Chemotherapy associated memory/learning loss and reversal with supplemental amino acids in a rat model

Abstract

IntroductionMost chemotherapy drugs (5‐FU, penclomedine (PEN), phosphamides) that alter memory are pyrimidines, pyridines or other pseudohetero‐cyclic rings that could interact with/antagonize the CNS N‐methyl‐D‐aspartate (NMDA)receptor complex ‐ a memory transmitter pathway. NMDA has numerous neurotransmitter substrates ‐ glutamate, serine, glycine, N‐methyl D‐spartate, all of which can also exist as pseudo‐pyridine or pyrroles. Agents that reverse the memory/learning deficiencies are described here.MethodsThe Morris water maze was modified to screen agents for behaviorial changes. Adult female rats were dosed IP once with PEN (100 mg/kg or 5‐FU (78 mg/kg) and compared vs. controls for learning/memory over 24 h. The time required for each rat to swim & find a pedestal was compared (6 consecutive swims ‐ avg/SD of the 1st vs 6th were compared). Either N‐acetyl cysteine (NAC)(200 mg/kg) or L‐lysine (50 mg/kg) was administered (PO) x 3 days pre‐chemotherapy. The results were compared with the NMDA binding assay in vitro in rat brain homogenates.ResultsPEN and 5‐FU had significant impacts on memory and learning with 1.5 & 2.5‐fold impairment, resp., after 3 hr., and >85% for PEN & 5‐FU at 24 h.,which continued for 1‐3 days, despite normal appearances. 5‐FU and PEN impairments were reversed 1.5 ‐ 2.3 fold with NAC and L‐lysine, resp.ConclusionDrugs that can exist in 5‐6 membered ring configurations could interact antagonize the NMDA receptor complex. NAC is a Lewis acid and L‐lysine a Lewis base, each reversing basic and acidic drugs, resp. The described behavorial screen is easy to use and could be useful in screening anti‐cancer agents for behavioral modification. Supported by NCI/SBIR grant ‐ 5R44CA85021.