heme precursor delta-aminolevulinate blocks peripheral myelin formation

• Published in: Journal of neurochemistry Vol. 106; no. 5; pp. 2068 - 2079
• Main Authors: Felitsyn, Natalia, McLeod, Colin, Shroads, Albert L, Stacpoole, Peter W, Notterpek, Lucia
• Format: Journal Article
• Language: English
• Published: Oxford, UK Oxford, UK : Blackwell Publishing Ltd 01.09.2008; Blackwell Publishing Ltd; Blackwell
• Subjects: Aminoacid disorders; Aminolevulinic Acid - metabolism; Aminolevulinic Acid - toxicity; Animals; Axons - drug effects; Axons - metabolism; Axons - pathology; Biochemistry; Biological and medical sciences; Blood diseases; Cell culture; Cells, Cultured; Coculture Techniques; delta-aminolevulinate; demyelination; dichloroacetate; Dichloroacetic Acid - toxicity; Dose-Response Relationship, Drug; Errors of metabolism; Free Radicals - metabolism; Ganglia, Spinal - drug effects; Ganglia, Spinal - metabolism; Ganglia, Spinal - physiopathology; Heme - biosynthesis; Medical sciences; Metabolic diseases; Mice; Myelin Proteins - drug effects; Myelin Proteins - metabolism; Myelin Sheath - drug effects; Myelin Sheath - metabolism; Myelin Sheath - pathology; Nerve Fibers, Myelinated - drug effects; Nerve Fibers, Myelinated - metabolism; Nerve Fibers, Myelinated - pathology; Neurology; Neurons, Afferent - drug effects; Neurons, Afferent - metabolism; Neurons, Afferent - pathology; neuropathy; Neurotoxins - metabolism; Neurotoxins - toxicity; Other metabolic disorders; oxidative stress; Oxidative Stress - drug effects; Oxidative Stress - physiology; Peripheral Nerves - drug effects; Peripheral Nerves - metabolism; Peripheral Nerves - pathology; Peripheral Nervous System Diseases - chemically induced; Peripheral Nervous System Diseases - metabolism; Peripheral Nervous System Diseases - physiopathology; peripheral neuropathy; Pigments (porphyrias, hyperbilirubinemias...); Proteins; Rats; Schwann cells; Schwann Cells - drug effects; Schwann Cells - metabolism; Schwann Cells - pathology; Porphyria; Skin disease; Tyrosinemia; Neuroglia; Lipids; Enzymopathy; Precursor; peripheral neuropathy; dichloroacetate; Schwann cell; demyelination; Heme; Pigments; Complication; Peripheral nerve disease; Aminoacid disorder; Drug; Urine; Photosensitivity; Nervous system diseases; Myelin; Schwann cells; delta-aminolevulinate; Metabolic diseases; Protein; Genetic disease; Porphyrin; Animal; Sensory neuron; oxidative stress
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/j.1471-4159.2008.05552.x

Delta-aminolevulinic acid (δ-ALA) is a heme precursor implicated in neurological complications associated with porphyria and tyrosinemia type I. Delta-ALA is also elevated in the urine of animals and patients treated with the investigational drug dichloroacetate (DCA). We postulated that δ-ALA may be responsible, in part, for the peripheral neuropathy observed in subjects receiving DCA. To test this hypothesis, myelinating cocultures of Schwann cells and sensory neurons were exposed to δ-ALA (0.1-1 mM) and analyzed for the expression of neural proteins and lipids and markers of oxidative stress. Exposure of myelinating samples to δ-ALA is associated with a pronounced reduction in the levels of myelin-associated lipids and proteins, including myelin protein zero and peripheral myelin protein 22. We also observed an increase in protein carbonylation and the formation of hydroxynonenal and malondialdehyde after treatment with δ-ALA. Studies of isolated Schwann cells and neurons indicate that glial cells are more vulnerable to this pro-oxidant than neurons, based on a selective decrease in the expression of mitochondrial respiratory chain proteins in glial, but not in neuronal, cells. These results suggest that the neuropathic effects of δ-ALA are attributable, at least in part, to its pro-oxidant properties which damage myelinating Schwann cells.