Supplement of Acetyl-L-carnitine (ALC) protects the neuron from stress and damage through several mechanism: many pre-clinical studies demonstrated that ALC prevent neuron degeneration and could represent a new weapon in motorneurons disease treatment.
Acetyl-L-carnitine (ALC) contains carnitine and acetyl moieties, both of which have neurobiological properties. ALC can readily cross the blood–brain barrier, so supplementing with this compound could feasibly affect brain metabolism.
ALC 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. Under conditions of impaired energy metabolism, such as fasting or experimental diabetes, carnitine levels increase in the mitochondrial matrix and carnitine-acylcarnitine translocase activity increases.
Studies in humans and animals suggest ALC has a favorable role in restoring cerebral energy metabolism.
Injection of ALC in rats led to reduced oxidation of glucose and increased glycogen synthesis in brain: the beneficial effects of ALC on cerebral energy metabolism are mediated by its 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 ALC or indirectly through carnitine's role in beta-oxidation of fatty acids.
After experimental treatment with ALC, changes in the activities of specific enzymes involved in the tricarboxylic acid (TCA) cycle, electron transport chain and amino acid metabolism have also been observed: the activities of citrate synthase and glutamate dehydrogenase were decreased while the activities of a-ketoglutarate dehydrogenase and cytochrome oxidase were increased.
As a consequence, ALC treatment increased the concentration of phosphocreatine and decreased the concentrations of lactate and inorganic phosphate in post-ischemic brain models. Therefore, ALC seems to provide protection during conditions of metabolic stress such as ischemia: ALC may induce post-ischemic return of neurological function in a post cardiac-arrest animal model through restoring the aerobic metabolism in brain.
Another suggested component of the protective effecs in ischemia and hypoxia ALC's ability to increase adenosine levels, which inhibits membrane excitability via the adenosine A2A receptors. This 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.
ALC reversed the declines in mitochondrial membrane potential and cardiolipin concentrations that are associated with aging. In the aging process, sphingomyelin and cholesterol tend also to accumulate in neurons, and both of these increases are attenuated by long-term ALC supplementation.
It has been demonstrated that ALC can reverse these alterations in membrane lipid content and function (improving age- related changes in metabolism) directly through supplying high-energy acyl groups or indirectly through restoring membranes and supplying energy to the brain.
Another possible explanation for ALC-induced changes in membrane phospholipid composition could be attributed to the inhibition of cytochrome b5 by acetylation of one or more of the six lysine residues found in cytochrome b5.
In addition, ALC may also affect membrane fluidity due to its amphiphilic structure that may directly interact with the surface charges on cell membranes : the carboxylic group can interact with charges on membrane phospholipids, glycolipids, and proteins.
The reason why ALC regluation of lipids metabolism might be crucial in neuroprotection is that alterations in neural phospholipid composition and further effects on signal transduction pathways have been found to be characteristic of many neurological disorders. Neural membranes contain a large amount of phospholipids which can be degraded through the action of phospholipase A2 to important lipid mediators such as docosahexaenoic acid (DHA) and arachidonic acid (AA), which further form eicosanoids and other important mediators in inflammatory and oxidative stress responses .
Furthermore, alterations to the composition of these phospholipids in membranes can alter membrane fluidity, permeability, and functioning of membrane proteins that act as important receptors and signals for multiple downstream reactions.
ALC may be protective against oxidative stress through a reduction in tissue lactic acidosis, which leads to formation of ROS, through shifts in both the mitochondrial and cytosolic redox state, and/or through the induction of antioxidant genes.
The combination of all these effects lead to a general increase in reducing power available for detoxification through the glutathione system (more specifically, they restored the ratio of reduced to oxidized glutathione).
Protection against mitochondrial alterations and cell death observed in ALC treatments appear to be linked to an increased expression of heme oxygenase-1 (HO-1). The up-regulation of heat shock protein(Hsp) 60, Hsp72, SOD, and a high expression of the redox-sensitive transcription factor Nrf2 also contributed to the increase in the anti-oxidant potential and in the maintenance of many repair systems crucial for cell survival and overall brain protection.
ALC has been found to be protective against lipid peroxidation and membrane breakdown, indicating it may have antioxidant capacity in the mitochondria.
Furthermore, treatment with acylcarnitines has been shown to significantly reduce the levels of circulating tumor necrosis factor-a (TNF-a) and interleukins, which could then protect against oxidative stress.
ALC has been shown to increase nerve growth factor (NGF) production and enhance NGF binding. NGF affects neuronal development and maintenance of neurons both in the peripheral and central nervous systems (CNS). Nevertheless, it is unclear if ALC's biological effects are due to the acetylation of one or more amino acids of NGF or by increasing NGF gene transcription/translation (most likely by acetylation of histone H4) or by a combination of these effects.
both neuroprotective and neurotrophic activity in primary moto- neurons exposed to excitotoxic agents or deprived of brain-derived neurotrophic factor (BDNF), thus justifying its use in clinical trials in patients with motoneuron injury, included Amyotrophic Lateral Sclerosis (ALS).
Some researchers suggest that some of ALC's neuroprotective actions in neurons may be due to effects on endogenous neurotransmitter: acetylcholine (ACh) (thanks to its potential to donate acetyl groups , ALC affects many aspects of ACh metabolism) and gamma-aminobutyric acid (GABA), a major inhibitory neurotransmitter in the mammalian brain . However, the effects of this interaction remains matter of debate.
This means that ALC could affect a broad spectrum of mitochondrial and intracellular enzymes, altering (even if the overall effects is not certain) many intracellular reactions.
As an example, it has been suggested that ALC could acetylate the lysines of many transmembrane proteins (both receptors and ion channels), modulating their function by changing the portion of protein exposed or accelerating their turnover (apparently, increasing the exposure to extracellular proteases)2.
As seen above, ALC can modulate gene expression through the acetylation of hystones.
Among the others, an important role in protection from neurodegenerative disorders is played by hsp60, hsp72 and SOD.
Less clear is the effect on "VDAC"http://en.wikipedia.org/wiki/Voltage-dependent_anion_channel: VDAC is a porin of the outer mithocondrial membrane involved in the formation of the mitochondrial permeability transition (MPT) complex, which is one of the apoptosis pathways.
Apparently, the ALC-induced upregulation of mGlu2 receptors  is related to the NF-κB p65 hypercetylation.
ALC plays a significant role in the HPA axis, preventing pathological brain deterioration in stressful conditions.
ALC is supposed to be involved in the regulation of many neurotransmitter, including catecholamine and dopamine (ALC levels seems to affect tyrosine hydroxylase rate). ALC may promote synapses formation and maintenance, probably as a consequence of its multiple effects on neuron metabolism and neurotransmitter concentration.
1 Delta G° (Kcal mol-1) at pH 7.0 and 38°C: ALC, -8.20; acetylcholine, -6.99; acetylCoA, -8.54; and ATP (terminal PO4), -7.60.
2 Another significant example is ALC's ability to acetylate lysine 28 of the A-beta peptide of beta-amyloid. The acetylation of -OH group of lysine 28 blocks the hyperphosphorylation (due to the disregulation of protein kinase Cdk5) which appears to be an essential steps in the formation of toxic betau-sheet aggregates of beta-amyloid.
3 The upregulation of mGlu2 Receptors via NF-κB p65 acetylation seems to be strongly related with the proneurogenic and antidepressant effects of Acetyl-L-Carnitine.