Velnacrine maleate improves delayed matching performance by aged monkeys

Velnacrine maleate is a novel, orally active acetylcholinesterase inhibitor of the acridine class with a longer duration of action than physostigmine. Velnacrine has shown efficacy in the treatment of Alzheimer's disease and in improving both normal and experimentally impaired mnemonic function in animals and humans. To characterize this action further, the present study evaluated velnacrine for its ability to ameliorate the decline in short-term memory associated with aging in non-human primates at two time points after velnacrine administration: (1) 30 min and (2) 24 h. Initially, doses of 1, 2, 4, and 6 mg/kg, PO (free base corrected) were administered once to each of six aged (25-40 years), memory-impaired macaques that had been trained to perform a delayed matching-to-sample (DMTS) paradigm. The dose associated with the greatest improvement in session performance was administered three more times to the same individual. Four of the six monkeys showed improved DMTS performance during the repeated best dose phase (phase 2). Almost all of the improvement occurred during long-delay trials. Compared to placebo trials, velnacrine induced a significant improvement of long delay DMTS (58.0-66.7%, 13.4% of the placebo value). Long delay DMTS remained significantly improved during the test session conducted 24 h following velnacrine administration. Pharmacokinetic analysis following administration of 4 or 6 mg/kg velnacrine to three aged monkeys revealed peak plasma concentrations ranging from 27 to 166 ng/ml, 30-60 min after dosing. Six hours after dosing velnacrine plasma levels decreased to 5.1-11.8 ng/ml; and 24 h after dosing, velnacrine plasma levels were less than the limit of quantitation (5 ng/ml). Thus, the improved DMTS performance observed 0.5-1.5 h after velnacrine administration coincided with the peak absorption of the drug in plasma; however, the improved DMTS performance observed 24 h post-dosing was not explained by plasma levels. Possibly, the 24-h improvement was induced by some secondary process, such as long term potentiation.