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

Abstract

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 8.5mg/kg/day, on novel object recognition (NOR) and reference memory in the Morris water maze (MWM). A dose of (1mg/kg/day) did not inhibit ChE or MAO but prevented the loss of NOR and reference memory in the MWM that occurs at 20.5months 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 (8.5mg/kg/day) inhibited brain ChE by ≈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 (8.5mg/kg/day) may have caused too much cortical ChE inhibition and acetylcholine elevation at 16months when NOR was intact. In support of this suggestion we showed that acute administration of ladostigil (8.5mg/kg) worsened NOR at this age. However, at 20months, when NOR was impaired and brain acetylcholine levels are 40% below normal, ladostigil (8.5mg/kg) reversed the memory deficit. Ladostigil (1mg/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 20months of age.