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

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Abstract

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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Acknowledgements

The authors would like to thank Corina Bejar who performed the Morris water maze tests.

The authors have no conflict of interest that could bias their work and none of them receives any remuneration from a Pharmaceutical company associated with the clinical development of ladostigil. The research was supported by independent funds of Marta Weinstock.

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  1. Institute of Drug Research, Hebrew University Medical Center, Ein Kerem, Jerusalem, 911120, Israel

    Rony Panarsky, Lisandro Luques & Marta Weinstock

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  1. Rony Panarsky
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Correspondence to Marta Weinstock.

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Panarsky, R., Luques, L. & Weinstock, M. Anti-Inflammatory Effects of Ladostigil and Its Metabolites in Aged Rat Brain and in Microglial Cells. J Neuroimmune Pharmacol 7, 488–498 (2012). https://doi.org/10.1007/s11481-012-9358-z

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