L-Carnitine and Acetyl-L-carnitine Roles and Neuroprotection in Developing Brain

Abstract

L-Carnitine functions to transport long chain fatty acyl-CoAs into the mitochondria for degradation by β-oxidation. Treatment with L-carnitine can ameliorate metabolic imbalances in many inborn errors of metabolism. In recent years there has been considerable interest in the therapeutic potential of L-carnitine and its acetylated derivative acetyl-L-carnitine (ALCAR) for neuroprotection in a number of disorders including hypoxia-ischemia, traumatic brain injury, Alzheimer's disease and in conditions leading to central or peripheral nervous system injury. 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.

Keywords: Acetyl-L-carnitine; Carnitine shuttle; Inborn errors of metabolism; L-Carnitine; Metabolism; Neonatal hypoxia-ischemia; Neuroprotection; Pediatric traumatic brain injury.

Figure 1. L-Carnitine biosynthesis in humans

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 S-adenosylhomocysteine and the methylated lysine. After lysosomal proteolytic release of the 6-N-trimethyllysine residue, 6-N-trimethyllysine is then metabolized by 6-N-trimethyllysine dioxygenase (enzyme 2) leading to the formation of the hydroxylated metabolite, 3-hydroxy-6-N-trimethyllysine. 3-hydroxy-6-N-trimethyllysine aldolase (enzyme 3) splits 3-hydroxy-6-N-trimethyllysine into glycine plus 4-N-trimethylaminobutyraldehyde, which is further dehydrogenated to 4-N-trimethylaminobutyrate (also known as γ-butyrobetaine) by 4-N-trimethylaminobutyraldehyde dehydrogenase (enzyme 4). The enzymes mentioned in these steps are ubiquitously expressed; therefore, γ-butyrobetaine can be produced in many tissues. The last step in carnitine synthesis is the hydroxylation of γ-butyrobetaine by γ-butyrobetaine dioxygenase (enzyme 5) forming 3-hydroxy-4-N-trimethylaminobutyrate (carnitine). The presence of γ-butyrobetaine dioxygenase is restricted to kidney, liver, and brain, therefore the complete pathway for endogenous carnitine biosynthesis only occurs in these tissues.

Figure 2. The carnitine shuttle

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. Acylcarnitines cross the inner mitochondrial membrane via a transporter, the carnitine/acylcarnitine translocase (CACT), in exchange for free L-carnitine. 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. 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.

Figure 3. Metabolism of ALCAR in brain

The mitochondrial membrane permeable acetyl-L-carnitine (ALCAR) is split in the mitochondrial matrix yielding acetyl-CoA and L-carnitine. Acetyl-CoA can be oxidized for energy via the tricarboxylic acid (TCA) cycle or incorporated into glutamate, glutamine or GABA. 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.g., fatty acid oxidation disorders).