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

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-1 beta, IL-6, TNF-alpha and inducible nitric oxide synthase (iNOS) in the parietal cortex. It was also shown that concentrations ranging from 1nM-1 mu M 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-alpha mRNA and protein by 25-35 % and IL-1 beta 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-alpha 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.