(±)-Acetylcarnitine chloride

(±)-Acetylcarnitine chloride is an agonist for cholinergic.

Acetylcholine receptor (AChR) is an integral membrane protein receptor for acetylcholine. There are two kinds of AChRs: nicotinic acetylcholine receptors and muscarinic acetylcholine receptors.

(±)-Acetylcarnitine chloride is a cholinergic agonist and an intermediate in lipid metabolism [1]. In retinal ganglion cells, acetylcarnitine and acetylcholine inhibited GABAergic responses to exogenous GABA and GABAergic inhibitory postsynaptic currents [2].

In dogs with coronary ligation, (-)-carnitine chloride (LCC) (300 mg/kg) and acetyl (-)-carnitine chloride (ALCC) (300 mg/kg) inhibited the ventricular arrhythmia. Also, LCC and ALCC improved oxidative phosphorylation rate and the mitochondrial function [1]. In the mouse hot plate test, acetyl-l-carnitine (ALCAR) (100 mg/kg) exhibited analgesia. While, U-73122 and neomycin (the phospholipase C (PLC) inhibitors) blocked the increase of the pain threshold induced by ALCAR. LiCl that impairing phosphatidylinositol synthesis antagonized the antinociception in a dose-dependent way. PMA and PDBu (PKC activators) blocked the increase of the pain threshold in a dose-dependent way. These results suggested that ALCAR analgesia required the participation of the PLC-IP3 pathway [3].

References:
[1].  Imai S, Matsui K, Nakazawa M, et al. Anti-arrhythmic effects of (-)-carnitine chloride and its acetyl analogue on canine late ventricular arrhythmia induced by ligation of the coronary artery as related to improvement of mitochondrial function. Br J Pharmacol, 1984, 82(2): 533-542.
[2].  Bähring R, Standhardt H, Martelli EA, et al. GABA-activated chloride currents of postnatal mouse retinal ganglion cells are blocked by acetylcholine and acetylcarnitine: how specific are ion channels in immature neurons? Eur J Neurosci, 1994, 6(7): 1089-1099.
[3].  Galeotti N, Bartolini A, Calvani M, et al. Acetyl-L-carnitine requires phospholipase C-IP3 pathway activation to induce antinociception. Neuropharmacology, 2004, 47(2): 286-294.

GABA-activated chloride currents of postnatal mouse retinal ganglion cells are blocked by acetylcholine and acetylcarnitine: how specific are ion channels in immature neurons?[Pubmed:7952289]

Eur J Neurosci. 1994 Jul 1;6(7):1089-99.

The goal of this study was to clarify pharmacological properties of GABAA receptors in cells of the mouse retinal ganglion cell layer in situ. Spontaneous synaptic currents and responses to exogenous GABA were recorded from individual neurons in retinal whole mounts (postnatal days 1-3) or retinal stripe preparations (postnatal days 4-6). Drugs were applied by a fast local superfusion system. Current responses were measured with the patch-clamp technique in the whole-cell configuration. All cells responded to exogenous GABA (average EC50 and Hill coefficient: 16.7 microM and 0.95 respectively) and generated GABAergic synaptic currents in response to elevated KCl. GABA-induced currents of retinal ganglion cells were blocked by bicuculline, picrotoxin and Zn2+, as well as strychnine, and increased by pentobarbital, clonazepam and 3 alpha-hydroxy-5 alpha-pregnan-20-one. In some retinal ganglion cells GABA caused an increase in the frequency of spontaneous synaptic currents, which points to a partially depolarizing action of this traditionally inhibitory neurotransmitter in the neural retina. Our major observation is that acetylcholine and acetylcarnitine blocked or reduced GABAergic inhibitory postsynaptic currents and responses to exogenous GABA. This effect was seen in only a fraction of retinal ganglion cells and occurred in both the undesensitized and the desensitized state of the GABAA receptor. The block was voltage-independent and persisted during coapplication with the nicotinic and muscarinic acetylcholine receptor antagonists D-tubocurarine and atropine. In contrast to GABA-activated Cl- currents, glycine-activated Cl- currents remained unaffected by acetylcholine and acetylcarnitine.(ABSTRACT TRUNCATED AT 250 WORDS)

Determination of acylcarnitines in urine of patients with inborn errors of metabolism using high-performance liquid chromatography after derivatization with 4'-bromophenacylbromide.[Pubmed:8222273]

Clin Chim Acta. 1993 Jul 16;216(1-2):53-61.

A high-performance liquid chromatographic method is presented for the determination of urinary acylcarnitines. After solid phase extraction on silica columns the acylcarnitines are converted to 4'-bromophenacyl esters with 4'-bromophenacylbromide in the presence of N,N-diisopropylethylamine. Complete derivatization was achieved at 37 degrees C within 30 min. The 4'-bromophenacyl esters were separated by high-performance liquid chromatography on a Hypersil BDS C8 reversed-phase column with a binary gradient containing varying proportions of acetonitrile, water and 0.1 M triethylamine phosphate buffer. Essentially baseline separation was obtained with a standard mixture containing 4'-bromophenacyl esters of carnitine and synthetic acylcarnitines of increasing chain length ranging from acetyl- to palmitoylcarnitine. The method was used to obtain urinary acylcarnitine profiles from patients with propionic, methylmalonic and isovaleric acidemia and with medium-chain and multiple acyl-CoA dehydrogenase deficiency. Quantification of the acylcarnitines was achieved using undecanoylcarnitine as internal standard.

Molecular basis of mitochondrial fatty acid oxidation defects.[Pubmed:1431593]

J Lipid Res. 1992 Aug;33(8):1099-110.

A dozen separate inherited disorders of mitochondrial fatty acid beta-oxidation have been described in humans. This represents about half of the potential sites for genetic error that can affect this important pathway of energy metabolism. As the characterization of these disorders at the clinical and biochemical levels has progressed rapidly, so has the delineation of the molecular defects that underlie them. The most commonly recognized disorder of beta-oxidation is medium-chain acyl-CoA dehydrogenase deficiency; a striking feature of this disorder is that there is a single point mutation that accounts for 90% of the variant alleles among patients with medium-chain acyl-CoA dehydrogenase deficiency. Molecular defects of other enzymes in the pathway have been identified, and it seems likely that a complete description of these defects at the molecular level is a realistic goal. In basic biological terms, such studies will lead to a better understanding of the genetic control exerted on this pathway. In clinical terms, they will lead to improved understanding of the molecular pathophysiology of these diseases and may well provide the necessary techniques to proceed with the screening of these disorders.

Urinary excretion of l-carnitine and acylcarnitines by patients with disorders of organic acid metabolism: evidence for secondary insufficiency of l-carnitine.[Pubmed:6441143]

Pediatr Res. 1984 Dec;18(12):1325-8.

Concentrations of l-carnitine and acylcarnitines have been determined in urine from patients with disorders of organic acid metabolism associated with an intramitochondrial accumulation of acyl-CoA intermediates. These included propionic acidemia, methylmalonic aciduria, isovaleric acidemia, multicarboxylase deficiency, 3-hydroxy-3-methylglutaric aciduria, methylacetoacetyl-CoA thiolase deficiency, and various dicarboxylic acidurias including glutaric aciduria, medium-chain acyl-CoA dehydrogenase deficiency, and multiple acyl-CoA dehydrogenase deficiency. In all cases, concentrations of acylcarnitines were greatly increased above normal with free carnitine concentrations ranging from undetectable to supranormal values. The ratios of acylcarnitine/carnitine were elevated above the normal value of 2.0 +/- 1.1. l-Carnitine was given to three of these patients; in each case, concentrations of plasma and urine carnitines increased accompanied by a marked increase in concentrations of short-chain acylcarnitines. These acylcarnitines have been examined using fast atom bombardment mass spectrometry in some of these diseases and have been shown to be propionylcarnitine in methylmalonic aciduria and propionic acidemia, isovalerylcarnitine in isovaleric acidemia, and hexanoylcarnitine and octanoylcarnitine in medium-chain acyl-CoA dehydrogenase deficiency. The excretion of these acylcarnitines is compatible with the known accumulation of the corresponding acyl-CoA esters in these diseases. In this group of disorders, the increased acylcarnitine/carnitine ratio in urine and plasma indicates an imbalance of mitochondrial mass action homeostasis and, hence, of acyl-CoA/CoA ratios. Despite naturally occurring attempts to increase endogeneous l-carnitine biosynthesis, there is insufficient carnitine available to restore the mass action ratio as demonstrated by the further increase in acylcarnitine excretion when patients were given oral l-carnitine.(ABSTRACT TRUNCATED AT 250 WORDS)