Acetyl-L-carnitine (ALCAR) contains carnitine and acetyl moieties, both of which have neurobiological properties. Carnitine is important in the β-oxidation of fatty acids and the acetyl moiety can be used to maintain acetyl-CoA levels. Other reported neurobiological effects of ALCAR include modulation of: (1) brain energy and phospholipid metabolism; (2) cellular macromolecules, including neurotrophic factors and neurohormones; (3) synaptic morphology; and (4) synaptic transmission of multiple neurotransmitters. Potential molecular mechanisms of ALCAR activity include: (1) acetylation of -NH2 and -OH functional groups in amino acids and N terminal amino acids in peptides and proteins resulting in modification of their structure, dynamics, function and turnover; and (2) acting as a molecular chaperone to larger molecules resulting in a change in the structure, molecular dynamics, and function of the larger molecule. ALCAR is reported in double-blind controlled studies to have beneficial effects in major depressive disorders and Alzheimer's disease (AD), both of which are highly prevalent in the geriatric population.
Carnitine (3-hydroxy-4-N-trimethylammoniobutanoate) (Figure 1) is present in biological cells and tissues in relatively high concentrations as either free carnitine or as acylcarnitines including acetyl-L-carnitine (ALCAR) (Figure 1). ALCAR induces many of its biological actions through the metabolic effects of its carnitine and acetyl moieties. Carnitine is important in the β-oxidation of fatty acids and the acetyl moiety can be used to maintain acetyl-CoA levels. In addition, the acetyl moiety of ALCAR can potentially be used to acetylate -NH2 and -OH functional groups in amino acids such as lysine, serine, threonine, tyrosine and N terminal amino acids in peptides and proteins, and possibly modify their structure, function, and turnover. ALCAR also has the potential to act as a molecular chaperone and interact with large molecules such as proteins and membrane lipids and change the conformation of the larger molecules and possibly alter their functional activity. The biological roles of ALCAR as a molecular chaperone and as an acetylating agent need more intense investigation.
Carnitine, a quaternary amine, is synthesized in vivo from lysine and methionine mainly in liver, kidney, and muscle with body stores mostly in skeletal and cardiac muscle.1 Exogenous carnitine (predominantly from meat and dairy products) is the source for about 75% of the body carnitines with an average non-vegetarian diet providing about 100–300 mg carnitine daily. Carnitine is absorbed readily from the GI tract by passive and active transport mechanisms. The liver receives carnitine via the portal system and subsequently releases it to the systemic circulation. Carnitine is taken up into cells by a stereospecific transport system resulting in a 10–100 fold gradient between intra and extracellular concentrations.2 Carnitine, a small, water-soluble molecule, readily diffuses through the renal glomerulus and 95% is reabsorbed to prevent renal loss.2
Acylcarnitines are synthesized by carnitine acyltransferases from acylCoA and carnitine. Carnitine induces fatty acid β-oxidation in the liver3, 4 and acylcarnitines are substrates for oxidation processes in mitochondria.5 A group of different acyltransferases catalyzes the formation of short-chain, medium-chain and long-chain acylcarnitines. The enzyme for short-chain acyl groups, carnitine acetyltransferase (MW approx. 70 kDa),6, 7 is located on the inner surface of the inner mitochondrial membrane (see Figure 2) and is also present in peroxisomes and microsomes.8 Carnitine acetyltransferase has a broad spectrum of substrates with maximal velocity for proprionylCoA followed by acetylCoA and butyrylCoA.9
ALCAR pharmacokinetics and brain uptake
ALCAR levels increase rapidly after i.v. administration (500 mg) to healthy volunteers declining to baseline after 12 h; carnitine levels increase more slowly, reach a peak in 30–60 min, and decline to baseline within 24 h.10 The measurements of mean renal clearance for both suggest saturable tubular reabsorption processes.
Parnetti et al11 studied the pharmacokinetics of oral and i.v. ALCAR administered to patients with senile dementia in a multiple dose regimen. Following i.v. bolus injection of 30 mg kg−1, plasma concentrations showed a biphasic curve with t½ of 0.073 h and 1.73 h, respectively. Oral treatment with 1.5 g daily for 50 days significantly increased both plasma and CSF ALCAR concentrations, suggesting that ALCAR penetrates the blood–brain barrier easily. ALCAR does not interact with either albumin or plasma proteins in rats, dogs, and humans.12
Kuratsune et al13 using 11C PET reported relatively high uptake of 11C labeled acetyl groups of ALCAR into brain of rhesus monkeys compared with 11C labeled N-methyl groups of either ALCAR or carnitine. This uptake was suppressed by i.v. administration of glucose. The authors suggested that endogenous serum acetyl-L-carnitine may have a role in transporting acetyl moieties into the brain, especially under conditions of metabolic stress.
Metabolic effects of ALCAR
Studies in humans and animals suggest ALCAR has a favorable role in restoring cerebral energy metabolism. First, ALCAR modulates glucose metabolism and stimulates glycogen synthesis in rats.14 Second, ALCAR increases plasma levels of adenosine and ATP,15 with the rise in adenosine levels preceding the rise in ATP. Third, ALCAR restores ammonia-induced depletion of brain energy stores in Sparse-fur mice which have elevated ammonia and glutamine levels.16 Fourth, ALCAR induces post-ischemic return of neurological function in a post cardiac arrest dog model via its effects on restoring aerobic brain metabolism.17 Fifth, the accumulation of carnitine and ALCAR in spermatozoa is correlated with progressive motility, suggesting that carnitine and ALCAR have importance in the maintenance of progressive motility which is dependent on efficient energy metabolism.18
The increase in adenosine levels before ATP after ALCAR administration suggests a role for ALCAR in the turnover of adenosine. Adenosine acts in a paracrine/autocrine manner to modulate cellular activity via specific membrane receptors19 and is an important mediator of cellular responses during cerebral ischemia and hypoxia.20 Adenosine, a metabolite of ATP, is produced from 5′-AMP by both cytoplasmic and ecto 5′-nucleotidases. S-adenosylhomocysteine hydrolase also produces adenosine and homocysteine by cleavage of 5′-adenosylhomocysteine, as well as using adenosine for 5′-adenosyl homocysteine synthesis. Adenosine can be converted to 5′-AMP by adenosine kinase and to inosine by adenosine deaminase. Studies in PC12 cells show that adenosine accumulates intra- and extracellularly during chronic hypoxia.21 The increase in adenosine appears to be due to a decrease in the enzymatic activities of adenosine deaminase and adenosine kinase with increases in enzymatic activities of both cytoplasmic and ecto 5′-nucleotidases. Kobayashi et al22 showed that adenosine inhibits membrane excitability in PC12 cells during hypoxia via the adenosine A2A receptors and Fredholm19 previously reported that adenosine receptors A1, A2A, A2B, and A3 were stimulated by increased levels of adenosine in the extracellular milieu during hypoxia. Therefore, ALCAR's ability to increase adenosine levels could have a protective effect in ischemia and hypoxia. ALCAR could potentially up-regulate the adenosine synthetic enzymes and/or down-regulate the degradative enzymes in order to increase adenosine levels. Whether ALCAR accomplishes this by interacting with or acetylating the enzymes is unknown.
We propose that beneficial effects of ALCAR on cerebral energy metabolism are mediated by ALCAR's role in supplying acetyl groups for the synthesis of acetyl-CoA which can enter the citric acid cycle. The acetyl groups could be supplied directly from ALCAR or indirectly through carnitine's role in β-oxidation of fatty acids (Figure 2). In addition, ALCAR's ability to increase adenosine levels could result in decreased membrane excitability which could have protective effects.
Hoppel23 suggested possible physiological roles of carnitine including: (1) involvement in β-oxidation of long chain fatty acids in mitochondria; (2) buffering mitochondrial acylCoA/CoA levels, probably by mass action as the system is near steady state equilibrium; (3) possible scavenger system for acyl groups; thus, when acylCoA accumulates in either tissues or mitochondria, carnitine acyltransferases catalyze its conversion to CoA and vice versa; and (4) intracellular transport of acyl groups such as the transport of acyl groups from peroxisomes to mitochondria for β-oxidation. All of these mechanisms involve lipid metabolism.
Fatty acid β-oxidation occurs mainly in the mitochondrial matrix. Activated long-chain fatty acids synthesized outside the mitochondrial inner membrane do not readily transverse this membrane, and a special transport system is needed. The activated fatty acids are first conjugated to carnitine to form an acylcarnitine by a reaction catalyzed by acyltransferase I bound to the outer side of the inner mitochondrial membrane. Acylcarnitine is then shuttled across the inner mitochondrial membrane via carnitine acylcarnitine translocase. The acyl group is transferred back to CoA on the matrix side of the membrane, by a reaction catalyzed by acyltransferase II. Finally, carnitine is transferred back to the outside of the inner mitochondrial membrane via carnitine acylcarnitine translocase in exchange for an incoming acylcarnitine (see Figure 2 for a schematic of the role of carnitine and ALCAR in the mitochondria). The acyl-CoA that is formed undergoes oxidative removal of successive two-carbon units in the form of acetyl-CoA starting at the carboxyl end of the fatty acid chain. For example, palmitoyl-CoA yields eight acetyl-CoA molecules. For each molecule of acetyl-CoA formed from fatty acid β-oxidation, a molecule of FADH2 and a molecule of NADH are formed. The acetyl-CoA produced is oxidized to CO2 in the citric acid cycle producing one GTP (or ATP) molecule, three NADH molecules, and one FADH2 molecule. The FADH2 and NADH produced are oxidized in the respiratory electron transfer chain with each NADH molecule generating three ATP molecules and each FADH2 molecule generating two ATP molecules. Therefore, each acetyl-CoA molecule produced by fatty acid β-oxidation can produce 17 ATP molecules. ALCAR also is produced from acetyl-CoA and carnitine by carnitine acetyltransferase. The activity of carnitine acylcarnitine translocase is regulated by the intra-mitochondrial carnitine content; increases of intra-mitochondrial carnitine increases the activity of this enzyme.24 Under conditions of impaired energy metabolism, such as fasting or experimental diabetes, carnitine levels increase in the mitochondrial matrix24 and carnitine acylcarnitine translocase activity increases. Thus, carnitine has a pivotal role in the transport of activated fatty acids for β-oxidation.
ALCAR's modulation of membranes
ALCAR administration alters mitochondrial inner membrane protein composition of rat cerebellum25 and significantly increases glycerophosphocholine levels in 6-month-old rats but slightly decreases glycerophosphocholine levels in 24-month-old rats.26 ALCAR also increases the membrane molecular dynamics of brain microsomes and liposomes produced from rat brain microsomal lipid extracts27 and carnitine partially shares this effect with ALCAR. Butterfield and Rangachari28 showed that ALCAR increases membrane cytoskeletal protein–protein interactions, but no change in lipid order or molecular dynamics could be demonstrated. Since carnitine was reported to exert the same effect, these authors suggested that the acetyl group of ALCAR is not hydrophobic enough to direct ALCAR to the bilayer phase of the membrane. ALCAR increases membrane stability, possibly by interacting with cytoskeletal proteins and altering cell membrane dynamics in the region close to the glycerol backbone of the phospholipid bilayer; this could be relevant for the modulation of membrane function.29 Paradies et al30 reported that ALCAR treatment restored mitochondrial cardiolipin levels and the activity of the mitochondrial phosphate carrier. All these data demonstrate that ALCAR has membrane-modifying effects. Some of these biological effects of ALCAR could be due to a physical-chemical mechanism and some of the effects could be secondary to the acetylation of proteins, such as cytoskeletal proteins.
ALCAR's modulation of proteins and peptides
Acetylation of proteins
ALCAR is a potentially important biological acetylating agent which could modify protein structure and activity by acetylating -NH2 and -OH functional groups in amino acids such as lysine, serine, threonine, tyrosine and N terminal amino acids. The potential for ALCAR to participate in transacetylation reactions is understandable given the free energy of hydrolysis of the acetyl bond of several biologically important acetyl esters and ATP (Δ G° (Kcal mol−1) at pH 7.0 and 38°C): ALCAR, −8.20;31 acetylcholine, −6.99;31 acetylCoA, −8.54;31 and ATP (terminal PO4), −7.60.32, 33 Therefore, ALCAR has a higher potential for group transfer than either acetylcholine or the terminal phosphate of ATP, and ALCAR's participation in biologically important transacetylation reactions appears likely. An example is ALCAR's ability to acetylate lysine 28 of the Aβ peptide of β-amyloid (M Calvani, Sigma Tau Pharmaceuticals, personal communication). The acetylation of lysine 28 inhibits the peptide from forming a β-turn34 and the β-turn is considered essential in forming potentially toxic β-sheet aggregates of β-amyloid (Figure 3). In PC12 cells, ALCAR increases the acetylated form of microtubules which are more stable than the unacetylated forms and protects the cells against apoptosis. This stabilization effect during ‘sprouting’ of neurites in PC12 cells may facilitate neurite formation.35 In PC12 cells ALCAR (1 mM) significantly increases the levels of acetylated histone H4 and in synergism with low doses of nerve growth factor (NGF) (1 ng ml−1) up-regulates the expression of NGF1-A neuronal specific transcriptional factor. A recent study demonstrated that ALCAR can acetylate α crystallin.36 Acetylating α crystallin results in decreased glycation of α crystallin. The glycated form of α crystallin appears to contribute to cataract formation. Other proteins also could be candidates for acetylation by ALCAR with a resultant change in peptide or protein structure and function. There is strong evidence demonstrating that acetylation of lysine residues in cytochrome P450 inhibits the electrostatic interaction of P450 with NADPH-cytochrome P450 reductase.37, 38 Recent studies show that ALCAR pretreatment ameliorates (−)nicotine-induced changes in membrane phospholipid metabolism and in particular leads to decreased levels of phosphatidylethanolamine plasmalogen and increased levels of phosphatidylethanolamine (Pettegrew et al, unpublished observation). A possible explanation for this ALCAR-induced change in membrane phospholipid composition could be inhibition of cytochrome b5 (which is involved in phosphatidylethanolamine-plasmalogen synthesis) by acetylation of one or more of the six lysine residues found in cytochrome b5.39 Many transmembrane proteins which function as receptors and ion channels are anchored to the membrane in part by a charged polylysine ‘washer’ on the cytoplasmic side of the membrane. It is plausible to suggest that ALCAR could acetylate these lysines and secondarily modulate the function of the protein by: (1) changing the portion of protein exposed to the extracellular space; (2) modulating the turnover of the protein by increasing the exposure of the protein to extracellular proteases; or (3) increasing the secretion of the protein.
Modulating the activity of NGF
NGF profoundly affects neuronal development and maintains neuronal differentiated states in various peripheral and central nervous system neurons. ALCAR-treated aged rats have improvement of age-related reduction in NGF-binding capacity found in hippocampus and basal forebrain areas40 and ALCAR increases choline acetyltransferase activity and NGF receptor expression in the developing rat striatum.41 Taglialatela et al42 reported that ALCAR: (1) enhances the response of PC12 cells to NGF suggesting that ALCAR may increase the response of aged neurons to neurotrophic factors within the CNS; (2) stimulates NGF receptors and neurite growth in PC12 cells;43, 44 and (3) increases NGF levels and choline acetyltransferase activity in rat CNS.45 Piovesan et al46 demonstrated that ALCAR increases choline acetyltransferase activity and NGF levels in the CNS of adult rats pretreated by total fimbria-fornix transection; these animals exhibit impairment of cholinergic activity similar to that seen during senescence. Taglialatela et al47 also reported that ALCAR improves spatial memory performance in aged rats with decreased intermediate performance associated with reduction of NGF levels in the basal forebrain, suggesting a non linear relationship between spatial memory performance and basal forebrain NGF levels. Together, these data suggest that ALCAR modulates the activity of NGF. It is not known if ALCAR's biological effects are due to its ability to acetylate one or more amino acids of NGF (eight lysine residues),48 by binding to NGF, by increasing NGF gene transcription/translation possibly by acetylation of histones or by a combination of these effects.
Modulating enzymatic activity
ALCAR induces post-ischemic return of neurological function in a post cardiac arrest dog model and this effect is suggested to be due to inhibition of post cardiac arrest oxidative injury to a variety of enzymes and other proteins.49 Gorini et al50 demonstrated that treatment with ALCAR decreased citrate synthase and glutamine dehydrogenase activities, and increased cytochrome oxidase and α-ketoglutarate dehydrogenase activities in intrasynaptic but not in non-synaptic mitochondria from rat cerebral cortex. ALCAR treatment increased the activity of acetylcholinesterase in synaptic plasma membranes from rat frontal cerebral cortex of 8-month-old rats51 and attenuated streptozotocin-induced decrease in hippocampal choline acetyltransferase activity.52 ALCAR increases particulate protein kinase C activity in the cortex both in vitro and in vivo in doses effective in improving spatial task learning in rats53 and subchronic administration of ALCAR enhances receptor-stimulated adenylate cyclase activity in young and aged rats.54 Villa and Gorini55 measured several mitochondrial enzyme activities and reported that in vivo administration of ALCAR decreased enzyme activities related to the Krebs cycle (ie, citrate synthase) mainly of synaptic mitochondria, suggesting a specific subcellular site of action, while it increased cytochrome oxidase activity of both synaptic and non-synaptic mitochondria. These data suggest that ALCAR has modulatory effects on a broad spectrum of mitochondrial and other intracellular enzymes, which can alter a number of intracellular reactions. Again, the mechanism responsible for ALCAR's action is unknown, but direct physiochemical interaction and protein acetylation are two possible mechanisms that need further study.
Most of the enzymes mentioned above, whose activity are altered by ALCAR, contain lysine amino acid residues that might be acetylated by ALCAR. Citrate synthase contains 14 lysine residues.56 When the positive charge on Lys 219 (exposed to aqueous solution on the membrane surface) of the C-terminal domain of cytochrome C oxidase is removed, the reaction rate is increased.57 αKetoglutarate dihydrogenase contains three lysines in the lipoyl domain and Lys 43 is the lysine that becomes lipoylated, located at the tip of an exposed β-turn. Acetylcholinesterase58 and choline acetyltransferase59 also contain lysines. Protein kinase C is synergistically activated by phosphatidylserine which binds to a lysine-rich cluster in the C2 domain.60 Lysine 938 of adenyl cyclase may be involved in a conformational transition subsequent to ATP binding and thus affect the conversion of ATP to cAMP.61 Many of the enzymes affected by ALCAR have lysine residues that are implicated in their activity and thus acetylation of lysine residues by ALCAR is a possible mechanism for ALCAR modulatory effects on these enzymes.
ALCAR's ability to acetylate -OH groups such as those on serine, threonine, and tyrosine could modulate protein structure and activity by removing those groups from potential phosphorylation by protein kinases. This could add another level of control over protein conformation and function with implications for disease states. For example, recent studies show the protein kinase Cdk5 is deregulated in Alzheimer's disease (AD),62 perhaps contributing to the increased phosphorylation of tau protein with subsequent aggregation of hyperphosphorylated tau into paired helical filaments. If these -OH groups could be blocked from phosphorylation, perhaps by acetylation by ALCAR, the production of paired helical filaments could be reduced.
Modulating hormonal activity
ALCAR affects the brain HPA axis and has a role in preventing pathological brain deterioration in stressful conditions.63 When administered to old rats, ALCAR improved regulation of the HPA axis and maintenance of glucocorticoid competence by the hippocampus. This was associated with improvement in acquiring passive avoidance behavior and reduced deposition of aging pigment.64 Costa et al65 studied the effect of ALCAR (20 mg kg−1 day−1 for 2 weeks) and piracetam treatment in 24 demented patients and found that ALCAR but not piracetam normalized the hyperfunctioning pituitary by lowering high cortisone and β-endorphin levels. This effect of ALCAR was associated with improved attention and verbal memory functions. ALCAR treatment attenuated the age-dependent increase of cold water swimming in rats, possibly by retarding the hippocampal glucocorticoid receptors loss needed to exert negative feedback control over HPA axis activity.66 These data suggest that ALCAR has regulatory effects on the HPA axis. De Simone and Calvani67 found that ALCAR treatment increased TSH levels in four HIV-positive subjects. ALCAR modulates melatonin secretion in both adult and old rats suggesting that ALCAR can modify noradrenergic neurotransmission and signal transduction in the pineal gland.68, 69 ALCAR added to perfused cultured hypothalamic cells and GTI-1 neuronal cells increases the pulsatile secretion of gonadotropin-releasing hormone by these cell cultures70 and prevents the decrease in plasma testosterone induced by a chronic swim test in rats.71 Krsmanovic et al72 reported increased gonadotropin release by ALCAR in a rat model attributing it to enhancement of GnRH neuronal function in the hypothalamus. Together, these data suggest that ALCAR can modulate the activity of hormonal systems and their regulating peptides.
ALCAR's modulation of gene expression
Taglialatela et al43 showed that ALCAR stimulates the production of NGF receptors in pheochromocytoma (PC12) cells and increases NGF receptor mRNA levels. ALCAR also has a neuromodulatory influence on neuronal phenotype during early embryogenesis in the chick embryo.73 ALCAR was administrated in ovo during embryonic days 1–3 and expression of cholinergic and GABAergic neuronal phenotypes was examined at day 8 using acetyltransferase and glutamic acid decarboxylase as markers. Alterations in the expression of these markers in cerebral hemispheres and diencephalon-midbrain-brainstem areas were observed following ALCAR treatment. ALCAR and butyrate were demonstrated by Pomponi and Neri74 to inhibit the cytogenetic expression of fragile X in vitro probably by acetylating and thus modifying histones regulating the chromatin complex. Pisano et al35 reported that ALCAR partially suppressed fragmentation of genomic DNA in PC12 cell culture induced to undergo apoptosis by deprivation of serum and NGF. ALCAR levels also are relatively high in the cellular nucleus and rise even higher during the earliest stages of cellular differentiation. All of these findings suggest an effect of ALCAR on gene activity which possibly could be related to acetylation of histones.
ALCAR's modulation of synaptic morphology and transmission
The developing and aging brain provides models to study the effects of various drugs on neuronal functioning. ALCAR has a neuromodulatory effect on neuronal cholinergic and GABAergic phenotypes during early embryogenesis in the chick embryo.73 In the aging rodent brain, ALCAR also has beneficial effects on receptor systems. ALCAR restores synaptic patterns, including the number of axosomatic synapses of granule cells and the number of synaptic vesicles in rat hippocampal giant synapses75 and chronic ALCAR treatment has a positive modulation on hippocampal synaptic structural dynamics, including the number of synapses, synaptic densities, and synaptic average area.76, 77 ALCAR also affects cholinergic transmission. ALCAR increases choline uptake into nerve terminals,78, 79 which would increase acetylcholine synthesis. ALCAR was shown to improve visual memory and attention in Down syndrome subjects80 suggesting that ALCAR might have cholinomimetic activity which contributed to the beneficial effect. Acetylcholinesterase activity in synaptic plasma membranes of 8-month-old rats is increased by ALCAR51 and in Sparse-fur mutant mice ALCAR treatment restores choline acetyltransferase activity levels and elevates β-NGF levels.81 ALCAR restores choline acetyltransferase activity in the hippocampus of rats with partial unilateral fimbria-fornix transection which produces degeneration of cholinergic pathways.82 Prickaerts et al83 demonstrated that chronic ALCAR administration to streptozotocin-treated rats attenuated choline acetyltransferase activity and the spatial memory impairment of these rats, and Taglialatela et al40 reported that ALCAR treatment increases choline acetyltransferase activity in the CNS system of aged rats and this was associated with increased NGF levels. ALCAR can counteract the age-dependent reduction of several CNS receptor systems, including NMDA receptors, NGF receptors, and glucocorticoid receptors84 and ALCAR prevents age-related NMDA receptor loss in hippocampus, striatum, and frontal cortex of rats.85 ALCAR releases dopamine in rat corpus striatum by a calcium-dependent exocytotic process86 and enhances acetylcholine release in the striatum and hippocampus of awake freely moving rats.87 Sershen et al88 demonstrated that ALCAR attenuates age-related changes in dopaminergic systems in rats and ALCAR, as well as carnitine, was reported to be a stereospecific neuroactive compound with cholinomimetic activity.89 ALCAR given to rats for 4 days elevates substantia nigra levels of GABA but not striatal dopamine.90 ALCAR ionophoretic administration on single neurons of the rat medullary-pontine reticular formation increases glutamate spontaneous and evoked firing and potentiated cholinergic and serotoninergic transmission, but has no effect on GABAergic and noradrenergic transmission.91 ALCAR administered subchronically enhances adenylate cyclase response to acetylcholine, norepinephrine, and dopamine in rat frontal cortex without affecting basal adenylate cyclase activity.54 ALCAR administered via microdialysis at different brain sites induces the release of amino acids, especially aspartate, glutamate and taurine in a concentration-dependent and regionally heterogenous manner92 and ALCAR lessens the reduction of taurine in old rats.88 In summary, ALCAR appears to have a neuromodulatory effect on synaptic morphology as well as on synaptic transmission in multiple neurotransmitter systems.
ALCAR's protection of brain tissue against neurotoxins
ALCAR can restore the thalamo-cortical system in rats prenatally exposed to ethanol93 and has a protective effect in rats injected i.c.v. with MPP+ solution.94 However, ALCAR did not have any normalizing effect on catecholamine concentrations, tyrosine hydroxylase, neurofilament or glial fibrillary acid protein, suggesting the ALCAR protective action could be related to energy metabolism and not to effects on dopaminergic systems. Forloni et al95 reported that ALCAR reduces the mortality in rat brain cell cultures after exposure to neurotoxic stimuli including NMDA and Aβ(25–35) peptide and ALCAR can inhibit cell apoptosis and retard DNA fragmentation and nuclear condensation in a teratocarcinoma cell line in which apoptosis was induced by serum deprivation.96 Although this last study was done in a non-brain tissue, it may indicate that ALCAR could have similar effects in CNS tissue. In general, these data suggest that ALCAR provides a protective effect against a variety of neurotoxins.
ALCAR's neuroprotection effect on aging processes and related disorders
Animal aging studies
ALCAR was reported to ameliorate the spatial memory performance of rats exposed to neonatal anoxia.97 Taglialatela et al47 reported improvement of spatial memory in aged rats could be achieved only in intermediate but not in good or poor classes of spatial learning performance. Caprioli et al98 reported that improvement could be achieved for novel but not for familiar environments. Since the improvement was not global, ALCAR might affect specific neuronal systems leading to specific types of improvement. ALCAR attenuates the decrease in hippocampal choline acetyltransferase activity following i.c.v. administration of streptozotocin which inhibits glucose utilization.52 The anti- amnesic effect of ALCAR is associated with an activating effect on protein kinase activity.53
Human AD studies
Three parallel design placebo-controlled studies of ALCAR in AD have been reported; each studied the possible effect of ALCAR vs placebo in preventing the deterioration associated with this disease over a period of 1 year.
Spangioli et al99 conducted a multi-center study of 130 patients with probable AD. Family history of dementia was not given for the patients. Sixty-three patients were randomized to ALCAR treatment (2 g daily) and 67 to placebo. The mean age for both groups was approximately 75 and 66–75% of the subjects in each group were women. Fourteen outcome measures were employed to assess function and cognitive impairment. After 1 year, both placebo and ALCAR groups deteriorated; however, the ALCAR group deteriorated significantly less than the placebo group in 13 out of 14 outcome measures. For example, with placebo treatment the mean ± SD score in Raven's matrices was reduced from 5.6 ± 3.9 to 3.8 ± 3.7 (mean delta of 1.8), and in the ALCAR group this measure was reduced from 6.7 ± 4.8 to 6.3 ± 4.7 (mean delta of 0.4), demonstrating less deterioration in the ALCAR group (P = 0.01). Similarly, the Verbal Judgement and Mental Calculation Test scores with placebo treatment were reduced from mean ± SD 25.8 ± 12.0 to 20.4 ± 14.3 (mean delta of 5.4), and for the ALCAR-treated group was reduced from 28.5 ± 14.0 to 26.8 ± 14.4 (mean delta of 1.7), showing less deterioration (P = 0.02) than the placebo group.
Pettegrew et al100 conducted a 31P-MRS double-blind, placebo-controlled study of ALCAR in 12 patients with probable AD. Five patients were treated for 1 year with placebo (one male, four females; age 64.2 ± 2.6; 13.4 ± 1.6 years of education (mean ± SEM)) and seven patients were treated for 1 year with ALCAR (3 g daily) (three males, four females, age 70.7 ± 3.3; 11.4 ± 0.9 years of education). The AD subjects were compared with 21 controls (11 males, 10 females; 70.5 ± 1.3 years; 14.8 ± 0.6 years of education). There was no significant difference in age or years of education between the ALCAR, placebo, and control groups. Two of the ALCAR and three of the placebo subjects had a family history for dementia. Apolipoprotein E (apoE) genotyping was not available at the time of the study. Alzheimer's disease and assessment scale—cognitive subscale (ADAS-Cog, patient is the information source) and Mini Mental Status (MMS) scales were used to assess the patients’ deterioration after 6 and 12 months of treatment. At entry, the MMS score of the ALCAR group was 18.4 ± 0.8, that of the placebo group was 18.0 ± 0.8, and that of the controls was 29.0 ± 0.3. The ADAS-cog score at entry was 22.1 ± 3.0 for the ALCAR group and 21.3 ± 2.7 for the placebo group. On the whole, ALCAR was found to be superior to placebo at 6 (P = 0.01) and 12 months (P = 0.01). MMS was not significantly different at 12 months from entry for the ALCAR group (P = 0.56), but the placebo group showed significant deterioration at 12 months from entry (P = 0.03). ADAS-cog was not significantly different at 6 months compared to entry for the ALCAR group (P = 0.64), but the placebo group showed a statistically significant deterioration (P = 0.01). Three of the placebo and two of the ALCAR-treated subjects had a family history of dementia. Over the 12 months of follow-up, the placebo-treated subjects with a family history of dementia had a decrease in MMS score of 1.66, compared with a mean decrease of 1.0 for the ALCAR-treated subjects (P = NS) and an increase in ADAS-Cog score of 8.3, compared with an increase of 0.16 for the ALCAR-treated subjects (P = 0.06). Therefore, even in those subjects with a family history of dementia the cognitive decline in the ALCAR-treated subjects appeared slowed compared with the placebo-treated subjects. ALCAR was found to increase brain phosphomonoester levels at 6 months compared to entry (P = 0.03) and to increase levels of ionized ends (α-ATP) at 6 months (P = 0.04) and phosphocreatine at 12 months (P = 0.005). The clinical effects of ALCAR were therefore associated with improvement in brain measures of membrane phospholipid and high-energy phosphate metabolism.
Thal et al101 conducted a multi-center study of ALCAR treatment for probable AD patients. This was a 1-year parallel randomized, placebo-controlled, double-blind study of 431 patients age 50 and above at entry, 340 completed the study. The ALCAR and placebo groups were matched for age, MMS, ADAS, and level of education at entry. ApoE genotyping was not performed on these subjects and family history of dementia was not given. Demographic data were presented for 419 subjects consisting of a group of intention to treat—last observation carried forward. Of these, 212 patients (43% male; age 71 ± 8) were randomized to placebo treatment and 207 patients (45% male; age 72 ± 7) were randomized to ALCAR treatment (3 g daily). Each treatment was given for 1 year. Outcome measures included the ADAS, MMSE, and Washington University Clinical Dementia Rating Scale (CDR). No difference was noted between the two groups as a whole. However, a group of patients below 65 years showed a trend for less deterioration with ALCAR treatment compared with placebo in ADAS-Cog scores (P = 0.11) and CDR scores (P = 0.056). With placebo treatment ADAS-Cog scores (mean ± SD) increased from 26 ± 11 to 35 ± 14 (mean delta = 9) and with ALCAR treatment this measure increased from 28 ± 11 to 35 ± 16 (mean delta = 7). This relatively younger group of patients also demonstrated an increase of CDR scores (mean ± SD) from 6.2 ± 3 to 9.5 ± 4 (mean delta = 3.2) with placebo; the CDR scores for the ALCAR-treated group increased from 6.1 ± 2 to 8 ± 4 (mean delta = 1.9), demonstrating less deterioration compared with placebo. Brooks et al102 reanalyzed the results of Thal et al101 for completers and reported that both ALCAR and placebo demonstrate the same rate of change in ADAS scores (0.68 points per month). However, multiple regression analysis of the data showed significant age × drug interaction characterized by younger subjects benefitting more from ALCAR treatment compared with older subjects. Further analysis suggested that the optimal cutoff point for ALCAR benefit may be 61 years of age.
On the whole, these studies suggest that ALCAR could have a therapeutic effect in decreasing the deterioration associated with AD. ALCAR treatment could be more beneficial in presenile AD than in senile AD. Regrettably, Thal et al101 did not report whether there was a statistically significant difference between the different centers participating in the study which could explain the lack of ALCAR superiority to placebo in the whole group of subjects.
For comparison, several studies have investigated the effects of cholinesterase inhibitors in AD. Tacrine, a cholinesterase inhibitor frequently used in the treatment of AD patients, was also reported to demonstrate positive103 as well as negative104 results in well controlled studies. In a meta analysis Qizilbash et al105 suggested that tacrine: (1) is mainly effective in reducing deterioration in the first 3 months of illness; (2) seems to have no effect on behavioral disturbances; and (3) that functional neuroanatomy seems to be not significantly affected.
Another cholinesterase inhibitor, rivastigmine, was examined by Rosler et al106 in a prospective, randomized, multi-center, double-blind, placebo-controlled, parallel group trial in which AD patients received either placebo or rivastigmine. Family history of dementia and apoE genotype data were not presented. Rivastigmine doses were increased in one of two fixed dose ranges (1–4 mg day−1 or 6–12 mg day−1) over the first 12 weeks with a subsequent assessment period of 14 weeks for a total study time of 26 weeks. Outcome measures were: (1) ADAS-Cog; (2) global function determined by clinician interview of patient and caregiver and; (3) a progressive deterioration scale based on activities of daily living with the caregiver as the information source. At the end of 26 weeks, compared with placebo, AD patients on 6–12 mg day−1 of rivastigmine had improvement in: (1) ADAS-cognitive scores (24% vs 16%, P < 0.05); (2) global function (37% vs 20%, P < 0.001); and (3) progressive deterioration scale (49% vs 39%, P = 0.04). Adverse events (mainly gastrointestinal) were reported in 23% of AD patients treated with 6–12 mg day−1 of rivastigmine, 7% treated with 1–4 mg day−1, and 7% of the patients on placebo.
A 24-week, double-blind, placebo-controlled trial of donepezil in 473 AD patients was reported by Rogers et al.107 No family history of dementia or apoE genotype data were given. Patients were randomly assigned to treatment with placebo (n = 162), 5 mg day−1 donezipil (n = 154), or 10 mg day−1 donezipil (n = 157) for 24 weeks followed by a 6-week, single-blind placebo washout. For the 10 mg day−1 donepezil group a blinded forced titration scheme was used in which subjects received 5 mg day−1 donepezil for the first week and then 10 mg day−1 for the remainder of the study. The donepezil 10 mg day−1 group (74.6 ± 0.64 years (mean ± SEM) was older than the placebo group (72.6 ± 0.6 years) (P = 0.03). Primary efficacy measures were the ADAS-cog and the Clinician's Interview Based Assessment of Change-Plus (CIBIC-plus) with the MMS, Clinical Dementia Rating Scale-Sum of the Boxes (CDR-SB), and patient-rated Quality of Life (QoL) used as secondary measures. Evaluations were at baseline, 6, 12, 18, and 24 weeks, and after 6 weeks of washout (30 weeks). Results for the ADAS-cog revealed that the placebo and donepezil groups all improved at 6 weeks followed by steady worsening in the placebo group and slight worsening in both donepezil groups compared with baseline. Compared with the placebo group, the ADAS-cog scores were significantly better for both donepezil groups at 12 weeks (5 mg day−1, P = 0.0007; 10 mg day−1, P = 0.0012), 18 weeks (5 mg day−1, P = 0.0012; 10 mg day−1, P < 0.0001), and 24 weeks (5 mg day−1, P < 0.0001; 10 mg day−1, P < 0.0001). In total, the ADAS-cog scores appear to deteriorate at a slower rate in the donepezil groups over the 24 weeks of follow-up. However, after 6 weeks of placebo washout (week 30) the values of ADAS-cog, for the placebo and two donepezil dosage groups were indistinguishable. Similar patterns of findings were observed for the MMS, CIBIC, and CDR-SB results. There were no observed differences in QoL measures among the placebo and donepezil groups at any time points. These results suggest that donepezil is primarily slowing symptoms associated with AD and not any underlying pathophysiological mechanism since after 6 weeks of placebo washout, the placebo and donepezil groups are clinically indistinguishable. Compared with the placebo group, the 10 mg day−1 donepezil group had significantly higher numbers of treatment-emergent signs and symptoms such as diarrhea (17%, P ≤ 0.05), nausea (17%, P ≤ 0.05), and vomiting (10%, P ≤ 0.05).
It is of interest that the percentage of AD patients who clinically improved on 6–12 mg day−1 of rivastigmine (24%) was very similar to the percentage who reported adverse gastrointestinal events (23%) and there was a significant difference in the number of gastrointestinal side effects between placebo and 10 mg day−1 donepezil (P ≤ 0.05). It should be pointed out that it is very difficult to conduct a double-blind trial of a cholinesterase inhibitor given the clinical side effects of these drugs, ie, the patient could know when they are on active drug because of the side effects. These and other concerns about study design of cholinesterase inhibitors have been pointed out by van Gool108 and Bayer.109
Interestingly, Farlow et al110 reported that the treatment outcome of tacrine depends on the apolipoprotein genotype and gender of the subjects with AD. And even the Thal et al101 study found that ALCAR was more beneficial in a subgroup of patients. Thus, future studies need to better define the sub-group of AD patients who could benefit from ALCAR. These data, taken together, suggest that ALCAR could have a neuroprotective effect on aging processes with more specific effects on ameliorating memory decline. It also suggests that within the context of the currently available drug therapies for AD, ALCAR may have a role in certain subgroups of AD patients, with fewer side effects compared with the anticholinesterases. Further studies also may examine the therapeutic efficacy of the combination of anticholinesterases and ALCAR in this disease.
Possible modes of action of ALCAR in AD
What is the possible mode of action of ALCAR in AD? In order to suggest possible mechanisms there is a need to demonstrate that ALCAR may either attenuate pathophysiological effects associated with this disease or augment physiological mechanisms compensating for dysfunctional processes caused by the disorder. Considering the research data presented above, we suggest that ALCAR may act at one or more of seven possible targets attenuating pathophysiological changes caused by this disorder.
Restoration of cell membranes
There is solid evidence for ALCAR's role in affecting membrane composition, molecular dynamics, and function. There also is solid evidence for a fundamental alteration in membrane phospholipid composition and metabolism in AD.111, 112, 113, 114, 115, 116, 117, 118, 119 Of considerable importance is the observation that the membrane molecular changes actually precede cognitive decline.120 In addition, there is in vivo evidence that ALCAR can reverse these membrane molecular and metabolic changes in some AD subjects.100
Restoration of synaptic function
The effects of ALCAR on synaptic functioning were presented above. There is considerable research data demonstrating dysfunctional synaptic functioning in normal aging and especially in AD. In particular, AD is associated with synaptic change and/or loss,121, 122, 123 including synaptic vesicles, recycling dysfunctions,124 and reduced synaptic proteins.125 The changes in membrane phospholipid metabolism found in AD and ALCAR's ability to restore these changes probably contribute to the effects of ALCAR on synaptic functioning in AD.
Augmentation of cholinomimetic activity
AD demonstrates a decrease in a variety of cholinergic indices including cholineacetyl transferase, acetylcholine esterase and the number of brain cholinergic neurons126 and ALCAR has a beneficial neuromodulatory effect on cholinergic neurotransmission. It is of note that some cholinomimetic agents are found to have some beneficial effect in slowing this disease process.127
Restoration of brain energy
ALCAR has a demonstrated ability to restore brain energy levels. Pettegrew et al117 demonstrated by 31P MRS a decrease in PCr levels in mildly demented AD subjects which correlated with the degree of cognitive decline. Similar PCr changes were observed in one subject 46 months prior to cognitive changes and the PCr changes correlated with measures of cognitive decline.120 Rapoport et al128 summarized more than 20 cross-sectional PET studies of brain functional activity in patients with probable AD. These studies demonstrate metabolic reductions in the neocortex showing increased severity in relation to the dementia severity. Another clue to impairment of brain energy metabolism in AD is research demonstrating reductions of key brain energy metabolite enzymes such as α-ketoglutarate dehydrogenase complex and cytochrome oxidase in this disease.129 ALCAR increases the activity of both cytochrome oxidase and α-ketoglutarate dehydrogenase in intrasynaptic but not in non-synaptic mitochondria from rat cerebral cortex.50 Rapoport et al130 and Chandrasekaran et al131 demonstrated downregulation of oxidative phosphorylation in AD, and Marcus et al132 demonstrated decreased uptake of glucose into microvessels from the temporal cortex of AD patients.
Protection against a variety of toxins
Several studies suggested increased free radical production in aging and AD. AD also is characterized by extracellular deposits of Aβ peptide and a variety of toxins, including aluminum, have been suggested to be involved in this disorder.126, 127, 128 ALCAR attenuates the effects of a variety of toxins which could contribute to its action in AD.
Possible neurotrophic effects via stimulating NGF
The cell loss in AD suggests a possible role for neurotrophic agents in the treatment of this disorder. NGF has been studied in AD and was shown to attenuate degenerative changes in cholinergic brain cells.127 ALCAR up-regulates NGF receptor expression and increases its activity, suggesting a possible neurotrophic role for ALCAR in AD.
Acetylation of proteins
ALCAR acetylates α-tubulin leading to stabilization of cytoplasmic microtubules. ALCAR also acetylates Aβ peptide (M Calvani, personal communication) and unacetylated Aβ forms potentially toxic β-sheet aggregates. Molecular simulation calculations of a fragment, Aβ(1–28), indicated that acetylation of Lys 28 could inhibit the formation of a β-sheet structure34 (Figure 3). The potential ability of ALCAR to acetylate microtubules and Aβ peptide could ameliorate the deposition of protein aggregates which comprise the two neuropathological hallmarks of AD, ie, neurofibrillary tangles and amyloid deposits. ALCAR also could acetylate -OH groups which would make them unavailable for phosphorylation by protein kinases. This could in theory reduce the hyperphosphorylation of tau protein which leads to the formation of paired helical filaments in AD.
ALCAR in geriatric depression
Mode of action of typical antidepressant drugs
One of the puzzling phenomena regarding the treatment of depression is the existence of a variety of antidepressants with no apparent similarity in molecular structure, suggesting that no apparently specific action on neurotransmitter systems or other cellular targets is needed. Indeed, there are now noradrenergic, serotoninergic, dopaminergic, cholinergic, peptidergic, and glutamatergic theories for depression, among others, demonstrating the lack of a specific dominating theory and the difficulty in finding a specific system or cellular target responsible for producing and maintaining depression. There are other serious limitations to hypotheses suggesting cathecholamine or indolamine receptor and neurotransmitter abnormalities in depression, since agonists of these systems are in general devoid of antidepressant activity. Also, evidence from animals and humans demonstrate that these neuroreceptors are affected almost immediately by drugs, but clinical improvement follows only weeks later.133 This further suggests that antidepressant action is not associated with specific short-term modulation of synaptic activity, but with extended molecular and cellular changes in neuronal activity, encompassing different levels, ie, first, second, and third messenger systems, as well as the modulation of a variety of regulatory proteins and lipids. The role of second messenger-regulated protein kinases in the brain and the action of antidepressant drugs has recently been reviewed.134
Evidence for alterations in membrane molecular dynamics in affective disorders
Over the past 25 years, evidence has accumulated in support of a possible membrane alteration in affective illness despite the existence of conflicting results. The earliest evidence included alterations in the extracellular-intracellular distribution of lithium and choline and altered Na+-K+ ATPase activity in these patients (for a review see Mallinger and Hanin135). It has been suggested that alterations in membrane molecular dynamics could contribute to the pathophysiology of some patients with bipolar affective illness.136, 137, 138, 139, 140 Other studies suggest that altered activity of membrane phospholipases (especially A2) could contribute to some of the functional membrane changes observed in some patients with affective illness (reviewed in Hibbeln et al141). Pettegrew et al142 demonstrated distinct alterations in erythrocyte membrane molecular dynamics of affective bipolar patients consisting of increased molecular motion of the phospholipid head group and hydrocarbon core areas of the membrane; those changes were modulated toward normal after 4 weeks of psychotropic treatment.
Changes in membrane composition and molecular dynamics could provide the molecular basis for alterations in membrane receptor function, cation transport and membrane enzyme activity (such as phospholipases and Na+-K+ ATPase) since a number of physical chemical studies have demonstrated the influence of membrane composition and molecular dynamics on the function of membrane proteins, such as receptors, enzymes and ion channels.143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153 Since many membrane receptors and channels contain several transmembrane helical regions,154, 155 the surrounding membrane phospholipids are poised to influence the structure and molecular dynamics of the transmembrane regions of receptors and ion channels.156, 157, 158, 159, 160, 161, 162 Membrane molecular dynamics also could influence the coupling of G-protein subunits to receptor subunits, the coupling of G-protein subunits to each other, and the coupling of G-protein subunits to membrane associated enzymes such as adenylcyclase and phospholipase C.
One central hypothesis is that some forms of affective illness are due to an alteration in membrane molecular dynamics, probably associated with altered lipid metabolism.115, 136, 138, 139, 140, 142 The alteration in membrane molecular dynamics, in turn, results in altered function of membrane proteins, such as receptors, ion channels, G-proteins, or second messenger molecular cascades. Since all of these membrane molecular constituents are highly interactive both structurally and functionally, many different molecular alterations could produce the same clinical phenotypes associated with affective disorders.
Evidence for the involvement of lipid metabolism in depression
Various data suggest alterations of fatty acids and lipid metabolism in depression. Low cholesterol levels are associated with higher prevalence of depressive symptoms and/or risk for suicide.163, 164, 165, 166, 167 Interestingly, the dexamethasone test (1 mg) in unipolar patients increased serum free fatty acids and correlated with L-tryptophan levels.168 Patients with major depression were found to have significantly decreased omega-3 fractions in cholesteryl esters and a high ratio of C20:4 omega-6/C20:5 omega-3 in phospholipid and cholesteryl esters in plasma.169 Peet et al170 and Edwards et al171 demonstrated low total plasma omega-3 polyunsaturated free fatty acids, especially docosahexanoic acid. Also, a variety of phospholipids, including phosphatidylinositols, were found to be altered in depression172 and Smythies et al173 demonstrated low phosphatidylcholine levels in erythrocyte membranes of depressed patients. Finally, Pettegrew et al120, 136, 138, 142 have suggested that one subtype of depression may involve abnormal lipid metabolism and membrane biophysical changes.
Evidence for ALCAR efficacy in depression
Tempesta et al174 conducted an open cross-over study of ALCAR and placebo in 24 depressed geriatric patients (age >70 years). These patients were treated with either 1 g of ALCAR or placebo for 1 month. ALCAR was found to be superior to placebo in patients demonstrating high baseline HDS scores.
Seven parallel, double-blind, placebo-controlled studies have examined ALCAR efficacy in various forms of geriatric depression.175, 176, 177, 178, 179, 180, 181 Six studies utilized the Hamilton rating scale among other scales to assess the depressive symptomatology, while one used the affective disorder cluster of the Sandoz Clinical Assessment Geriatric Scale.176 Five of the studies had 20–28 subjects each and two studies178, 179 had 60 subjects each (30 on ALCAR treatment and 30 on placebo).
The first of these seven studies was that of Villardita et al.175 This study examined the efficacy of ALCAR vs placebo in 28 patients of both sexes, age 65–78. The diagnostic system used was not mentioned. The baseline HDS (21 items) score was 26 ± 3, suggesting the subjects were moderately depressed. Sixteen patients were treated for 40 days with either ALCAR (1.5 g daily) or placebo. No difference was noted between these groups after 20 days. However, after 40 days of treatment ALCAR was superior to placebo (Student's t-test: P < 0.001, the effect size was above 1).
The second study was by Nasca et al.177 These authors studied 20 patients diagnosed with involutive depression by ICD-9. There were 20 subjects, age 55–75, 16 males and four females. After a washout period of 14 days, 10 received ALCAR (2 g daily) and 10 received placebo. Each of these treatments was administered in combination with mianserine for the first 20 days and then ALCAR alone for another 20 days. These patients were suffering from severe depression with baseline HDS above 40 (44 and 45) for both groups. No difference was noted between the groups after 20 days, but these authors reported a significant improvement with ALCAR treatment after 40 days (Mann-Whitney test, P < 0.001). Unfortunately, evaluation of the magnitude of change with each treatment arm was not possible since mean HDS scores were not reported for the 40-day time point.
Three double-blind studies were reported in 1990 by Garzya et al,180 Bella et al,178 and Fulgente et al.179 Garzya et al180 studied 28 patients with DSM-III-R depressive disturbances (300.4), age 70–80. Fourteen patients received ALCAR (1.5 g daily) and 14 received placebo. There was no difference in HDS (17 items) scores between the groups after 15 days of treatment, but ALCAR treatment was superior to placebo at 30 and 60 days of treatment (P < 0.01). HDS scores of patients on ALCAR improved from 22 ± 3 at baseline to 14 ± 6 at 30 days, but no further improvement was noted at 60 days (14 ± 6). HDS scores of patients on placebo improved from 20 ± 2 at baseline to 18 ± 5 at 30 days and no further improvement was noted at 60 days (18 ± 5). ALCAR treatment was better than placebo; however, the majority of patients on ALCAR demonstrated only partial remission after 60 days of treatment.
Bella et al178 and Fulgente et al179 each studied 60 patients diagnosed with DSM-III-R dysthymic disorder. Both studies had similar parallel-group, placebo-control, double-blind designs. In each study, 60 patients (30 on ALCAR and 30 on placebo) were administered ALCAR (3 g daily) or placebo, each given for 60 days. HDS scores of patients were assessed at baseline, 30, and 60 days. In the Bella et al178 study, the mean baseline HDS score for the ALCAR group was reduced from 21 to 12 at 30 days and 11 at 60 days and the mean baseline HDS score for the placebo group was reduced from 21 to 20 at 30 days and 19 at 60 days. ALCAR treatment was statistically superior to placebo treatment at 30 and 60 days. In the Fulgente et al179 study, ALCAR treatment was also superior to placebo at 30 and 60 days (P < 0.0001). The mean HDS score for the ALCAR group was reduced from 25 ± 2 at baseline to 13 ± 4 at 30 days and 12 ± 5 at 60 days. For the placebo group, HDS scores were reduced from 24 ± 3 at baseline to 22 ± 3 at 30 and 60 days. Thus, both studies encompassing 120 subjects showed a mean HDS score reduction of over 40% for the ALCAR group at 30 days compared with a mean reduction of less than 10% for placebo at the same time point, and a mean HDS reduction of 50% for ALCAR at 60 days compared with up to 10% for placebo at the identical time points. It is of note that no further substantial benefit was seen for ALCAR beyond 30 days of treatment.
Another small-scale, parallel-group, placebo-controlled, double-blind study was reported by Gecele et al.181 These authors studied 28 patients age 66–79 diagnosed with major depression according to DSM-III-R. All patients were males. Fourteen patients were treated with ALCAR (2 g a day) for 40 days and another 14 patients received placebo for an identical period of time. These authors did not specifically report mean HDS scores at baseline and 40 days. However, mean baseline HDS scores obtained by examination of a figure appearing in the manuscript indicates that the approximate mean baseline HDS score for the ALCAR-treated group was 39 and for the placebo group it was 33–34. In the ALCAR group, the mean reduction of HDS scores after 40 days appears to be 10 points, while for the placebo it appears to be less than 5 points. HDS scores of six out of 14 patients in the ALCAR group dropped under 20 while this was true for only three out of 14 in the placebo group. The ALCAR group showed a statistically significant reduction in HDS scores compared with placebo at 40 days (P < 0.05).
It is interesting to note that ALCAR also was reported to have some effect on depressive symptoms found in adult (non geriatric) patients with AIDS and AIDS-related disorders. De Simone et al176 studied 25 patients, 12 males and 13 females, mean age 36; 12 diagnosed with AIDS, six with AIDS-related complex, five with lymphadenopathy syndrome, and two with HIV-seropositive condition. All patients had depressive symptoms. The affective disorders cluster of the Sandoz Clinical Assessment Geriatric Scale was used to assess the depressive symptomatology. ALCAR treatment showed within group a statistically significant reduction in the affective disorder cluster (P < 0.001), but no difference was noted for the placebo group. Unfortunately, these authors did not provide a statistical analysis of the comparison between ALCAR and placebo groups.
Although different methodologies were used in these studies, including different sub-groups of depressed patients (ie, major depression vs dysthymic disorder), it appears that ALCAR has an antidepressant effect in a variety of depressive spectrum disorders. Such an effect is observed in geriatric depression after about 4 weeks or more of treatment. It was suggested that time to remission of patients demonstrating depression of late life is about 2 weeks longer compared with younger patients.182 On the whole, the results of the larger ALCAR studies support a role for ALCAR in depression even when compared with the results obtained with other antidepressants including fluoxetine (eg, Koran et al183).
Common membrane mechanisms in the treatment of depression
ALCAR, myo-inositol,184 omega-3 fatty acids,185 and lithium186 have been found to have antidepressant effects. Myo-inositol deficiency was reported to affect lipid metabolism.187 Recently, Pettegrew et al188 found that myo-inositol treatment increases rat brain phosphatidylethanolamine plasmalogen levels. This phospholipid strongly enhances the fusion of membranes189 and could enhance the fusion of synaptic vesicles to the synaptic plasma membrane which would enhance the release of neurotransmitters. Thus, myo-inositol affects lipid metabolism and phospholipid composition which could alter membrane physical-chemical properties. Interestingly, ALCAR increases myo-inositol levels in a model of rat diabetic neuropathy injected with streptozocin190 and delays the development of myo-inositol deficiency in the same model.191
ALCAR also can potentially supply acetyl groups needed for the synthesis of fatty acids including omega-3 fatty acids. Administration of omega-3 polyunsaturated free fatty acids could affect the ratio of saturated to unsaturated fatty acids available for synthesis of phospholipids, and thus alter the physical-chemical properties of membranes.
ALCAR shares with lithium its effect on brain phosphomonoester levels100, 192 and both tend to increase brain sphingomyelin.193 Lithium also increases CNS choline194 and inhibits the phosphatidylinositol cycle (PI).195, 196 ALCAR increases choline acetyltransferase activity and increases choline uptake into nerve terminals.197, 198 Recently, lithium was reported to inhibit PLA2 which could alter membrane phospholipid metabolism.199 In addition, lithium was reported to increase the motion of macromolecules on the membrane surface of normal human erythrocytes,140 and was reported to affect many other targets associated with the cell membrane.200, 201, 202, 203
We suggest that the antidepressant activity of ALCAR, myo-inositol, omega-3 fatty acids, and lithium are related to their effect on membrane phospholipid metabolism and membrane physical-chemical properties. Such a mechanism could affect the secretion of hormones, neurotransmitters, and cytokines, as well as affecting second messenger systems including the PI cycle and a variety of intracellular metabolites, such as prostaglandins, all suggested to be involved in the pathogenesis of depression.133 Pharmacological analysis of the broad range cellular effects of these agents in general, and those associated with lipid metabolism and membrane structure and function in particular, are needed along with pharmacological dissections at the neuroreceptor level of agents with antidepressant activity.
ALCAR contains carnitine and acetyl moieties, both of which have neurobiological properties. ALCAR is reported to affect brain energy and phospholipid metabolism and to interact with cell membranes, proteins, and enzymes. ALCAR modulates the activity of NGF, and several hormones. ALCAR demonstrates a neuromodulatory effect on synaptic morphology and on multiple neurotransmitter synaptic transmission, including that of acetylcholine. This suggests that ALCAR can affect multiple CNS systems and targets. ALCAR is reported to have beneficial effects in two major psychiatric disorders found in high prevalence in the geriatric population, that is AD and major depression. We suggest that ALCAR's mode of action in AD may involve restoration of cell membranes, as well as synaptic function, augmenting cholinergic activity, restoring brain energy, protecting against toxins, exerting neurotrophic effects via stimulating NGF, and acetylation of proteins. ALCAR's antidepressant effect may involve its effects on lipid metabolism and the cell membrane and it may share such activity with omega-3 free fatty acids, lithium, and myo-inositol. Proposed relationships between preclinical mechanisms and clinical actions of ALCAR are speculative at this time. In addition, in spite of impressive preclinical data, clinical results for ALCAR are more modest which is the case for many drugs. This review will hopefully stimulate further preclinical and clinical studies of ALCAR.
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Pettegrew, J., Levine, J. & McClure, R. Acetyl-L-carnitine physical-chemical, metabolic, and therapeutic properties: relevance for its mode of action in Alzheimer's disease and geriatric depression. Mol Psychiatry 5, 616–632 (2000). https://doi.org/10.1038/sj.mp.4000805
- Alzheimer's disease
- geriatric depression
- lipid metabolism
- energy metabolism
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