期刊
EUROPEAN JOURNAL OF PHARMACOLOGY
卷 896, 期 -, 页码 -出版社
ELSEVIER
DOI: 10.1016/j.ejphar.2021.173907
关键词
Antiepileptic drugs; NPC1-Null mice; Lifespan; Cholesterol trafficking; Late endosomes/lysosomes; Endoplasmic reticulum
资金
- JSPS KAKENHI [17K08303]
- Grants-in-Aid for Scientific Research [17K08303] Funding Source: KAKEN
NPC is caused by a loss of function of NPC1 or NPC2 protein, leading to accumulation of free-cholesterol in cells and resulting in cell damage and neurodegenerative disease. Antiepileptic drug primidone may enhance free-cholesterol trafficking in NPC cells, potentially offering a treatment option for NPC.
Niemann-Pick disease type C (NPC) is caused by a loss of function of either NPC1 or NPC2 protein, resulting in the accumulation of unesterified, free-cholesterol (free-C) in cells/tissues and thus leading to cell/tissue damage. In the brain of patients/animals with NPC, as a consequence of the accumulation of free-C in late endosomes/ lysosomes (LE/LY) in cells, multiple lipids including complex sphingolipids are accumulated, and almost all patients/animals ultimately develop progressive/fatal neurodegeneration. Several reagents that are considered to act in the brain show beneficial effects on NPC-model animals. In the present study, we investigated the effects of antiepileptic drugs, such as primidone and valproic acid, on the accumulation of free-C in NPC1-null CHO cells and NPC1* fibroblasts, human fibroblasts established from a patient with NPC1 mutation. Like valproic acid, treatment with primidone reduced free-C levels in LE/LY in NPC1-null/mutant cells. Down-regulation of cholesterol ester levels in NPC1-null cells and up-regulation of HMG-CoA reductase and low-density lipoprotein receptor mRNA levels in NPC1* cells were partially recovered by primidone treatment. Thus, primidone was suggested to enhance free-C trafficking from LE/LY to endoplasmic reticulum in NPC1-null/mutant cells. In NPC1-null mice, oral application of primidone (100 mg/kg/day) extended lifespan by approximately 5 days, although the first days showing ataxia, a typical symptom of neuromotor dysfunction, were not affected. Our findings suggest the potential of primidone for the treatment of NPC.
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