Myriocin, a serine palmitoyltransferase inhibitor, alters regional brain neurotransmitter levels without concurrent inhibition of the brain sphingolipid biosynthesis in mice

Department of Physiology and Pharmacology, College of Veterinary Medicine, The University of Georgia, Athens, GA 30602-7389, USA.
Toxicology Letters (Impact Factor: 3.26). 03/2004; 147(1):87-94. DOI: 10.1016/j.toxlet.2003.10.016
Source: PubMed


Myriocin is a specific serine palmitoyltransferase (SPT) inhibitor whose effect on the brain is unknown. Brain amine metabolism and sphingolipid biosynthesis were studied in mice treated intraperitoneally with 0, 0.1, 0.3 or 1 mg/kg per day of myriocin for 5 days. Regional concentrations of dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), 5-hydroxytryptamine (5-HT, serotonin), 5-hydroxyindoleacetic acid (5-HIAA) and norepinephrine (NE), were determined. Sphinganine (Sa) and sphingosine (So) concentrations and SPT activity in brain and liver were used to evaluate the impact of myriocin on sphingolipid biosynthesis. Myriocin treatment increased DA in striatum and hippocampus and reduced it in cortex. NE concentration decreased in cerebellum and 5-HT levels were reduced in cortex and in medulla oblongata. Changes in ratios for DOPAC/DA and HVA/DA were observed in hippocampus, cortex and midbrain. Brain Sa, So and SPT activity remained unchanged, whereas Sa and SPT activity decreased in liver. Results showed that myriocin may alter the levels and metabolism of brain amines and this effect is not related with inhibition of sphingolipid biosynthesis in the nervous system.

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    • "The current paradigm focuses primarily on regulation at the level of either the first enzyme involved in de novo synthesis, SPT, or of the enzymes involved in the breakdown of more complex sphingolipids, sphingomyelinases [4,23,29–31]. However, these may not be the only critical control points [32] [33], and it has been suggested that the balance between SPT and UGCG can function as a key regulatory 'rheostat' for sphingolipid metabolism [34]. In fact, UGCG has the potential to serve as a crucial control point within the sphingolipid metabolism pathway (Fig. 1) for decisions involving cell growth and death in at least two ways. "
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