Effects of acetyl-L-carnitine treatment and stress exposure on the nerve growth factor receptor (p75NGFR) mRNA level in the central nervous system of aged rats.
Prog Neuropsychopharmacol Biol Psychiatry (ENGLAND) Jan 1995, 19 (1) p117-33

There is growing evidence that the nerve growth factor protein (NGF), a neurotrophic factor for peripheral and central nervous system (CNS) neurons, may play a role in the modulation of the hypothalamo-pituitary-adrenocortical axis (HPAA). While NGF binding is decreased in rodent CNS after stress exposure, this reduction is prevented by treatment with Acetyl-L-Carnitine (ALCAR), a chemical substance able to prevent some degenerative events associated with aging. The authors studied the effect of cold stress on the low-affinity NGF receptor (p75NGFR) mRNA levels in the basal forebrain and cerebellum of aged rats chronically treated with ALCAR. The present results show that ALCAR abolished the age-associated reduction of p75NGFR mRNA levels in the basal forebrain of old animals, but did not affect the response to stress stimuli. Also, treatment with ALCAR maintained p75NGFR mRNA levels in the cerebellum of old animals at levels almost identical to those observed in young control animals. These results suggest a neuroprotective effect for ALCAR on central cholinergic neurons exerted at the level of transcription of p75NGFR. The restoration of p75NGFR levels could increase trophic support by NGF of these CNS cholinergic neurons which are implicated in degenerative events associated with aging.

Acetyl-L-carnitine treatment increases nerve growth factor levels and choline acetyltransferase activity in the central nervous system of aged rats.
Exp Gerontol (ENGLAND) Jan-Feb 1994, 29 (1) p55-66

The hypothesis that some neurodegenerative events associated with ageing of the central nervous system (CNS) may be due to a lack of neurotrophic support to neurons is suggestive of a possible reparative pharmacological strategy intended to enhance the activity of endogenous neurotrophic agents. Here we report that treatment with acetyl-l-carnitine (ALCAR), a substance which has been shown to prevent some impairments of the aged CNS in experimental animals as well as in patients, is able to increase the levels and utilization of nerve growth factor (NGF) in the CNS of old rats. The stimulation of NGF levels in the CNS can be attained when ALCAR is given either for long or short periods to senescent animals of various ages, thus indicating a direct effect of the substance on the NGF system which is independent of the actual degenerative stage of the neurons. Furthermore, long-term treatment with ALCAR completely prevents the loss of choline acetyltransferase (ChAT) activity in the CNS of aged rats, suggesting that ALCAR may rescue cholinergic pathways from age-associated degeneration due to lack of retrogradely transported NGF.

Acetyl-L-carnitine affects aged brain receptorial system in rodents.
Life Sci (ENGLAND) 1994, 54 (17) p1205-14

Acetyl-L-carnitine (ALCAR), the acetyl ester of carnitine, is regarded as a compound of considerable interest because of its capacity to counteract several physiological and pathological modifications typical of brain ageing processes. In particular, it has been demonstrated that ALCAR can counteract the age-dependent reduction of several receptors in the central nervous system of rodents, such as the NMDA receptorial system, the Nerve Growth Factor (NGF) receptors, those of glucocorticoids, neurotransmitters and others, thereby enhancing the efficiency of synaptic transmission, which is considerably slowed down by ageing. The present review thus postulates the importance of ALCAR administration in preserving and/or facilitating the functionality of carnitines, the concentrations of which are diminished in the brain of old animals.

Stimulation of nerve growth factor receptors in PC12 by acetyl-L-carnitine.
Biochem Pharmacol (ENGLAND) Aug 4 1992, 44 (3) p577-85

Acetyl-L-carnitine (ALCAR) prevents some deficits associated with aging in the central nervous system (CNS), such as the aged-related reduction of nerve growth factor (NGF) binding. The aim of this study was to ascertain whether ALCAR could affect the expression of an NGF receptor (p75NGFR). Treatment of PC12 cells with ALCAR increased equilibrium binding of 125I-NGF. ALCAR treatment also increased the amount of immunoprecipitable p75NGFR from PC12 cells. Lastly, the level of p75NGFR messenger RNA (mRNA) in PC12 was increased following ALCAR treatment. These results are in agreement with the hypothesis that there is a direct action of ALCAR on p75NGFR expression in aged rodent CNS.

Culture of dorsal root ganglion neurons from aged rats: effects of acetyl-L-carnitine and NGF.
Int J Dev Neurosci (ENGLAND) Aug 1992, 10 (4) p321-9

In vitro neuronal preparations are used to study the action mechanism of substances which are active in normal and pathological brain aging. One major concern with in vitro assays is that the use of embryonic or adult neurons may hamper an appreciation of the relevance of these substances on aged nervous tissue. In the present study for the first time cultures of aged dorsal root ganglia from 24-months-old rats were maintained in vitro up to 2 weeks. This model was used to investigate the neurotrophic/neuroprotective action of nerve growth factor and acetyl-L-carnitine. A large population of aged dorsal root ganglia neurons was responsive to nerve growth factor (100 ng/ml). Nerve growth factor induced an increase of initial rate of axonal regeneration and influenced the survival time of these neurons. Acetyl-L-carnitine (250 microM) did not affect the axonal regeneration but substantially attenuated the rate of neuronal mortality. A significant difference was evident between the acetyl-L-carnitine-treated and the untreated neurons from the first cell counting (day 3 in culture). After 2 weeks the number of aged neurons treated with acetyl-L-carnitine was almost double that of the controls. The effects of acetyl-L-carnitine on aged DRG neurons potentially explain the positive effects in clinical and in vivo experimental studies.

Acetyl-L-carnitine enhances the response of PC12 cells to nerve growth factor.
Brain Res Dev Brain Res (NETHERLANDS) Apr 24 1991, 59 (2) p221-30

We have demonstrated that treatment of rat pheochromocytoma (PC12) cells with acetyl-L-carnitine (ALCAR) stimulates the synthesis of nerve growth factor receptors (NGFR). ALCAR has also been reported to prevent some age-related impairments of the central nervous system (CNS). In particular, ALCAR reduces the loss of NGFR in the hippocampus and basal forebrain of aged rodents. On these bases, a study on the effect of NGF on the PC12 cells was carried out to ascertain whether ALCAR induction of NGFR resulted in an enhancement of NGF action. Treatment of PC12 cells for 6 days with ALCAR (10 mM) stimulated [125I]NGF PC12 cell uptake, consistent with increased NGFR levels. Also, neurite outgrowth elicited in PC12 cells by NGF (100 ng/ml) was greatly augmented by ALCAR pretreatment. When PC12 cells were treated with 10 mM ALCAR and then exposed to NGF (1 ng/ml), an NGF concentration that is insufficient to elicit neurite outgrowth under these conditions, there was an ALCAR effect on neurite outgrowth. The concentration of NGF necessary for survival of serum-deprived PC12 cells was 100-fold lower for ALCAR-treated cells as compared to controls. The minimal effective dose of ALCAR here was between 0.1 and 0.5 mM. This is similar to the reported minimal concentration of ALCAR that stimulates the synthesis of NGFR in these cells. The data here presented indicate that one mechanism by which ALCAR rescues aged neurons may be by increasing their responsiveness to neuronotrophic factors in the CNS.

Effect of acetyl-L-carnitine on forebrain cholinergic neurons of developing rats.
Int J Dev Neurosci (ENGLAND) 1991, 9 (1) p39-46

It has been shown that the endogenous compound, acetyl-L-carnitine (ALCAR), acts in the brain as a metabolic cofactor in the synthesis of acetylcholine. In these studies, ALCAR was injected into the brain of developing rats every other day for the first three weeks after birth in order to assess its effect on forebrain cholinergic neurons. The results showed that intracerebroventricular (icv) administration of ALCAR causes an increase of choline acetyltransferase (ChAT) activity and of nerve growth factor receptor expression in the striatum. Biological assays of brain tissues revealed that the level of nerve growth factor (NGF) in the hippocampus also increases. The ability of brain cholinergic tissues to respond to exogenous administration of ALCAR is discussed.

Nerve growth factor binding in aged rat central nervous system: effect of acetyl-L-carnitine.
J Neurosci Res (UNITED STATES) Aug 1988, 20 (4) p491-6

The nerve growth factor protein (NGF) has been demonstrated to affect neuronal development and maintenance of the differentiated state in certain neurons of the peripheral and central nervous system (CNS) of mammals. In the CNS, NGF has sparing effects on cholinergic neurons of the rodent basal forebrain (BF) following lesions where it selectively induces choline acetyltransferase (ChAT). NGF also induces ChAT in the areas to which BF provides afferents. In aged rats, there is a reduction in the NGF-binding capacity of sympathetic ganglia. Here, we wish to report that there is a decrease in the NGF-binding capacity of the hippocampus and basal forebrain of aged (26-month-old) rats as compared to 4-month-old controls but no change in NGF binding in cerebellum. In all instances, equilibrium binding dissociation constants did not differ significantly. Treatment of rats with acetyl-L-carnitine, reported to improve cognitive performance of aged rats, ameliorates these age-related deficits.

Carnitine and acetyl-L-carnitine content of human hippocampus and erythrocytes in Alzheimer's disease
Journal of Nutritional and Environmental Medicine (United Kingdom), 1995, 5/1 (35-39)

We have studied carnitine and acetyl-L-carnitine content of hippocampus and erythrocytes from Alzheimer's disease patients and elderly control subjects. Carnitine content was similar in erythrocytes from Alzheimer's disease patients and controls, but in contrast acetyl-L-carnitine content was significantly lower in the Alzheimer's disease patients compared with control subjects. On post-mortem samples from hippocampus, carnitine and acetyl-L-carnitine content did not differ significantly between patients when related to the protein content.

Advances in the pharmacotherapy of Alzheimer's disease
EUR. ARCH. PSYCHIATRY CLIN. NEUROSCI. (Germany), 1994, 244/5 (261-271)

The authors reviewed the literature on the agents proposed for the treatment of Alzheimer's disease (AD). Different classes of drugs have been tested for this indication including psychostimulants, anticoagulants, vasodilators, hyperbaric oxygen, hormones, nootropics, cholinomimetics, monoaminergics and neuropeptides without conclusive evidence of being beneficial for the treatment of this condition. Among the cholinomimetics recent research data seems to indicate that they might produce modest benefits in mild-to-moderate AD patients. Recently, other drugs have also been proposed including neurotrophic factors, phosphatidylserine, argistension converting enzyme (ACE) inhibitors, calcium channel blockers, acetyl-L-carnitine, xanthine derivatives, anti-inflammatory agents, aluminum chelate agents, and D-cycloserine. Of these new strategies few hold promise of more substantial benefits for AD, with the possibility of altering the course of the disease, but these drugs await confirmatory trials.

Neuroprotective activity of acetyl-L-carnitine: Studies in vitro
NEUROSCI. RES. (USA), 1994, 37/1 (92-96)

The neuroprotective properties of acetyl-L-carnitine (ALCAR) were investigated in primary cell cultures from rat hippocampal formation and cerebral cortex of 17-day-old rat embryos. Chronic exposure to ALCAR (10-50 microM for 10 days) reduced the cell mortality induced by 24 hr fetal calf serum deprivation. Protection was partial when the neuronal cells, chronically treated with ALCAR (50 microM), were exposed to glutamate (0.25-1 mM) and kainic acid (250-500 microM) for 24 hr. The neurotoxicity induced by N-methyl-D- aspartate (NMDA, 250 microM) was attenuated by the acute co-exposure with ALCAR (1 mM), the chronic treatment with ALCAR (50 microM) significantly reduced the neuronal death induced by NMDA (0.25-1 mM). Cell mortality was also investigated in ALCAR-treated hippocampal cultures chronically treated with beta-amyloid fragment 25-35. ALCAR appeared to have neuroprotective activity. This suggests an explanation of the positive results obtained with ALCAR in the treatment of Alzheimer's disease.

Acetyl-L-carnitine and Alzheimer's disease: Pharmacological beyond the cholinergic sphere
ANN. NEW YORK ACAD. SCI. (USA), 1993, 695/- (324-326)

Since ALCAR and L-carnitine are 'shuttles' of long chain fatty acids between the cytosol and the mitochondria to undergo beta-oxidation, they play an essential role in energy production and in clearing toxic accumulations of fatty acids in the mitochondria. ALCAR has been considered of potential use in senile dementia of the Alzheimer type (SDAT) because of its ability to serve as a precursor for acetylcholine. However, pharmacological studies with ALCAR in animals have demonstrated its facility to maximize energy production and promote cellular membrane stability, particularly its ability to restore membranal changes that are age-related. Since recent investigations have implicated abnormal energy processing leading to cell death, and severity-dependent membrane disruption in the pathology of Alzheimer's disease, we speculate that the beneficial effects associated with ALCAR administration in Alzheimer patients are due not only to its cholinergic properties, but also to its ability to support physiological cellular functioning at the mitochondrial level. This hypothetical mechanism of action is discussed with respect to compelling supportive animal studies and recent observations of significant decrease of carnitine acetyltransferase (the catalyst of L-carnitine acylation to acetyl-L-carnitine) in autopsied Alzheimer brains.

Acetyl-L-carnitine: A drug able to slow the progress of Alzheimer's disease?
ANN. NEW YORK ACAD. SCI. (USA), 1991, 640/- (228-232)

Defects in cholinergic neurotransmission do not, by themselves, constitute the sole pathophysiologic concomitants of Alzheimer's disease (AD). Recent findings point out that abnormalities in membrane phospholipid turnover and in brain energy metabolism may also characterize AD. Acetyl-L-carnitine (ALC) is an endogenous substance that, acting as an energy carrier at the mitochondrial level, controls the availability of acetyl-L-CoA. ALC has a variety of pharmacologic properties that exhibit restorative or even protective actions against aging processes and neurodegeneration. A review of a series of controlled clinical studies suggests that ALC may also slow the natural course of AD.

Pharmacokinetics of IV and oral acetyl-L-carnitine in a multiple dose regimen in patients with senile dementia of Alzheimer Type
EUR. J. CLIN. PHARMACOL. (Germany), 1992, 42/1 (89-93)

Acetyl-L-carnitine (ALC), a physiological component of the L-carnitine family, has been proposed for treating Alzheimer's disease in pharmacological doses. As this condition requires prolonged therapy, its kinetics has been examined after a multiple dose regimen, involving different routes of administration, in 11 patients suffering from Senile Dementia of Alzheimer Type. The study design comprised a 3-day basal observation period, sham treatment with repeated blood sampling; treatment with 30 mg.kg-1 i.v. given twice for 10 days (plasma kinetics was studied on the 7th day), and 50 days of 2.0 g/day p.o. given in three daily doses. Total acid soluble L-carnitine, L-carnitine and acetyl-L-carnitine in plasma and CSF were evaluated using an enantioselective radioenzyme assay. Short chain L-carnitine esters were calculated as the difference between total and free-L-carnitine. The plasma concentrations of individual components of the L-carnitine family did not change during the three days of the basal period, nor were they affected during the sham therapy period. Following the i.v. bolum injections, the plasma concentrations showed a biphasic curve, with average t(one-half) of 0.073 h and 1.73 h, respectively. At the end of oral treatment, plasma acetyl-L-carnitine and L-carnitine short chain esters were significantly higher than during the run-in phase. The CSF concentrations paralleled those in plasma, suggesting that ALC easily crosses the blood-brain barrier. It is concluded that i.v. and oral administration of multiple doses of ALC can increase its plasma and CSF concentration in patients suffering from Alzheimer's disease.

Double-blind, placebo-controlled study of acetyl-l-carnitine in patients with Alzheimer's disease
CURR. MED. RES. OPIN. (United Kingdom), 1989, 11/10 (638-647)

A randomized, double-blind, placebo-controlled, parallel-group clinical trial was carried out to compare 24-week periods of treatment with 1 g acetyl-l-carnitine twice daily and placebo in the treatment of patients with dementia of the Alzheimer type. A total of 36 patients entered the trial, of whom 20 patients (7 active, 13 placebo) completed the full 24 weeks. Whilst several of the efficacy indices showed little change in either group during the trial, there was an apparent trend for more improvement in the acetyl-l-carnitine group in relation to the Names Learning Test and a computerized Digit Recall Test, both related to aspects of short-term memory. Similarly, there was a trend for reaction time in the computerized classification test to show less deterioration in the active treatment group. Changes within groups, and changes between groups, failed to reach statistical significance, at least partially because of the small number of patients available for analysis. Two indices of overall therapeutic benefit showed a trend for less deterioration in the active-treatment group than in the placebo group. Nausea and/or vomiting occurred in 5 patients in the acetyl-l-carnitine group. Laboratory tests revealed no signs of drug toxicity. The results suggest that acetyl-l-carnitine may have a beneficial effect on some clinical features of Alzheimer-type dementia, particularly those related to short-term memory.