Institute of Drug Research, Hebrew University Medical Center, Ein Kerem, Jerusalem, Israel.
J Neuroimmune Pharmacol. 2012 Jun;7(2):488-98. doi: 10.1007/s11481-012-9358-z. Epub 2012 Mar 28.
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.
在阿尔茨海默病、轻度认知障碍（MCI）的前驱期和老年大鼠中，已经报道了线粒体功能受损，伴随着小胶质细胞激活以及一氧化氮（NO）和促炎细胞因子的释放。本研究表明，16 个月大的大鼠用拉多司替吉（1mg/kg/天）治疗 6 个月，可预防 22 个月时空间记忆缺陷的发展，并显著降低顶叶皮层中 IL-1β、IL-6、TNF-α 和诱导型一氧化氮合酶（iNOS）的基因表达。还表明，拉多司替吉及其三种活性代谢物的浓度范围为 1nM-1μM，可抑制脂多糖（LPS）诱导的小鼠小胶质细胞一氧化氮（NO）的释放，抑制率高达 35-40%。拉多司替吉及其代谢物（10nM）还可使 TNF-αmRNA 和蛋白减少 25-35%，IL-1β和诱导型一氧化氮合酶（iNOS）mRNA 减少 20-35%。10nM 的浓度处于拉多司替吉（1mg/kg/天）口服给予大鼠后在血浆中发现的母体药物 R-MCPAI 和 R-HPAI 的浓度范围内。所有化合物均抑制 IkB-α 的降解和 NF-kB p65 亚基的核转位。它们还抑制 p38 和 ERK1/2 丝裂原活化蛋白激酶（MAPK）的磷酸化，但对 JNK 没有影响。我们提出，抗炎活性可能有助于拉多司替吉对衰老或毒素诱导的小胶质细胞激活引起的记忆损伤发展的神经保护作用。
