The heme precursor delta-aminolevulinate blocks peripheral myelin formation.
Delta-aminolevulinic acid (delta-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 delta-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 delta-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 delta-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 delta-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 delta-ALA are attributable, at least in part, to its pro-oxidant properties which damage myelinating Schwann cells.
Felitsyn
Natalia
N
Department of Neuroscience, College of Medicine, McKnight Brain Institute, University of Florida, Gainesville, Florida 32610-0244, USA.
McLeod
Colin
C
Shroads
Albert L
AL
Stacpoole
Peter W
PW
Notterpek
Lucia
L
D000622:Aminolevulinic Acid / Q000378:metabolism / Q000633:toxicity*; D000818:Animals; D001369:Axons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D018920:Coculture Techniques; D003999:Dichloroacetic Acid / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D005609:Free Radicals / Q000378:metabolism; D005727:Ganglia, Spinal / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D006418:Heme / Q000096:biosynthesis; D051379:Mice; D009185:Myelin Proteins / Q000187:drug effects / Q000378:metabolism; D009186:Myelin Sheath / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009413:Nerve Fibers, Myelinated / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009475:Neurons, Afferent / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009498:Neurotoxins / Q000378:metabolism / Q000633:toxicity; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D010525:Peripheral Nerves / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced* / Q000378:metabolism / Q000503:physiopathology; D051381:Rats; D012583:Schwann Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology
D005609:Free Radicals; D009185:Myelin Proteins; D009498:Neurotoxins; D006418:Heme; D000622:Aminolevulinic Acid; D003999:Dichloroacetic Acid