Anti-Inflammatory Effects of Ladostigil and Its Metabolites in Aged Rat Brain and in Microglial Cells

被引:0
|
作者
Rony Panarsky
Lisandro Luques
Marta Weinstock
机构
[1] Hebrew University Medical Center,Institute of Drug Research
来源
Journal of Neuroimmune Pharmacology | 2012年 / 7卷
关键词
Aging rats; Cytokines; Lipopolysaccharide; Microglia; Mitogen activated protein kinase; Nitric oxide;
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学科分类号
摘要
Impaired mitochondrial function accompanied by microglial activation and the release of nitric oxide (NO) and pro-inflammatory cytokines has been reported in Alzheimer's disease, its prodromal phase of Mild Cognitive Impairment (MCI) and in aged rats. The present study showed that 6 months treatment of 16 month old rats with ladostigil (1 mg/kg/day), a novel drug designed for the treatment of MCI, prevented the development of spatial memory deficits at 22 months of age and significantly decreased the gene expression of IL-1β, IL-6, TNF-α and inducible nitric oxide synthase (iNOS) in the parietal cortex. It was also shown that concentrations ranging from 1nM-1 μM of ladostigil and three of its active metabolites inhibited the release of nitric oxide (NO) induced by lipopolysaccharide (LPS) from mouse microglial cells by up to 35–40 %. Ladostigil and its metabolites (10nM) also reduced TNF-α mRNA and protein by 25–35 % and IL-1β and inducible nitric oxide synthase (iNOS) mRNA by 20–35 %. The concentration of 10nM is in the range of that of the parent drug, R-MCPAI and R-HPAI found in plasma after oral administration of ladostigil (1 mg/kg/day) to rats. All the compounds inhibited the degradation of IkB-α and nuclear translocation of the p65 subunit of NF-kB. They also inhibited phosphorylation of p38 and ERK1/2 mitogen-activated protein kinase (MAPK), but had no effect on that of JNK. We propose that the anti-inflammatory activity may contribute towards the neuroprotective action of ladostigil against the development of memory impairments induced by aging or toxin-induced microglial activation.
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页码:488 / 498
页数:10
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