Dose-dependent Effects of Ladostigil on Microglial Activation and Cognition in Aged Rats

The current study determined the effects of chronic treatment of aging rats with ladostigil, a cholinesterase (ChE) and monoamine oxidase (MAO) inhibitor, at doses of 1 and 8.5 mg/kg/day, on novel object recognition (NOR) and reference memory in the Morris water maze (MWM). A dose of (1 mg/kg/day) did not inhibit ChE or MAO but prevented the loss of NOR and reference memory in the MWM that occurs at 20.5 months of age. This anti-aging effect was associated with a reduction in the expression of CD11b, a marker of microglial activation, in the fornix and parietal cortex and restoration of microglial morphology to that in young adult rats. Ladostigil (8.5 mg/kg/day) inhibited brain ChE by a parts per thousand 30 % and MAO A and B by 55-59 %, and had a similar, or greater effect than the low dose on microglia, but was less effective in preventing the decline in NOR. Ladostigil (8.5 mg/kg/day) may have caused too much cortical ChE inhibition and acetylcholine elevation at 16 months when NOR was intact. In support of this suggestion we showed that acute administration of ladostigil (8.5 mg/kg) worsened NOR at this age. However, at 20 months, when NOR was impaired and brain acetylcholine levels are 40 % below normal, ladostigil (8.5 mg/kg) reversed the memory deficit. Conclusion: Ladostigil (1 mg/kg/day) prevents the development of age-related memory deficits by a combination of immunomodulatory and antioxidant effects. A dose causing 30 % ChE inhibition is necessary in order to reverse existing memory deficits at 20 months of age.