ABSTRACT
Several studies have reported on the beneficial effects of memantine on behavioral and psychological symptoms of dementia (BPSD) in patients with Alzheimer's disease. However, the effects of memantine on BPSD-like behaviors in animals have not been well addressed. Here, the effects of memantine on memory disturbance and BPSD-like behaviors were evaluated in thiamine-deficient (TD) mice. Memantine (3 and 10â¯mg/kg, b.i.d.) was orally administered to ddY mice fed a TD diet for 22â¯days. During the treatment period, the forced swimming test, elevated plus-maze test, passive avoidance test, and locomotor activity test were performed. Neurotransmitter levels in the brain were analyzed after the treatment period. Daily oral administration of memantine ameliorated the memory disturbances, anxiety-like behavior, and depression-like behavior observed in TD mice. Memantine did not have a significant effect on monoamine levels, but increased glutamate levels in the hippocampus in TD mice. These results suggest that memantine prevents or suppresses the progression of BPSD-like behaviors that develop due to TD. This effect may be mediated in part by the enhancement of glutamatergic neuron activity in the hippocampus.
Subject(s)
Behavior, Animal/drug effects , Dementia/chemically induced , Dementia/psychology , Memantine/pharmacology , Memory/drug effects , Thiamine Deficiency/psychology , Administration, Oral , Animals , Anxiety/drug therapy , Biogenic Monoamines/metabolism , Body Weight/drug effects , Dementia/drug therapy , Depression/drug therapy , Disease Models, Animal , Glutamic Acid/metabolism , Hippocampus/drug effects , Hippocampus/metabolism , Locomotion/drug effects , Male , Maze Learning/drug effects , Memantine/administration & dosage , MiceABSTRACT
Memantine, an uncompetitive glutamatergic N-methyl-d-aspartate (NMDA) receptor antagonist, is widely used as a medication for the treatment of Alzheimer's disease (AD). We previously reported that chronic treatment of AD with memantine reduces the amount of insoluble ß-amyloid (Aß) and soluble Aß oligomers in animal models of AD. The mechanisms by which memantine reduces Aß levels in the brain were evaluated by determining the effect of memantine on Aß aggregation using thioflavin T and transmission electron microscopy. Memantine inhibited the formation of Aß(1-42) aggregates in a concentration-dependent manner, whereas amantadine, a structurally similar compound, did not affect Aß aggregation at the same concentrations. Furthermore, memantine inhibited the formation of different types of Aß aggregates, including Aßs carrying familial AD mutations, and disaggregated preformed Aß(1-42) fibrils. These results suggest that the inhibition of Aß aggregation and induction of Aß disaggregation may be involved in the mechanisms by which memantine reduces Aß deposition in the brain.
