title: Effect of curcumin in a mouse model of Pelizaeus-Merzbacher disease.
abstract: PLP1 amino acid substitutions cause accumulation of misfolded protein and induce endoplasmic reticulum (ER) stress, causing Pelizaeus-Merzbacher disease (PMD), a hypomyelinating disorder of the central nerve system. Currently no effective therapy is available for PMD. Promoted by its curative effects in other genetic disease models caused by similar molecular mechanisms, we tested if curcumin, a dietary compound, can rescue the lethal phenotype of a PMD mouse model (myelin synthesis deficient, msd). Curcumin was administered orally to myelin synthesis deficit (msd) mice at 180 mg·kg(-1)·day(-1) from the postnatal day 3. We evaluated general and motor status, changes in myelination and apoptosis of oligodendrocytes by neuropathological and biochemical examination, and transcription levels for ER-related molecules. We also examined the pharmacological effect of curcumin in cell culture system. Oral curcumin treatment resulted in 25% longer survival (p<0.01). In addition, oligodendrocytes undergoing apoptosis were reduced in number (p<0.05). However, no apparent improvement in motor function, neurological phenotype, and myelin formation was observed. Curcumin treatment did not change the expression of ER stress markers and subcellular localization of the mutant protein in vitro and/or in vivo. Curcumin partially mitigated the clinical and pathological phenotype of msd mice, although molecular mechanisms underlying this curative effect are yet undetermined. Nonetheless, curcumin may serve as a potential therapeutic compound for PMD caused by PLP1 point mutations.
authors.affiliation: Department of Mental Retardation and Birth Defect Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Japan.
authors.forename: Li-Hua
authors.initials: LH
authors.lastname: Yu
authors.forename: Toshifumi
authors.initials: T
authors.lastname: Morimura
authors.forename: Yurika
authors.initials: Y
authors.lastname: Numata
authors.forename: Ryoko
authors.initials: R
authors.lastname: Yamamoto
authors.forename: Naoko
authors.initials: N
authors.lastname: Inoue
authors.forename: Barbara
authors.initials: B
authors.lastname: Antalfy
authors.forename: Yu-ichi
authors.initials: Y
authors.lastname: Goto
authors.forename: Kimiko
authors.initials: K
authors.lastname: Deguchi
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Osaka
authors.forename: Ken
authors.initials: K
authors.lastname: Inoue
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002490:Central Nervous System / Q000378:metabolism / Q000473:pathology; D003474:Curcumin / Q000008:administration & dosage*; D004195:Disease Models, Animal; D015870:Gene Expression / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D018991:Myelin Proteolipid Protein / Q000235:genetics / Q000378:metabolism*; D009186:Myelin Sheath / Q000378:metabolism; D009836:Oligodendroglia / Q000187:drug effects; D009900:Optic Nerve / Q000378:metabolism / Q000473:pathology; D020371:Pelizaeus-Merzbacher Disease / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology
chemical_list: D018991:Myelin Proteolipid Protein; C472930:PLP1 protein, human; D003474:Curcumin