Alcar acetyl l-carnitine

Added: Lenisha Endo - Date: 29.09.2021 19:25 - Views: 27981 - Clicks: 2260

Try out PMC Labs and tell us what you think. Learn More. Treatment with L-carnitine can ameliorate metabolic imbalance in many inborn errors of metabolism. There is compelling evidence from preclinical studies that L-carnitine and ALCAR can improve energy status, decrease oxidative stress and prevent subsequent cell death in models of adult, neonatal and pediatric brain injury.

ALCAR can provide an acetyl moiety that can be oxidized for energy, used as a precursor for acetylcholine, or incorporated into glutamate, glutamine and GABA, or into lipids for myelination and cell growth. Administration of ALCAR after brain injury in rat pups improved long-term functional outcomes, including memory.

Additional studies are needed to better explore the potential of L-carnitine and ALCAR for protection of developing brain as there is an urgent need for therapies that can improve outcome after neonatal and pediatric brain injury. L-Carnitine is a naturally occurring compound found in most, if not all, mammalian tissues including brain [ 1 ].

Human plasma and tissues, including brain, contain free L-carnitine as well as acylated derivatives with varying length carbon chains, including the acetylated and palmitoylated derivatives [ 1 ]. In recent years there has been considerable interest in the therapeutic potential of L-carnitine and Alcar acetyl l-carnitine ALCAR for neuroprotection [ 147 — 22 ]. Therapeutic efficacy of L-carnitine treatment for infants affected by some inborn errors of metabolism has been reported [ 132123 — 36 ]. A clinical trials and case studies have reported efficacy of ALCAR for neuroprotection in conditions leading to central or peripheral nervous system injury in adults [ 147 — 22 ].

Although relatively few studies have determined the efficacy of acetyl-L-carnitine for neuroprotection in models of developmental brain injury, from these studies are promising [ 12192037 — 39 ]. The carbon backbone of L-carnitine comes from 6-N-trimethyllysine, a product of protein degradation after lysosomal proteolysis [ 4041 ]. The detailed biosynthetic pathway of L-carnitine is shown in Figure 1. In the first step of L-carnitine biosynthesis, a lysine residue bound to some proteins is post-translationally methylated by a methyltransferase enzyme 1 to form a 6- N -trimethyllysine residue.

The methyl groups are transferred from S-adenosylmethionine yielding Alcar acetyl l-carnitine and the methylated lysine. After lysosomal proteolytic release of the 6- N -trimethyllysine residue, 6- N -trimethyllysine is then Alcar acetyl l-carnitine by 6- N -trimethyllysine dioxygenase enzyme 2 leading to the formation of the hydroxylated metabolite, 3-hydroxy N -trimethyllysine. In the diet, carnitine is obtained primarily from red meat and dairy products [ 1 ].

There are also dietary supplements containing the L-isomer L-carnitine with high purity [ 42 ]. Uptake into brain also occurs primarily via the OCTN2 transporter [ 14445 ]. Immunohistochemical studies show that labeling for OCTN 1, 2 and 3 is distributed in many regions of mouse brain and spinal cord in Alcar acetyl l-carnitine pattern consistent with possible roles in modulating bioenergetics and cholinergic neurotransmission [ 51 ]. The enzyme acyl-CoA synthase converts long chain fatty acids to fatty acyl-CoAs, which are subsequently converted to acylcarnitines by the enzyme carnitine palmitoyltransferase I CPT I localized in the outer mitochondrial membrane [ 143 ].

The enzyme carnitine palmitoyltransferase II CPT II which is localized in the inner mitochondrial membrane converts acylcarnitines back to acyl CoAs and free L-carnitine, which exits the mitochondria and serves as the substrate for CPT I to form more acylcarnitine [ 143 ]. Therefore, the transfer of acyl moieties from fatty acyl-CoA esters to carnitine also replenishes intracellular free CoA that is crucial for intermediary Alcar acetyl l-carnitine [ 53 ].

L-carnitine and acetyl-L-carnitine enter the cells from blood or extracellular milieu through the OCTN2 transporter. The enzyme acyl-CoA synthase not shown converts long chain fatty acids to fatty acyl-CoAs, which are subsequently converted to acylcarnitines by the enzyme carnitine palmitoyltransferase I CPT I localized in the outer mitochondrial membrane.

The enzyme carnitine palmitoyltransferase II CPT IIwhich is localized in the inner mitochondrial membrane, converts acylcarnitines back to acyl-CoAs and free L-carnitine, which exits the mitochondria and serves as the substrate for CPT I to form more acylcarnitine. Carbons from acyl-CoAs imported into the mitochondrial matrix through the carnitine shuttle can be oxidized for energy or metabolized via the TCA cycle and incorporated into glutamate, glutamine and GABA.

The carnitine shuttle is essential to prevent accumulation of long chain fatty acids and long chain acyl-CoAs which can be deleterious to cells [ 14354 ]. The enzyme carnitine acetyltransferase CAT has a crucial role in the metabolic flexibility of cells, as it transfers a 2-carbon moiety from acetyl-CoA to L-carnitine, forming the membrane permeable compound acetyl-L-carnitine; this serves to regulate intracellular trafficking of carbons between mitochondria and cytosol [ 55 ]. In developing brain the acetyl moiety may be oxidized for energy and incorporated into neurotransmitters and lipids [ 57 ].

The importance of the carnitine shuttle is underscored by the report that a polymorphism of the CPT II gene that le to decreased enzyme activity may be associated with acute encephalopathy associated with influenza [ 5859 ] and that Alcar acetyl l-carnitine of the OCTN2 transporter can lead to neurological manifestations including cognitive impairment and seizures [ 51 ]. Deficiency in the OCTN2 carnitine transporter is a rare inherited disease that le to systemic primary carnitine deficiency [ 6263 ]. It is associated with depletion of intracellular carnitine, low serum carnitine concentrations and increased urinary excretion of carnitine and its derivatives [ 6263 ].

Patients normally respond to pharmacological doses of oral L-carnitine, particularly if supplementation is implemented prior to organ damage [ 64 ]. Treatment of these carnitine shuttle disorders is primarily based on avoidance of fasting and metabolic decompensation in the patients [ 63 ].

Secondary carnitine deficiency may arise from different causes, including acquired prolonged utilization of some medications or associated with inborn errors of metabolism e. Carnitine levels are normally less depleted in secondary carnitine deficiency when compared to OCTN2-deficient patients, and therefore smaller doses of L-carnitine can restore the carnitine levels in Alcar acetyl l-carnitine shorter period of time than in patients with primary deficiency [ 41 ]. Disorders of fatty acid oxidation and organic acidemias can lead to secondary carnitine deficiency by trapping free carnitine by conjugating it with acyl moieties which accumulate in these conditions.

It is postulated that clinical symptoms, including CNS complications such as convulsion, coma and lethargy, may be triggered by the accumulation of metabolites and their acyl-CoA derivatives that disrupt intermediary metabolism [ 66 — 69 ]. The hydrolysis of the acyl-CoA derivatives and subsequent accumulation of free organic acids can lead to severe acidosis that can be life threatening [ 3 ].

There are reports showing improvement after L-carnitine therapy in patients with some organic acidemias, including propionic acidemia, methylmalonic acidemia, and glutaric acidemia type I [ 71 — 75 ]. More recent reports have demonstrated that L-carnitine supplementation as adjuvant therapy contributes to the amelioration of blood markers of oxidative damage in patients affected by phenylketonuria [ 76 ], maple syrup urine disease [ 77 ], and disorders of propionate metabolism [ 78 ].

Likewise, metabolites accumulated after long term utilization of pharmacological therapies, such as valproate [ 79 ] and the antibiotic cefditoren pivoxil [ 80 ], can be conjugated to carnitine and result in carnitine depletion. Secondary carnitine deficiency may also arise from other deleterious conditions such as hemodialysis or renal tubular dysfunction, which result in excessive loss of carnitine in urine. Secondary carnitine deficiency may also occur in malnutrition or prematurity, due to reduced intake or uptake of carnitine from the diet, or reduced reuptake in kidney [ 418182 ].

Treatment with L-carnitine ameliorated symptoms of encephalopathy subsequent to long term use of valproate [ 79 ], and the antibiotic cefditoren pivoxil [ 80 ]. Case reports indicate that improvement with L-carnitine treatment was also seen in hyperammonemic encephalopathy caused by carnitine deficiency that manifested several years after gastrointestinal bypass surgery [ 83 ] and in encephalopathy secondary to gluten enteropathy [ 84 ].

Ueno et al. Rats treated with L-carnitine had decreased oxidative DNA damage and lipid peroxidation [ 86 ], greater myelin sheath thickness and enhanced expression of oligodendrocyte markers after chronic hypoperfusion. At 28 days after onset of hypoperfusion, rats treated with L-carnitine had increased phosphorylated Akt and mammalian target of rapamycin mTORas well as increased levels of phosphorylated high-molecular weight neurofilament pNFH compared to vehicle treated rats [ 86 ]. Yu et al.

Wainwright et al. Pretreatment with L-carnitine led to ificantly less tissue loss in the ipsilateral hemisphere, compared to vehicle controls at both 7 days and 28 days after HI. Dying neurons labeled with Fluro-Jade B were present in the hippocampus and cortex of vehicle treated pups after HI. In contrast, no cells labeled with Fluro-Jade B were present Alcar acetyl l-carnitine the brain of rat pups pretreated with L-carnitine [ 19 ]. Interestingly there was no protection in rat pups treated with L-carnitine at 1 and 4 hours after HI [ 19 ].

The authors proposed that L-carnitine could prevent the accumulation of acyl-CoAs in mitochondria, which they hypothesized is a key early event involved in the pathophysiology of hypoxic-ischemic injury [ 19 ]. This hypothesis from Wainwright et al. L-Carnitine has been shown to reduce the level of acyl-CoAs in mitochondria by converting them to acylcarnitine esters [ 92 ]. Thus treatment with L-carnitine enables CPT I to transfer the acyl groups from acyl-CoAs to free carnitine, yielding acylcarnitine esters, which prevents the accumulation of, and subsequent damage from, high levels of acyl-CoAs [ 19 ].

An in vitro study by Rau et al. The changes in enzymes and carnitine homeostasis were ameliorated by treatment with L-carnitine for 2 hours prior to OGD [ 54 ]. This study underscores the vulnerability of CPT I, CPT Alcar acetyl l-carnitine, and carnitine homeostasis to oxidative stress in a widely used in vitro model of ischemia and reperfusion [ 54 ].

A of studies have used the ratio of acylcarnitines to free carnitine as an index of carnitine homeostasis [ 1920535493 ]. The studies from Wainwright and coworkers discussed above suggest that maintaining carnitine homeostasis in brain tissue can prevent dysfunction and death of neurons in models of hypoxic-ischemic injury [ 54 ]. As noted above, ALCAR is one of the most common metabolites of carnitine found in plasma and tissues of humans and mammals [ 1 ]. ALCAR has documented neuroprotective effects and is also sold as a dietary supplement [ 7121318223797 — 99 ].

ALCAR has several properties that could have neuroprotective effects including providing carnitine and an acyl moiety that can be used for energy [ 57], and for synthesis of acetylcholine [ ], amino acid neurotransmitters [ 57 ] and lipids [ ] as discussed in more detail below.

ALCAR has been found to have anti-inflammatory effects [ 7 ], lead to stabilization of membranes [ 1 ], act as an antioxidant protecting against oxidative stress [ 3753, ], enhance the activity of nerve growth factor [ ], and potentiate energy metabolism [ 5797 ], and cholinergic responses [ 1]. ALCAR administration induced mitochondrial biogenesis in hypoxic rats [ 15 ], and increased mitochondrial mass after spinal cord injury [ 13 ]. Recent reports demonstrate that administration of ALCAR after injury can improve mitochondrial function [ 38 ], decrease swelling in brain after injury [ 3739 ], and prevent loss of tissue in pediatric injury models [ 123739 ].

Since ALCAR is metabolized to acetyl CoA, it has the potential to acetylate histones, which can modify gene expression [], and to acetylate proteins and enzymes, which can greatly modify activity [ — ]. ALCAR enters the brain rapidly in primates [ ] and rodents and is metabolized in mitochondria to free carnitine and acetyl-CoA [ 157 ] as shown in Figure 3. Thus ALCAR provides both carnitine for the transport of fatty acids across mitochondrial membranes, and acetyl-CoA that can be incorporated into lipids [ ], oxidized in the TCA cycle for energy production and incorporated into neurotransmitters [ 157 ].

Scafidi et al. This key study showed that the acetyl moiety of ALCAR was metabolized for energy and incorporated into the carbon skeleton of the neurotransmitters GABA and glutamate in developing brain [ 57 ]. This pathway is considered to be neuroprotective as it can provide pyruvate when glycolysis is inhibited [ — ]. Furthermore, the acetyl moiety from ALCAR can enter the TCA cycle when metabolism via the pyruvate dehydrogenase complex is impaired as occurs in hypoxia and traumatic brain injury [— ].

Overall, the data from Scafidi et al. Such a pattern is not found with metabolism of other substrates including glucose and acetate []. The continued increase in metabolite labeling may be due to reutilization of the acetyl CoA subsequent to oxidation of fatty acids that were synthesized from the acetyl moiety of the labeled ALCAR.

This possibility is Alcar acetyl l-carnitine by the findings of Ricciolini et al. The citrate formed from the condensation of acetyl CoA and oxaloacetate OAA can also exit the mitochondria and following cleavage by citrate lyase it provides cytosolic OAA, and acetyl-CoA which can be used for lipid synthesis or as a precursor for acetylcholine.

Free L-carnitine in the mitochondrial matrix can be used to form carnitine derivatives of acyl-CoA conjugates, therefore reducing their toxicity in conditions where the levels of these compounds are high e. Ricciolini et al. Thus, the acetyl moiety from ALCAR can be oxidized for energy, serve as a precursor for acetylcholine, and be incorporated into amino acid neurotransmitters and lipids in brain [ 57].

Aureli et al. Interestingly, administration of ALCAR led to increased levels of proglycogen, a low molecular weight glycogen precursor, in brain compared to the levels in untreated rats [ ]. The highest increases in rCMRglc were seen in the basal forebrain, septal and brainstem regions [ ]. Although the mechanism is not known, acetyl CoA from ALCAR metabolism may have been used for synthesis of acetylcholine, which may Alcar acetyl l-carnitine contributed to enhanced cholinergic neurotransmission [ ]. This latter finding is consistent with reports that uptake and metabolism of acetate occurs primarily in astrocytes [], in contrast to ALCAR which is metabolized in both neurons and astrocytes [ 57 ].

As noted above, clinical trials and case studies have reported efficacy of ALCAR for neuroprotection in conditions leading to central CNS or peripheral nervous system injury in adults [ 147 — 22 ]. Calabrese et al. Smeland et al. They found increased glucose levels and decreased [3- 13 C]lactate in both hippocampus and cortex, but no changes in the incorporation of 13 C from metabolism of [1- 13 C]glucose into the amino acids glutamate, GABA and glutamine.

However, the cortex of ALCAR treated mice had a higher total content of adenosine nucleotides and phosphocreatine, in conjunction with a higher ratio of phosphocreatine to creatine, all of which indicate increased energy levels. Mice supplemented with ALCAR had increased levels of noradrenaline and myo -inositol, and decreased GABA concentration in the hippocampus, and increased levels of serotonin in the cerebral cortex [ ]. In preclinical studies supplementation with ALCAR improved learning and synaptic transmission in aged rats [ — ]. In a clinically relevant model of global ischemia after canine cardiac arrest, treatment with ALCAR reduced the amount of protein carbonyls which are formed after oxidative stress in brain [ ].

In vivo 1 H-magnetic resonance spectroscopy 1 H-MRS in the same rat pups showed that treatment with ALCAR after HI improved lactate levels and maintained creatine concentration in the ipsilateral hippocampus compared to saline treated pups [ 37 ]. After HI on postnatal day 7 both male and female pups showed impairment in several measurements of social play; however, treatment with ALCAR did not rescue deficits in social play [ 39 ].

Treatment with ALCAR after HI led to improved performance on simple motor tests including negative geotaxis, which was impaired in both male and female pups [ 39 ]. Righting reflex and suspension on a dowel was impaired only in male pups after HI; ALCAR treatment improved performance on these tests [ 39 ]. Treatment with ALCAR after HI led to short term and long term improvement in novel object recognition in male pups compared to saline treated pups [ 39 ]. Using the same neonatal rat pup model, Demarest et al.

ALCAR administration after HI increased mitochondrial glutathione peroxidase activity in brain of male pups at 20 hours after injury. Treatment with ALCAR after HI decreased the ificant increase in protein carbonyl formation that was found only in the brain of male pups in both hemispheres of the cerebral cortex, hippocampus and perirhinal cortex [ 38 ]. Using the postnatal day 7 rat pup model of HI described above, Demarest et al.

Pups treated with ALCAR after HI had a ificant increase in the activity of citrate synthase in the ipsilateral hemisphere compared to sham pups and controls. Survivors of pediatric TBI frequently have long-term Alcar acetyl l-carnitine, social, psychological and cognitive impairments [] that can last into adulthood [ — ]. Additional therapies are needed to improve outcome after TBI in children. Thus treatment with ALCAR during the first 48 hours after HI on postnatal day 7, or after TBI on day 21—22 led to long-term protection of the ipsilateral hemisphere and improved behavioral outcome [ 1239 ].

It is important to note that there was no evidence that administration of ALCAR to 7 day old rat pups was harmful in either males or females studied until 35 days of age [ 39 ]. In recent years there have been increasing concerns about possible adverse effects of general anesthesia on the rapidly developing brains of infants and young children. Several studies have also reported that L-carnitine, and particularly ALCAR can protect the developing brain from deleterious effects of exposure to clinically used anesthetic agents [ — ].

Treatment with ALCAR protected from neuroinflammation and apoptosis resulting from anesthesia [ — ]. It is particularly important that some of these studies used newborn or very young nonhuman primates [, ]. De Simone et al. Maintaining acetylcholine levels is important as this neurotransmitter has a crucial role in learning and memory []. Cholinergic pathways in the basal forebrain and hippocampus are necessary for attention, learning and memory [ ].

Acetylcholine triggers hippocampal and cortical synaptic plasticity in part through astrocyte-neuron interactions [ ]. The carnitine shuttle has a role in providing acetyl-CoA groups for acetylcholine synthesis Figure 3and in buffering the level of free coenzyme A in the cytosol which can inhibit acetylcholine synthesis via choline acetyltransferase [ ]. Furukawa et al. Another study by this group [ ] reported that administration of multiple doses of the acetylcholine receptor agonist carbacol decreased microglial activation and inflammation, and decreased brain damage after hypoxia-ischemia in 7 day old rat pups.

There is an urgent need for therapies that can improve outcome after neonatal and pediatric brain injury as current therapies are only partially effective [, — ]. The developing brain has high energy needs for basic cellular functions and for synthesis of neurotransmitters, nucleic acids, proteins, carbohydrates and lipids needed for cell growth and myelination [ ].

Acute injury to pediatric brain can disrupt the complex and highly regulated normal developmental processes [ ].

Alcar acetyl l-carnitine

email: [email protected] - phone:(960) 800-4887 x 1410