the acetyl-CoA pool is pyruvate [12-13] (a metabolite of glucose), which is converted to acetyl-CoA by pyruvate dehydrogenase (PDC) in the mitochondrial matrix [11] (though PDC may exist extra-mitochondrially [14]). Glucose is slightly less preferred as a source, presumably because it must first be converted to pyruvate. Citrate and acetate play a role, though much less than pyruvate or glucose. ALCAR is preferred about 66% as much as glucose in this rat brain model [11]:
An important point is that ALCAR does not compete with glucose [8] or pyruvate [23] in relative contribution to final ACh production. This means that, even in abnormally high concentrations, ALCAR and other acetyl-CoA substrates still maintain an individual dose-response relationship. This is because the enzymes CarAT and ChAT have a very large amount of excess capacity at the physiological concentrations of their respective substrates, and so are far from saturation [8, 15].
The CarAT reaction has an equilibrium constant near unity [9-10], but is also reversible [29]; this reversibility means that ALCAR may be produced if acetyl-CoA and L-carnitine are in excess (in a certain area). Some of these other substrates (esp. pyruvate) are converted to acetyl-CoA inside the mitochondrial matrix [11]. CarAT itself is a membrane-bound enzyme, probably active at both inner and outer mitochondrial membrane sites [30-32]. One hypothesis is that, since carnitine is able to "shuttle" acetyl groups through the membrane [16-17, 30-35], ALCAR is used to transfer the acetyl groups from mitochondrial pyruvate-derived acetyl-CoA to the cellular cytoplasm, where it can be utilized by ChAT [8, 15]. (CoA and acetyl-CoA are able to pass the mitochondrial membrane directly in the presence of Ca2+ ions, but the required ion concentration is higher than has been demonstrated as possible in intact nerve cells [15, 37-40]). Thus, in addition to providing the acetyl moieity directly, ALCAR/carnitine may also serve as a carrier molecule to bring acetyl-CoA from other substrates, into the cytoplasm.
ALCAR also increases the utilization of glucose in the brain [22, 60], probably by stimulating non-oxidative pyruvate dehydrogenase activity [66, 68], which effectively increases the amount of ACh synthesized from glucose/pyruvate [66]. Utilization increases to varying extents in different regions, and increases more in the aged (who generally suffer from decreased glucose utilization) [62-63].
ALCAR is also able to increase the utilization of alternative energy sources like ketone bodies and lipid substrates [67, 69]; evidence also suggests that more ALCAR is taken up into the brain when levels of glucose are low [61].
It's also interesting that glucose and exogenous choline combine synergistically to increase ACh release [64], in a model of awake mice, when neither alone had much of an effect. While it isn't necessarily healthy to increase glucose intake, ALCAR's enhancement of glucose utilization (theoretically resulting in the same thing: more acetyl-CoA) may result in something of the same synergy.
In the above reactions, CoA is recycled continuously. It is tempting to attempt to increase the quantitiy of this substrate as well, to drive the CarAT reaction forward from another direction. A potential drawback exists, in that CoA is a potent inhibitor of the forward action of the ChAT enzyme [8, 36]. An elegant feature of the CarAT-ChAT enzyme loop is that, in synthesizing acetyl-CoA, levels of this inhibitory product are decreased, allowing an increase in ChAT activity.
It is unknown whether supplementation of pantothenic acid (B5) or pantethine, precursors of CoA, will increase acetyl-CoA more than they interfere with ChAT. Only one paper exists which demonstrates an increase in ACh due to B5 supplementation [55], but it may only be applicable to correcting ACh deficiency due to B5 deficit (see discussion here). From the anecdotal reports of pantethine use, it sounds like ACh is being increased, if anything. Clearly, more experimentation is required. However, I suggest that moderate doses should be used, as increasing the pool of unacetylated CoA will have a negative impact on ACh production [15]:
Choline Uptake
Transport of choline into nerve terminals, where it is converted into acetylcholine by the aforementioned process, is carried out by high- and low-affinity choline transporters (CHT); high-affinity choline uptake (HACU) is responsible for most of this process under normal circumstances. ALCAR has been shown to increase the uptake of choline, though the mechanism is not fully understood; as the release of ACh from the terminal results in an influx of new choline, this alone is no doubt implicated to some degree.
Choline Acetyltransferase
Many studies demonstrate that ALCAR increases activity of this enzyme; indeed, this is the most obvious cholinergic mechanism mentioned in the relevant abstracts. However, this enzyme functions at the convergence of many cholinergic processes, making it difficult to ascertain the exact mechanisms responsible.
As ChAT is the enzyme necessary for synthesis of acetylcholine, any process increasing ACh production and release should concomitantly increase its activity. However, this doesn't rule out the possibility of a direct action on the enzyme. Nerve growth factor (NGF) has such a stimulatory effect on ChAT activity. To complicate this further, ALCAR interacts with NGF in several ways (see below), which may also increase its effect on ChAT in several ways. However, there is evidence to show that ALCAR increases ChAT activity in the absence of NGF, and that increased NGF levels do not necessarily elevate the enzyme activity.
ALCAR demonstrates the greatest efficacy in ameliorating age-related deficits in ChAT activity.
NGF
ALCAR has been shown to increase hippocampal levels of NGF. ALCAR also modulates the action of NGF by increasing the expression of its low-affinity receptor, p75-NGFR, and perhaps by acetylating some of NGF's amino acids. This has the effect of potentiating its action, by which much lower amounts produce the same neurotrophic effect. This effect feeds back into stimulation of ChAT, and greater ACh production.
ALCAR most effectively induces NGF activity in aged animals, who suffer a decrease in NGF activity in parallel with a cholinergic deficit.
ALCAR arginyl amide produces a direct neurotrophic effect on neurite outgrowth and cellular morphology. However, only two studies have been conducted, both by the manufacturer Sigma Tau, and it is unknown whether this putative effect translate to an in vivo efficacy.
Direct Action
ALCAR has a very slight direct agonistic effect on ACh receptors, but it is orders of magnitude smaller than that of the neurotransmitter; there is almost no chance that it plays any practical role.
Acetylcholine Release
Or, "the proof is in the pudding." An actual and significant increase in ACh levels has been shown in several studies, which demonstrates that these mechanisms actually do exert an influence.
Other neurological mechanisms
Dopamine: ALCAR ameliorates age-related decline in D2 receptor density, and induces release of vesicular dopamine in the corpus striatum of rats.
NMDA: Reduces age-related decrease in receptors, but increases receptor density by decreasing amounts in adult and young rats.
GABA: Increased the density of GABA-benzodiazepine (but not GABA-A) receptors in aged rats.
Calcium channel: Ameliorated age-related decrease in L-type voltage-gated Ca2+ channel receptors in the hippocampal membrane.
Glucocorticoid: Prevented age-related decrease in number of binding sites.
Neuroprotection: ALCAR inhibits increases in lipid hydroperoxidation, increases expression of NF-κB and mGlu2/3, inhibits ceramide generation, enhances histone acetylation, attenuates apoptosis, and protects against the neurotoxic effects of NMDA (in large doses), MPPP(+), NGF/BDNF/serum deprivation, and ischemia.
Adverse Effects
Anxiety: One study in rats showed that acute (i.e. single) doses of ALCAR were anxiogenic; this study also showed that in chronic administration, 10 and 100mg/kg had no effect on anxiety, while 50mg/kg was anxiolytic [85]. This is suggestive of a bell-shaped response curve, which is consistent with dose-reponse curve of other effects in the Ames studies.
Ultrastructure: One abstract mentions that ALCAR induced a decrease in axosomatic synapses in young rats, in contrast to ameliorated decreases in axosomatic synapses and giant synapsis vesicles in aged rats [86]. Without the full text, and knowledge of the dosage, ROA, and age of the "young" animals, it is difficult to predict whether this is cause for concern in human; though most studies use "young" as an age category quite separate from "adult."
Due to poor planning on my part, I didn't store the medline URLs in my reference list. I will work on linking these, but in the meantime, typing the title into google scholar is probably the easiest way to retrieve the abstract (clicking All Versions will call up the pubmed link).
1
Life Sci. 1981 Mar 9;28(10):1091-3.
Piracetam diminishes hippocampal acetylcholine levels in rats.
Wurtman RJ, Magil SG, Reinstein DK.
2
Clin Neuropharmacol. 1986;9 Suppl 3:S39-47.
Effect of oxiracetam and piracetam on central cholinergic mechanisms and active-avoidance acquisition.
Spignoli G, Pedata F, Giovannelli L, Banfi S, Moroni F, Pepeu G.
3
J Neurochem. 1982 Dec;39(6):1704-9.
Exogenous choline enhances the synthesis of acetylcholine only under conditions of increased cholinergic neuronal activity.
Trommer BA, Schmidt DE, Wecker L.
4
Neuropharmacology. 1981 Jun;20(6):535-9.
CNS effects of choline administration: evidence for temporal dependence.
Schmidt DE, Wecker L.
PMID: 7242873 [PubMed - indexed for MEDLINE]
5
Life Sci. 1996;58(22):1995-2002.
Elevation of cerebrospinal fluid choline levels by nicotinamide involves the enzymatic formation of N1-methylnicotinamide in brain tissue.
Vargas HM, Jenden DJ.
6
J Pharmacol Exp Ther. 1997 Sep;282(3):1139-45.
Acetylcholine release and choline availability in rat hippocampus: effects of exogenous choline and nicotinamide.
Köppen A, Klein J, Erb C, Löffelholz K.
7
Neurochem Int. 1995 Jun;26(6):635-41.
Effect of externally added carnitine on the synthesis of acetylcholine in rat cerebral cortex cells.
Wawrzeńczyk A, Nałecz KA, Nałecz MJ.
8
Neurochem Res. 1990 Jun;15(6):597-601.
Acetyl-L-carnitine as a precursor of acetylcholine.
White HL, Scates PW.
9
Neurochem Res. 1989 May;14(5):489-93.
Uptake of acetyl-L-carnitine in the brain.
Burlina AP, Sershen H, Debler EA, Lajtha A.
10
Biochem J. 1966 Apr;99(1):32-40.
Some kinetic studies on the mechanism of action of carnitine acetyltransferase.
Chase JF, Tubbs PK.
11
J Neurochem. 1981 Apr;36(4):1323-30.
Utilization of citrate, acetylcarnitine, acetate, pyruvate and glucose for the synthesis of acetylcholine in rat brain slices.
Dolezal V, Tucek S.
12
Biochem J. 1970 Jul;118(3):443-50.
A study on the precursors of the acetyl moiety of acetylcholine in brain slices. Observations on the compartmentalization of the acetyl-coenzyme A pool.
Nakamura R, Cheng SC, Naruse H.
13
Neurochem Int. 2008 Dec;53(6-8):193-8. Epub 2008 Jul 1.
High-affinity choline uptake and acetylcholine-metabolizing enzymes in CNS white matter. A quantitative study.
Hassel B, Solyga V, Lossius A.
14
Nature. 1978 Aug 3;274(5670):497-500.
Evidence for extramitochondrial pyruvate dehydrogenase involved in acetylcholine synthesis in nerve endings.
Lefresne P, Beaujouan JC, Glowinski J.
15
J Neurochem. 1985 Jan;44(1):11-24.
Regulation of acetylcholine synthesis in the brain.
Tucek S.
16
J Biol Chem. 1962 Dec;237:3628-32.
Carnitine in intermediary metabolism. The metabolism of fatty acid esters of carnitine by mitochondria.
BREMER J.
17
Adv Lipid Res. 1963;1:285-334.
CARNITINE AND ITS ROLE IN FATTY ACID METABOLISM.
FRITZ IB.
18
J Neurochem. 1968 Dec;15(12):1391-405.
(14C) acetylcholine synthesis by cortex slices of rat brain.
Browning ET, Schulman MP.
19
Biochim Biophys Acta. 1970 Jun;208(3):538-40.
Precursors of acetyl groups in acetylcholine in the brain in vivo.
Tucek S, Cheng SC.
20
J Neurochem. 1974 Jun;22(6):893-914.
Provenance of the acetyl group of acetylcholine and compartmentation of acetyl-CoA and Krebs cycle intermediates in the brain in vivo.
Tucek S, Cheng SC.
21
J Neurochem. 1973 Apr;20(4):1083-97.
Acetylcholine synthesis from (2- 14 C)pyruvate in rat striatal slices.
Lefresne P, Guyenet P, Glowinski J.
22
Biochem Pharmacol. 1980 Feb;29(2):167-74.
Studies on the metabolic pathway of the acetyl group for acetylcholine synthesis.
Gibson GE, Shimada M.
23
Biochimie. 1977;59(2):197-215.
Origin of the acetyl moiety of acetylcholine synthesized in rat striatal synaptosomes.
Lefresne P, Hamon M, Beaujouan JC, Glowinski J.
24
J Neurochem. 1980 Jul;35(1):249-54.
Acetyl-CoA synthesizing enzymes in cholinergic nerve terminals.
Sterri SH, Fonnum F.
25
Wecker L. (1990) Choline utilization by central cholinergic neurons. in Nutrition and the Brain, eds Wurtman R. J., Wurtman J. J. (Raven Press, New York), 8:147–162.
26
J Biol Chem. 1975 Jun 25;250(12):4445-50.
Equilibrium constants of the reactions of choline acetyltransferase, carnitine acetyltransferase, and acetylcholinesterase under physiological conditions.
Pieklik JR, Guynn RW.
27
J Biol Chem. 1982 Nov 10;257(21):12820-5.
Kinetic studies of the choline acetyltransferase reaction using isotope exchange at equilibrium.
Hersh LB.
28
J Neurosci Res. 1995 Jun 15;41(3):403-8.
Stimulation of choline acetyl transferase activity by l- and d-carnitine in brain areas of neonate rats.
Ayala CA.
29
J Biol Chem. 1962 Jul;237:2228-31.
Carnitine in intermediary metabolism. Reversible acetylation of carnitine by mitochondria.
BREMER J.
30
J Cell Sci. 1970 Jan;6(1):29-51.
Cytochemical localization of transferase activities: carnitine acetyltransferase.
Higgins JA, Barrnett RJ.
31
Am J Physiol. 1964 Mar;206:531-5.
EFFECTS OF CARNITINE ON ACETYL-COA OXIDATION BY HEART MUSCLE MITOCHONDRIA.
FRITZ IB, YUE KT.
32
Br Med Bull. 1968 May;24(2):158-64.
Membranes and fatty acid metabolism.
Tubbs PK, Garland PB.
33
Biochim Biophys Acta. 1963 Oct 8;78:77-84.
ACYL COENZYME A AS AN INTERMEDIATE IN THE MITOCHONDRIAL ACYLATION OF CARNITINE BY ALPHA-KETO ACIDS.
NORUM KR, BREMER J.
34
J Biol Chem. 1965 May;240:2188-92.
CARNITINE ACETYLTRANSFERASE. II. INHIBIITON BY CARNITINE ANALOGUES AND BY SULFHYDRYL REAGENTS.
FRITZ IB, SCHULTZ SK.
35
J Biol Chem. 1966 Sep 10;241(17):4092-7.
The role of carnitine and carnitine acyltransferase in biological acetylations and fatty acid synthesis.
Bressler R, Brendel K.
36
J Neurochem. 1973 Feb;20(2):297-307.
Kinetics of choline acetyltransferases (EC 2.3.1.6) from human and other mammalian central and peripheral nervous tissues.
White HL, Wu JC.
37
Biochem J. 1967 Sep;104(3):749-56.
The use of choline acetyltransferase for measuring the synthesis of acetyl-coenzyme A and its release from brain mitochondria.
Tucek S.
38
Science. 1981 Sep 25;213(4515):1495-7.
Acetylcholine synthesis in synaptosomes: mode of transfer of mitochondrial acetyl coenzyme A.
Benjamin AM, Quastel JH.
39
Can J Physiol Pharmacol. 1983 Feb;61(2):154-8.
Calcium-dependent release of acetyl-coenzyme A from liver mitochondria.
Benjamin AM, Murthy CR, Quastel JH.
40
Ritny J. and TuCek S. (1983) Ca2+ ions and the output of acetylcoenzyme
A from brain mitochondria. Gen. Physiol. Biophys. 2;27 - 37.
41
Pharmacol Rev. 1980 Dec;32(4):315-35.
Precursor control of neurotransmitter synthesis.
Wurtman RJ, Hefti F, Melamed E.
42
J Pharmacol Exp Ther. 1982 Feb;220(2):322-8.
Effects of phosphatidylcholine administration to rats on choline in blood and choline and acetylcholine in brain.
Jope RS.
43
J Neurochem. 1989 Feb;52(2):568-75.
Acute choline supplementation in vivo enhances acetylcholine synthesis in vitro when neurotransmitter release is increased by potassium.
Wecker L, Cawley G, Rothermel S.
44
J Neurochem. 1990 Oct;55(4):1231-6.
Small rises in plasma choline reverse the negative arteriovenous difference of brain choline.
Klein J, Köppen A, Löffelholz K.
45
J Neurochem. 1992 Mar;58(3):870-6.
Uptake and metabolism of choline by rat brain after acute choline administration.
Klein J, Köppen A, Löffelholz K, Schmitthenner J.
46
J Pharmacol Exp Ther. 1993 Aug;266(2):720-5.
Synergistic effect of nicotinamide and choline administration on extracellular choline levels in the brain.
Köppen A, Klein J, Holler T, Löffelholz K.
47
Prog Brain Res. 1993;98:197-200.
Choline, a precursor of acetylcholine and phospholipids in the brain.
Löffelholz K, Klein J, Köppen A.
48
J Neurochem. 1977 Jan;28(1):229-31.
Effects of oral choline administration on serum and CSF choline levels in patients with Huntington's disease.
Growdon JH, Cohen EL, Wurtman RJ.
PMID: 137960 [PubMed - indexed for MEDLINE]
49
Science. 1978 Jan 6;199(4324):86-7.
Choline administration: modification of the central actions of atropine.
Wecker L, Dettbarn WD, Schmidt DE.
50
Brain Res. 1980 Feb 17;184(1):234-8.
Neuropharmacological consequences of choline administration.
Wecker L, Schmidt DE.
51
Pharmacol Res Commun. 1977 Sep;9(8):755-61.
Effect of choline, phosphorylcholine and dimethylaminoethanol on brain acetylcholine level in the rat.
Pedata F, Wieraszko A, Pepeu G.
52
J Neurochem. 1979 Apr;32(4):1331-3.
Choline administration and acetylcholine in brain.
Flentge F, Van den Berg CJ.
53
J Neurochem. 1979 Mar;32(3):961-7.
Relationship between choline availability and acetylcholine synthesis in discrete regions of rat brain.
Wecker L, Dettbarn WD.
54
J Neurochem. 1982 Apr;38(4):1160-3.
Increase in exogenous choline fails to elevate the content or turnover rate of cortical, striatal, or hippocampal acetylcholine.
Brunello N, Cheney DL, Costa E.
55
Br J Pharmacol. 1988 Sep;95(1):77-82.
Effects of ethanol and pantothenic acid on brain acetylcholine synthesis.
Rivera-Calimlim L, Hartley D, Osterhout D.
56
J Physiol. 1982 Jan;322:53-69.
The synthesis of acetylcholine in skeletal muscles of the rat.
Tucek S.
57
J Physiol. 1982 Dec;333:189-99.
Free and bound acetylcholine in frog muscle.
Miledi R, Molenaar PC, Polak RL.
58
Pflugers Arch. 1982 Jan;392(3):225-9.
Choline acetyltransferase in the heart of adult rats.
Slavíková J, Tucek S.
59
J Physiol. 1983 Jan;334:461-74.
The synthesis and release of acetylcholine in normal and denervated rat diaphragms during incubation in vitro.
Dolezal V, Tucek S.
60
17 Thomitzek, W.D., Die Wirkung van Derivaten des (-) und (+) Acetylcarnitins auf die Bildung von
Acetylcholine, Biochem. Pharmacol., Conference Issue, 2nd Int. Pharmacol. Meeting (1963), S. 161.
61
Biochem Biophys Res Commun. 1997 Feb 13;231(2):488-93.
High uptake of [2-11C]acetyl-L-carnitine into the brain: a PET study.
Kuratsune H, Watanabe Y, Yamaguti K, Jacobsson G, Takahashi M, Machii T, Onoe H, Onoe K, Matsumura K, Valind S, Kitani T, Långström B.
62
Brain Res. 2002 Oct 4;951(2):330-5.
Effects of acetyl-L-carnitine on regional cerebral glucose metabolism in awake rats.
Ori C, Freo U, Pizzolato G, Dam M.
63
Brain Res. 2009 Mar 9;1259:32-9. Epub 2008 Dec 24.
Cerebral metabolic effects of acetyl-l-carnitine in rats during aging.
Freo U, Dam M, Ori C.
64
Neuroscience. 2001;103(2):365-71.
Glucose plus choline improve passive avoidance behaviour and increase hippocampal acetylcholine release in mice.
Kopf SR, Buchholzer ML, Hilgert M, Löffelholz K, Klein J.
65
Can J Physiol Pharmacol. 1997 May;75(5):423-30.
Decompensation of hepatic and cerebral acyl-CoA metabolism in BALB/cByJ mice by chronic riboflavin deficiency: restoration by acetyl-L-carnitine.
Rao KV, Qureshi IA.
66
J Mol Cell Cardiol. 1995 Nov;27(11):2465-72.
Stimulation of non-oxidative glucose utilization by L-carnitine in isolated myocytes.
Abdel-aleem S, Sayed-Ahmed M, Nada MA, Hendrickson SC, St Louis J, Lowe JE.
67
Brain Res. 1990 Aug 27;526(1):108-12.
Aging brain: effect of acetyl-L-carnitine treatment on rat brain energy and phospholipid metabolism. A study by 31P and 1H NMR spectroscopy.
Aureli T, Miccheli A, Ricciolini R, Di Cocco ME, Ramacci MT, Angelucci L, Ghirardi O, Conti F.
68
Brain Res. 1998 Jun 15;796(1-2):75-81.
Acetyl-L-carnitine modulates glucose metabolism and stimulates glycogen synthesis in rat brain.
Aureli T, Di Cocco ME, Puccetti C, Ricciolini R, Scalibastri M, Miccheli A, Manetti C, Conti F.
69
J Neurochem. 1998 Dec;71(6):2510-7.
Role of acetyl-L-carnitine in rat brain lipogenesis: implications for polyunsaturated fatty acid biosynthesis.
Ricciolini R, Scalibastri M, Kelleher JK, Carminati P, Calvani M, Arduini A.
70
Neurosci Lett. 2002 Sep 6;329(3):334-8.
Acetyl-L-carnitine shows neuroprotective and neurotrophic activity in primary culture of rat embryo motoneurons.
Bigini P, Larini S, Pasquali C, Muzio V, Mennini T.
71
Brain Res. 1995 Mar 13;674(1):142-6.
Spatial discrimination learning and choline acetyltransferase activity in streptozotocin-treated rats: effects of chronic treatment with acetyl-L-carnitine.
Prickaerts J, Blokland A, Honig W, Meng F, Jolles J.
72
J Neurosci Res. 1988 Aug;20(4):491-6.
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, Werrbach-Perez K, Perez-Polo R.
73
Brain Res. 1994 Jan 7;633(1-2):77-82.
Acetyl-L-carnitine treatment increases choline acetyltransferase activity and NGF levels in the CNS of adult rats following total fimbria-fornix transection.
Piovesan P, Pacifici L, Taglialatela G, Ramacci MT, Angelucci L.
74
Neuroscience. 1985 Jan;14(1):55-68.
Nerve growth factor increases choline acetyltransferase but not survival or fiber outgrowth of cultured fetal septal cholinergic neurons.
Hefti F, Hartikka J, Eckenstein F, Gnahn H, Heumann R, Schwab M.
75
Trends in Neurosciences Volume 9, 1986, Pages 570-573
The role of nerve growth factor in the CNS
Sigrun Korsching
76
Science. 1987 Sep 4;237(4819):1154-62.
The nerve growth factor 35 years later.
Levi-Montalcini R.
77
Ciba Found Symp. 1987;126:82-95.
Neurotrophic factors and neuronal death.
Thoenen H, Barde YA, Davies AM, Johnson JE.
78
Rizza V, Morale MC, Guarcello V, Guerrera F (1986): Effects of l-carnitine and acetyl-l-carnitine on lipid metabolism in rat brain. Biol Psych 1985. In: Chagass C, Josiassen RC, Bridger WH, Weiss KJ, Stoff D, Simpson GM (eds) “Developments in Psychiatry,” Volume 7, pp. 1346-1348.
79
Int J Dev Neurosci. 1992 Oct;10(5):361-73.
Effects of nerve growth factor and acetyl-L-carnitine arginyl amide on the human neuronal line HCN-1A.
Westlund KN, Lu Y, Werrbach-Perez K, Hulsebosch CE, Morgan B, Pizzo DP, Eisenberg HM, Perez-Polo JR.
80
Gynecol Oncol. 2009 Mar;112(3):631-6.
Effect of acetyl-l-carnitine on ovarian cancer cells' proliferation, nerve growth factor receptor (Trk-A and p75) expression, and the cytotoxic potential of paclitaxel and carboplatin.
Engle DB, Belisle JA, Gubbels JA, Petrie SE, Hutson PR, Kushner DM, Patankar MS.
81
J Neurosci Res. 2008 Sep;86(12):2705-21.
Hypoxia-induced deactivation of NGF-mediated ERK1/2 signaling in hippocampal cells: neuroprotection by acetyl-L-carnitine.
Barhwal K, Hota SK, Prasad D, Singh SB, Ilavazhagan G.
82
Neurochem Int. 2003 Aug;43(3):225-33.
Effect of PPF and ALCAR on the induction of NGF- and p75-mRNA and on APP processing in Tg2576 brain.
Chauhan NB, Siegel GJ.
83
Neurochem Res. 1995 Jan;20(1):1-9.
Neurite outgrowth in PC12 cells stimulated by acetyl-L-carnitine arginine amide.
Taglialatela G, Navarra D, Olivi A, Ramacci MT, Werrbach-Perez K, Perez-Polo JR, Angelucci L.
84
Biochem Pharmacol. 1992 Aug 4;44(3):577-85.
Stimulation of nerve growth factor receptors in PC12 by acetyl-L-carnitine.
Taglialatela G, Angelucci L, Ramacci MT, Werrbach-Perez K, Jackson GR, Perez-Polo JR.
85
Int J Neuropsychopharmacol. 2005 Mar;8(1):65-74. Epub 2004 Sep 22.
Effect of intraperitoneal acetyl-L-carnitine (ALCAR) on anxiety-like behaviours in rats.
Levine J, Kaplan Z, Pettegrew JW, McClure RJ, Gershon S, Buriakovsky I, Cohen H.
86
Drugs Exp Clin Res. 1987;13(3):185-9.
Ultrastructural aspects of ageing rat hippocampus and effects of L-acetyl-carnitine treatment.
Badiali de Giorgi L, Bonvicini F, Bianchi D, Bossoni G, Laschi R.
To do:
Update ChAT, NGF
This research project grew out of a desire to explain an effect I observed in myself: ALCAR fulfilled a very definite requirement for choline supplementation in piracetam usage. Taking even small amounts of ALCAR with alpha GPC resulted in a tension headache (sign of ACh overload), while much larger doses of either did not. This suggested to me that ALCAR had some kind of synergistic (i.e. multiplicative) effect somewhere in the acetylcholine pathway.
This is very much a work in progress; research of this kind generates a torrential cascade of references, and leads into general areas of inquiry in the pursuit of adequate explanation. But enough people have been asking about these mechanisms that I felt it would be helpful to publish a document with the most relevant details, if not a complete explanation. There are several more mechanisms by which ALCAR impacts the acetylcholine system, which are mentioned briefly at the end of the review. These will be fleshed out and referenced as I have time to read more papers, and adjustments will be made to existing explanations as I receive more full texts.
Feel free to post comments here, though I've created a forum thread to announce updates, discuss the research, and collect experience accounts of those who have tried the ALCAR + piracetam combination.
Piracetam and Choline
There is some confusion about the cholinergic potential of ALCAR, that results from the terminology we use on the board. We say that piracetam requires a "choline source," when what we more precisely mean is that we need to increase production and release of acetylcholine (ACh) to compensate for the hippocampal ACh depletion that piracetam causes [1-2].
The most common way to achieve this is by exogenous supplementation of choline, or a precursor which is converted into (or already is) one of the forms of choline useful in the brain [41]. Exogenous choline protects against artificial ACh depletion [3] (like piracetam), and increases the rate of resynthesis [3, 42, 49-50]. Improved choline supply may also provide a "backup" pool which may be mobilized for synthesis later [4-5, 43]; and increases the magnitude of ACh production in response to neural [3] or chemical [6-7, 42] stimulation.
But there are some drawbacks to this route. A certain elevated concentration of extracellular brain choline is required to effect an increase in ACh [6]; this is one of the reasons why many studies show no increase of ACh in response to exogenous choline [49-54]. An increase in plasma choline results in a net Ch increase in the brain [44], though by a lesser factor [48]. Most of this is rapidly taken up into cells or phosphorylated, and the surplus removed to the CSF [45, 47]—resulting in a small level of sustained extracellular choline [45-46]. In the absence of neural or chemical stimulation, increasing the amount of choline in the brain will only provide a very small and short-lived spike in basal ACh release in the hippocampus and cortex [6, 25]. The fact that added choline does not result in increased basal ACh shows that there are many systems of regulation—activity dependence, phosphorylation, plasma-brain-CSF exchange, choline uptake transporters, and recycling system—which make choline supplementation alone an inefficient and possibly ineffective means. This is where ALCAR comes in.
The Acetyl Moieity
This incredibly helpful graphic illustrates the course of the acetyl moieity (group) that ends up in acetyl-choline [8]:
The first enzyme (on the left) is Carnitine Acetyltransferase (CarAT), which transfers the acetyl group from ALCAR to acetyl-Coenzyme A (acetyl-CoA). Then the enzyme Choline Acetyltransferase (ChAT) transfers the acetyl group to choline to yield ACh. (This process has been demonstrated in slices of rat brains [8, 11, 23], and proposed by several others who could not construct the proper experimental system to demonstrate all of the effects [22-23]).
So, how might increasing availability of the acetyl moeity help us? The answer is in the equilibria of the coupled enzyme reaction above. The CarAT reaction has equilibrium near unity [9-10]; this means that it will utilize about half of any added substrates (ALCAR) to synthesize new products (acetyl-CoA). However, the equilibrium of the ChAT reaction is greatly in favor of the products (Keq of 12.3 [26] or 13.3 [27]); the vast majority of an added substrate will be converted into ACh. In other words, provided that CoA and choline are available, ALCAR should have a dose-dependent impact on amount of acetylcholine produced. (see Acetylcholine Release, below)
(It is worth noting that CarAT is able to acetylate choline directly [36], but with a very low affinity. It is speculated that it plays virtually no role in brain ACh biosynthesis [15]. However, it has been shown to account for up to half of ACh production in some muscular models [56-59], so a possible role in the brain cannot be discounted.)
Other enzymes and substrates are also responsible for the synthesis of acetyl-CoA, and are responsible for a greater amount than is contributed by ALCAR [11, 18-21]. The substrate which makes the largest contribution to the acetyl-CoA pool is pyruvate [12-13] (a metabolite of glucose), which is converted to acetyl-CoA by pyruvate dehydrogenase (PDC) in the mitochondrial matrix [11] (though PDC may exist extra-mitochondrially [14]). Glucose is slightly less preferred as a source, presumably because it must first be converted to pyruvate. Citrate and acetate play a role, though much less than pyruvate or glucose. ALCAR is preferred about 66% as much as glucose in this rat brain model [11]:
An important point is that ALCAR does not compete with glucose [8] or pyruvate [23] in relative contribution to final ACh production. This means that, even in abnormally high concentrations, ALCAR and other acetyl-CoA substrates still maintain an individual dose-response relationship. This is because the enzymes CarAT and ChAT have a very large amount of excess capacity at the physiological concentrations of their respective substrates, and so are far from saturation [8, 15].
The CarAT reaction has an equilibrium constant near unity [9-10], but is also reversible [29]; this reversibility means that ALCAR may be produced if acetyl-CoA and L-carnitine are in excess (in a certain area). Some of these other substrates (esp. pyruvate) are converted to acetyl-CoA inside the mitochondrial matrix [11]. CarAT itself is a membrane-bound enzyme, probably active at both inner and outer mitochondrial membrane sites [30-32]. One hypothesis is that, since carnitine is able to "shuttle" acetyl groups through the membrane [16-17, 30-35], ALCAR is used to transfer the acetyl groups from mitochondrial pyruvate-derived acetyl-CoA to the cellular cytoplasm, where it can be utilized by ChAT [8, 15]. (CoA and acetyl-CoA are able to pass the mitochondrial membrane directly in the presence of Ca2+ ions, but the required ion concentration is higher than has been demonstrated as possible in intact nerve cells [15, 37-40]). Thus, in addition to providing the acetyl moieity directly, ALCAR/carnitine may also serve as a carrier molecule to bring acetyl-CoA from other substrates, into the cytoplasm.
Glucose
ALCAR also increases the utilization of glucose in the brain [22, 60], probably by stimulating non-oxidative pyruvate dehydrogenase activity [66, 68], which effectively increases the amount of ACh synthesized from glucose/pyruvate [66]. Utilization increases to varying extents in different regions, and increases more in the aged (who generally suffer from decreased glucose utilization) [62-63].
ALCAR is also able to increase the utilization of alternative energy sources like ketone bodies and lipid substrates [67, 69]; evidence also suggests that more ALCAR is taken up into the brain when levels of glucose are low [61].
It's also interesting that glucose and exogenous choline combine synergistically to increase ACh release [64], in a model of awake mice, when neither alone had much of an effect. While it isn't necessarily healthy to increase glucose intake, ALCAR's enhancement of glucose utilization (theoretically resulting in the same thing: more acetyl-CoA) may result in something of the same synergy.
CoA Supplementation
In the above reactions, CoA is recycled continuously. It is tempting to attempt to increase the quantitiy of this substrate as well, to drive the CarAT reaction forward from another direction. A potential drawback exists, in that CoA is a potent inhibitor of the forward action of the ChAT enzyme [8, 36]. An elegant feature of the CarAT-ChAT enzyme loop is that, in synthesizing acetyl-CoA, levels of this inhibitory product are decreased, allowing an increase in ChAT activity.
It is unknown whether supplementation of pantothenic acid (B5) or pantethine, precursors of CoA, will increase acetyl-CoA more than they interfere with ChAT. Only one paper exists which demonstrates an increase in ACh due to B5 supplementation [55], but it may only be applicable to correcting ACh deficiency due to B5 deficit (see discussion here). From the anecdotal reports of pantethine use, it sounds like ACh is being increased, if anything. Clearly, more experimentation is required. However, I suggest that moderate doses should be used, as increasing the pool of unacetylated CoA will have a negative impact on ACh production [15]:
In Progress
Choline Uptake
Transport of choline into nerve terminals, where it is converted into acetylcholine by the aforementioned process, is carried out by high- and low-affinity choline transporters (CHT); high-affinity choline uptake (HACU) is responsible for most of this process under normal circumstances. ALCAR has been shown to increase the uptake of choline, though the mechanism is not fully understood; as the release of ACh from the terminal results in an influx of new choline, this alone is no doubt implicated to some degree.
Choline Acetyltransferase
Many studies demonstrate that ALCAR increases activity of this enzyme; indeed, this is the most obvious cholinergic mechanism mentioned in the relevant abstracts. However, this enzyme functions at the convergence of many cholinergic processes, making it difficult to ascertain the exact mechanisms responsible.
As ChAT is the enzyme necessary for synthesis of acetylcholine, any process increasing ACh production and release should concomitantly increase its activity. However, this doesn't rule out the possibility of a direct action on the enzyme. Nerve growth factor (NGF) has such a stimulatory effect on ChAT activity. To complicate this further, ALCAR interacts with NGF in several ways (see below), which may also increase its effect on ChAT in several ways. However, there is evidence to show that ALCAR increases ChAT activity in the absence of NGF, and that increased NGF levels do not necessarily elevate the enzyme activity.
ALCAR demonstrates the greatest efficacy in ameliorating age-related deficits in ChAT activity.
NGF
ALCAR has been shown to increase hippocampal levels of NGF. ALCAR also modulates the action of NGF by increasing the expression of its low-affinity receptor, p75-NGFR, and perhaps by acetylating some of NGF's amino acids. This has the effect of potentiating its action, by which much lower amounts produce the same neurotrophic effect. This effect feeds back into stimulation of ChAT, and greater ACh production.
ALCAR most effectively induces NGF activity in aged animals, who suffer a decrease in NGF activity in parallel with a cholinergic deficit.
ALCAR arginyl amide produces a direct neurotrophic effect on neurite outgrowth and cellular morphology. However, only two studies have been conducted, both by the manufacturer Sigma Tau, and it is unknown whether this putative effect translate to an in vivo efficacy.
Direct Action
ALCAR has a very slight direct agonistic effect on ACh receptors, but it is orders of magnitude smaller than that of the neurotransmitter; there is almost no chance that it plays any practical role.
Acetylcholine Release
Or, "the proof is in the pudding." An actual and significant increase in ACh levels has been shown in several studies, which demonstrates that these mechanisms actually do exert an influence.
Other neurological mechanisms
Dopamine: ALCAR ameliorates age-related decline in D2 receptor density, and induces release of vesicular dopamine in the corpus striatum of rats.
NMDA: Reduces age-related decrease in receptors, but increases receptor density by decreasing amounts in adult and young rats.
GABA: Increased the density of GABA-benzodiazepine (but not GABA-A) receptors in aged rats.
Calcium channel: Ameliorated age-related decrease in L-type voltage-gated Ca2+ channel receptors in the hippocampal membrane.
Glucocorticoid: Prevented age-related decrease in number of binding sites.
Neuroprotection: ALCAR inhibits increases in lipid hydroperoxidation, increases expression of NF-κB and mGlu2/3, inhibits ceramide generation, enhances histone acetylation, attenuates apoptosis, and protects against the neurotoxic effects of NMDA (in large doses), MPPP(+), NGF/BDNF/serum deprivation, and ischemia.
Adverse Effects
Anxiety: One study in rats showed that acute (i.e. single) doses of ALCAR were anxiogenic; this study also showed that in chronic administration, 10 and 100mg/kg had no effect on anxiety, while 50mg/kg was anxiolytic [85]. This is suggestive of a bell-shaped response curve, which is consistent with dose-reponse curve of other effects in the Ames studies.
Ultrastructure: One abstract mentions that ALCAR induced a decrease in axosomatic synapses in young rats, in contrast to ameliorated decreases in axosomatic synapses and giant synapsis vesicles in aged rats [86]. Without the full text, and knowledge of the dosage, ROA, and age of the "young" animals, it is difficult to predict whether this is cause for concern in human; though most studies use "young" as an age category quite separate from "adult."
References
Due to poor planning on my part, I didn't store the medline URLs in my reference list. I will work on linking these, but in the meantime, typing the title into google scholar is probably the easiest way to retrieve the abstract (clicking All Versions will call up the pubmed link).
1
Life Sci. 1981 Mar 9;28(10):1091-3.
Piracetam diminishes hippocampal acetylcholine levels in rats.
Wurtman RJ, Magil SG, Reinstein DK.
2
Clin Neuropharmacol. 1986;9 Suppl 3:S39-47.
Effect of oxiracetam and piracetam on central cholinergic mechanisms and active-avoidance acquisition.
Spignoli G, Pedata F, Giovannelli L, Banfi S, Moroni F, Pepeu G.
3
J Neurochem. 1982 Dec;39(6):1704-9.
Exogenous choline enhances the synthesis of acetylcholine only under conditions of increased cholinergic neuronal activity.
Trommer BA, Schmidt DE, Wecker L.
4
Neuropharmacology. 1981 Jun;20(6):535-9.
CNS effects of choline administration: evidence for temporal dependence.
Schmidt DE, Wecker L.
PMID: 7242873 [PubMed - indexed for MEDLINE]
5
Life Sci. 1996;58(22):1995-2002.
Elevation of cerebrospinal fluid choline levels by nicotinamide involves the enzymatic formation of N1-methylnicotinamide in brain tissue.
Vargas HM, Jenden DJ.
6
J Pharmacol Exp Ther. 1997 Sep;282(3):1139-45.
Acetylcholine release and choline availability in rat hippocampus: effects of exogenous choline and nicotinamide.
Köppen A, Klein J, Erb C, Löffelholz K.
7
Neurochem Int. 1995 Jun;26(6):635-41.
Effect of externally added carnitine on the synthesis of acetylcholine in rat cerebral cortex cells.
Wawrzeńczyk A, Nałecz KA, Nałecz MJ.
8
Neurochem Res. 1990 Jun;15(6):597-601.
Acetyl-L-carnitine as a precursor of acetylcholine.
White HL, Scates PW.
9
Neurochem Res. 1989 May;14(5):489-93.
Uptake of acetyl-L-carnitine in the brain.
Burlina AP, Sershen H, Debler EA, Lajtha A.
10
Biochem J. 1966 Apr;99(1):32-40.
Some kinetic studies on the mechanism of action of carnitine acetyltransferase.
Chase JF, Tubbs PK.
11
J Neurochem. 1981 Apr;36(4):1323-30.
Utilization of citrate, acetylcarnitine, acetate, pyruvate and glucose for the synthesis of acetylcholine in rat brain slices.
Dolezal V, Tucek S.
12
Biochem J. 1970 Jul;118(3):443-50.
A study on the precursors of the acetyl moiety of acetylcholine in brain slices. Observations on the compartmentalization of the acetyl-coenzyme A pool.
Nakamura R, Cheng SC, Naruse H.
13
Neurochem Int. 2008 Dec;53(6-8):193-8. Epub 2008 Jul 1.
High-affinity choline uptake and acetylcholine-metabolizing enzymes in CNS white matter. A quantitative study.
Hassel B, Solyga V, Lossius A.
14
Nature. 1978 Aug 3;274(5670):497-500.
Evidence for extramitochondrial pyruvate dehydrogenase involved in acetylcholine synthesis in nerve endings.
Lefresne P, Beaujouan JC, Glowinski J.
15
J Neurochem. 1985 Jan;44(1):11-24.
Regulation of acetylcholine synthesis in the brain.
Tucek S.
16
J Biol Chem. 1962 Dec;237:3628-32.
Carnitine in intermediary metabolism. The metabolism of fatty acid esters of carnitine by mitochondria.
BREMER J.
17
Adv Lipid Res. 1963;1:285-334.
CARNITINE AND ITS ROLE IN FATTY ACID METABOLISM.
FRITZ IB.
18
J Neurochem. 1968 Dec;15(12):1391-405.
(14C) acetylcholine synthesis by cortex slices of rat brain.
Browning ET, Schulman MP.
19
Biochim Biophys Acta. 1970 Jun;208(3):538-40.
Precursors of acetyl groups in acetylcholine in the brain in vivo.
Tucek S, Cheng SC.
20
J Neurochem. 1974 Jun;22(6):893-914.
Provenance of the acetyl group of acetylcholine and compartmentation of acetyl-CoA and Krebs cycle intermediates in the brain in vivo.
Tucek S, Cheng SC.
21
J Neurochem. 1973 Apr;20(4):1083-97.
Acetylcholine synthesis from (2- 14 C)pyruvate in rat striatal slices.
Lefresne P, Guyenet P, Glowinski J.
22
Biochem Pharmacol. 1980 Feb;29(2):167-74.
Studies on the metabolic pathway of the acetyl group for acetylcholine synthesis.
Gibson GE, Shimada M.
23
Biochimie. 1977;59(2):197-215.
Origin of the acetyl moiety of acetylcholine synthesized in rat striatal synaptosomes.
Lefresne P, Hamon M, Beaujouan JC, Glowinski J.
24
J Neurochem. 1980 Jul;35(1):249-54.
Acetyl-CoA synthesizing enzymes in cholinergic nerve terminals.
Sterri SH, Fonnum F.
25
Wecker L. (1990) Choline utilization by central cholinergic neurons. in Nutrition and the Brain, eds Wurtman R. J., Wurtman J. J. (Raven Press, New York), 8:147–162.
26
J Biol Chem. 1975 Jun 25;250(12):4445-50.
Equilibrium constants of the reactions of choline acetyltransferase, carnitine acetyltransferase, and acetylcholinesterase under physiological conditions.
Pieklik JR, Guynn RW.
27
J Biol Chem. 1982 Nov 10;257(21):12820-5.
Kinetic studies of the choline acetyltransferase reaction using isotope exchange at equilibrium.
Hersh LB.
28
J Neurosci Res. 1995 Jun 15;41(3):403-8.
Stimulation of choline acetyl transferase activity by l- and d-carnitine in brain areas of neonate rats.
Ayala CA.
29
J Biol Chem. 1962 Jul;237:2228-31.
Carnitine in intermediary metabolism. Reversible acetylation of carnitine by mitochondria.
BREMER J.
30
J Cell Sci. 1970 Jan;6(1):29-51.
Cytochemical localization of transferase activities: carnitine acetyltransferase.
Higgins JA, Barrnett RJ.
31
Am J Physiol. 1964 Mar;206:531-5.
EFFECTS OF CARNITINE ON ACETYL-COA OXIDATION BY HEART MUSCLE MITOCHONDRIA.
FRITZ IB, YUE KT.
32
Br Med Bull. 1968 May;24(2):158-64.
Membranes and fatty acid metabolism.
Tubbs PK, Garland PB.
33
Biochim Biophys Acta. 1963 Oct 8;78:77-84.
ACYL COENZYME A AS AN INTERMEDIATE IN THE MITOCHONDRIAL ACYLATION OF CARNITINE BY ALPHA-KETO ACIDS.
NORUM KR, BREMER J.
34
J Biol Chem. 1965 May;240:2188-92.
CARNITINE ACETYLTRANSFERASE. II. INHIBIITON BY CARNITINE ANALOGUES AND BY SULFHYDRYL REAGENTS.
FRITZ IB, SCHULTZ SK.
35
J Biol Chem. 1966 Sep 10;241(17):4092-7.
The role of carnitine and carnitine acyltransferase in biological acetylations and fatty acid synthesis.
Bressler R, Brendel K.
36
J Neurochem. 1973 Feb;20(2):297-307.
Kinetics of choline acetyltransferases (EC 2.3.1.6) from human and other mammalian central and peripheral nervous tissues.
White HL, Wu JC.
37
Biochem J. 1967 Sep;104(3):749-56.
The use of choline acetyltransferase for measuring the synthesis of acetyl-coenzyme A and its release from brain mitochondria.
Tucek S.
38
Science. 1981 Sep 25;213(4515):1495-7.
Acetylcholine synthesis in synaptosomes: mode of transfer of mitochondrial acetyl coenzyme A.
Benjamin AM, Quastel JH.
39
Can J Physiol Pharmacol. 1983 Feb;61(2):154-8.
Calcium-dependent release of acetyl-coenzyme A from liver mitochondria.
Benjamin AM, Murthy CR, Quastel JH.
40
Ritny J. and TuCek S. (1983) Ca2+ ions and the output of acetylcoenzyme
A from brain mitochondria. Gen. Physiol. Biophys. 2;27 - 37.
41
Pharmacol Rev. 1980 Dec;32(4):315-35.
Precursor control of neurotransmitter synthesis.
Wurtman RJ, Hefti F, Melamed E.
42
J Pharmacol Exp Ther. 1982 Feb;220(2):322-8.
Effects of phosphatidylcholine administration to rats on choline in blood and choline and acetylcholine in brain.
Jope RS.
43
J Neurochem. 1989 Feb;52(2):568-75.
Acute choline supplementation in vivo enhances acetylcholine synthesis in vitro when neurotransmitter release is increased by potassium.
Wecker L, Cawley G, Rothermel S.
44
J Neurochem. 1990 Oct;55(4):1231-6.
Small rises in plasma choline reverse the negative arteriovenous difference of brain choline.
Klein J, Köppen A, Löffelholz K.
45
J Neurochem. 1992 Mar;58(3):870-6.
Uptake and metabolism of choline by rat brain after acute choline administration.
Klein J, Köppen A, Löffelholz K, Schmitthenner J.
46
J Pharmacol Exp Ther. 1993 Aug;266(2):720-5.
Synergistic effect of nicotinamide and choline administration on extracellular choline levels in the brain.
Köppen A, Klein J, Holler T, Löffelholz K.
47
Prog Brain Res. 1993;98:197-200.
Choline, a precursor of acetylcholine and phospholipids in the brain.
Löffelholz K, Klein J, Köppen A.
48
J Neurochem. 1977 Jan;28(1):229-31.
Effects of oral choline administration on serum and CSF choline levels in patients with Huntington's disease.
Growdon JH, Cohen EL, Wurtman RJ.
PMID: 137960 [PubMed - indexed for MEDLINE]
49
Science. 1978 Jan 6;199(4324):86-7.
Choline administration: modification of the central actions of atropine.
Wecker L, Dettbarn WD, Schmidt DE.
50
Brain Res. 1980 Feb 17;184(1):234-8.
Neuropharmacological consequences of choline administration.
Wecker L, Schmidt DE.
51
Pharmacol Res Commun. 1977 Sep;9(8):755-61.
Effect of choline, phosphorylcholine and dimethylaminoethanol on brain acetylcholine level in the rat.
Pedata F, Wieraszko A, Pepeu G.
52
J Neurochem. 1979 Apr;32(4):1331-3.
Choline administration and acetylcholine in brain.
Flentge F, Van den Berg CJ.
53
J Neurochem. 1979 Mar;32(3):961-7.
Relationship between choline availability and acetylcholine synthesis in discrete regions of rat brain.
Wecker L, Dettbarn WD.
54
J Neurochem. 1982 Apr;38(4):1160-3.
Increase in exogenous choline fails to elevate the content or turnover rate of cortical, striatal, or hippocampal acetylcholine.
Brunello N, Cheney DL, Costa E.
55
Br J Pharmacol. 1988 Sep;95(1):77-82.
Effects of ethanol and pantothenic acid on brain acetylcholine synthesis.
Rivera-Calimlim L, Hartley D, Osterhout D.
56
J Physiol. 1982 Jan;322:53-69.
The synthesis of acetylcholine in skeletal muscles of the rat.
Tucek S.
57
J Physiol. 1982 Dec;333:189-99.
Free and bound acetylcholine in frog muscle.
Miledi R, Molenaar PC, Polak RL.
58
Pflugers Arch. 1982 Jan;392(3):225-9.
Choline acetyltransferase in the heart of adult rats.
Slavíková J, Tucek S.
59
J Physiol. 1983 Jan;334:461-74.
The synthesis and release of acetylcholine in normal and denervated rat diaphragms during incubation in vitro.
Dolezal V, Tucek S.
60
17 Thomitzek, W.D., Die Wirkung van Derivaten des (-) und (+) Acetylcarnitins auf die Bildung von
Acetylcholine, Biochem. Pharmacol., Conference Issue, 2nd Int. Pharmacol. Meeting (1963), S. 161.
61
Biochem Biophys Res Commun. 1997 Feb 13;231(2):488-93.
High uptake of [2-11C]acetyl-L-carnitine into the brain: a PET study.
Kuratsune H, Watanabe Y, Yamaguti K, Jacobsson G, Takahashi M, Machii T, Onoe H, Onoe K, Matsumura K, Valind S, Kitani T, Långström B.
62
Brain Res. 2002 Oct 4;951(2):330-5.
Effects of acetyl-L-carnitine on regional cerebral glucose metabolism in awake rats.
Ori C, Freo U, Pizzolato G, Dam M.
63
Brain Res. 2009 Mar 9;1259:32-9. Epub 2008 Dec 24.
Cerebral metabolic effects of acetyl-l-carnitine in rats during aging.
Freo U, Dam M, Ori C.
64
Neuroscience. 2001;103(2):365-71.
Glucose plus choline improve passive avoidance behaviour and increase hippocampal acetylcholine release in mice.
Kopf SR, Buchholzer ML, Hilgert M, Löffelholz K, Klein J.
65
Can J Physiol Pharmacol. 1997 May;75(5):423-30.
Decompensation of hepatic and cerebral acyl-CoA metabolism in BALB/cByJ mice by chronic riboflavin deficiency: restoration by acetyl-L-carnitine.
Rao KV, Qureshi IA.
66
J Mol Cell Cardiol. 1995 Nov;27(11):2465-72.
Stimulation of non-oxidative glucose utilization by L-carnitine in isolated myocytes.
Abdel-aleem S, Sayed-Ahmed M, Nada MA, Hendrickson SC, St Louis J, Lowe JE.
67
Brain Res. 1990 Aug 27;526(1):108-12.
Aging brain: effect of acetyl-L-carnitine treatment on rat brain energy and phospholipid metabolism. A study by 31P and 1H NMR spectroscopy.
Aureli T, Miccheli A, Ricciolini R, Di Cocco ME, Ramacci MT, Angelucci L, Ghirardi O, Conti F.
68
Brain Res. 1998 Jun 15;796(1-2):75-81.
Acetyl-L-carnitine modulates glucose metabolism and stimulates glycogen synthesis in rat brain.
Aureli T, Di Cocco ME, Puccetti C, Ricciolini R, Scalibastri M, Miccheli A, Manetti C, Conti F.
69
J Neurochem. 1998 Dec;71(6):2510-7.
Role of acetyl-L-carnitine in rat brain lipogenesis: implications for polyunsaturated fatty acid biosynthesis.
Ricciolini R, Scalibastri M, Kelleher JK, Carminati P, Calvani M, Arduini A.
70
Neurosci Lett. 2002 Sep 6;329(3):334-8.
Acetyl-L-carnitine shows neuroprotective and neurotrophic activity in primary culture of rat embryo motoneurons.
Bigini P, Larini S, Pasquali C, Muzio V, Mennini T.
71
Brain Res. 1995 Mar 13;674(1):142-6.
Spatial discrimination learning and choline acetyltransferase activity in streptozotocin-treated rats: effects of chronic treatment with acetyl-L-carnitine.
Prickaerts J, Blokland A, Honig W, Meng F, Jolles J.
72
J Neurosci Res. 1988 Aug;20(4):491-6.
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, Werrbach-Perez K, Perez-Polo R.
73
Brain Res. 1994 Jan 7;633(1-2):77-82.
Acetyl-L-carnitine treatment increases choline acetyltransferase activity and NGF levels in the CNS of adult rats following total fimbria-fornix transection.
Piovesan P, Pacifici L, Taglialatela G, Ramacci MT, Angelucci L.
74
Neuroscience. 1985 Jan;14(1):55-68.
Nerve growth factor increases choline acetyltransferase but not survival or fiber outgrowth of cultured fetal septal cholinergic neurons.
Hefti F, Hartikka J, Eckenstein F, Gnahn H, Heumann R, Schwab M.
75
Trends in Neurosciences Volume 9, 1986, Pages 570-573
The role of nerve growth factor in the CNS
Sigrun Korsching
76
Science. 1987 Sep 4;237(4819):1154-62.
The nerve growth factor 35 years later.
Levi-Montalcini R.
77
Ciba Found Symp. 1987;126:82-95.
Neurotrophic factors and neuronal death.
Thoenen H, Barde YA, Davies AM, Johnson JE.
78
Rizza V, Morale MC, Guarcello V, Guerrera F (1986): Effects of l-carnitine and acetyl-l-carnitine on lipid metabolism in rat brain. Biol Psych 1985. In: Chagass C, Josiassen RC, Bridger WH, Weiss KJ, Stoff D, Simpson GM (eds) “Developments in Psychiatry,” Volume 7, pp. 1346-1348.
79
Int J Dev Neurosci. 1992 Oct;10(5):361-73.
Effects of nerve growth factor and acetyl-L-carnitine arginyl amide on the human neuronal line HCN-1A.
Westlund KN, Lu Y, Werrbach-Perez K, Hulsebosch CE, Morgan B, Pizzo DP, Eisenberg HM, Perez-Polo JR.
80
Gynecol Oncol. 2009 Mar;112(3):631-6.
Effect of acetyl-l-carnitine on ovarian cancer cells' proliferation, nerve growth factor receptor (Trk-A and p75) expression, and the cytotoxic potential of paclitaxel and carboplatin.
Engle DB, Belisle JA, Gubbels JA, Petrie SE, Hutson PR, Kushner DM, Patankar MS.
81
J Neurosci Res. 2008 Sep;86(12):2705-21.
Hypoxia-induced deactivation of NGF-mediated ERK1/2 signaling in hippocampal cells: neuroprotection by acetyl-L-carnitine.
Barhwal K, Hota SK, Prasad D, Singh SB, Ilavazhagan G.
82
Neurochem Int. 2003 Aug;43(3):225-33.
Effect of PPF and ALCAR on the induction of NGF- and p75-mRNA and on APP processing in Tg2576 brain.
Chauhan NB, Siegel GJ.
83
Neurochem Res. 1995 Jan;20(1):1-9.
Neurite outgrowth in PC12 cells stimulated by acetyl-L-carnitine arginine amide.
Taglialatela G, Navarra D, Olivi A, Ramacci MT, Werrbach-Perez K, Perez-Polo JR, Angelucci L.
84
Biochem Pharmacol. 1992 Aug 4;44(3):577-85.
Stimulation of nerve growth factor receptors in PC12 by acetyl-L-carnitine.
Taglialatela G, Angelucci L, Ramacci MT, Werrbach-Perez K, Jackson GR, Perez-Polo JR.
85
Int J Neuropsychopharmacol. 2005 Mar;8(1):65-74. Epub 2004 Sep 22.
Effect of intraperitoneal acetyl-L-carnitine (ALCAR) on anxiety-like behaviours in rats.
Levine J, Kaplan Z, Pettegrew JW, McClure RJ, Gershon S, Buriakovsky I, Cohen H.
86
Drugs Exp Clin Res. 1987;13(3):185-9.
Ultrastructural aspects of ageing rat hippocampus and effects of L-acetyl-carnitine treatment.
Badiali de Giorgi L, Bonvicini F, Bianchi D, Bossoni G, Laschi R.
Revisions
v1.0 2010-08-26To do:
Update ChAT, NGF
