Memantine (MEM) has been used to treat patients with Alzheimer' disease though inhibition of reactive oxygen species (ROS), Ca(2+)entry and glutamate receptor. The Ca(2+)permeable TRPA1, TRPM2 and TRPV1 channels are activated in the hippocampus by ROS, and antioxidant MEM as a potent TRPA1, TRPM2 and TRPV1 channel antagonist may reduce A beta-induced oxidative stress and apoptosis in the neurons. In the current study, we investigated the neuroprotective properties of MEM in A beta-induced hippocampal neuron cultures. Freshly isolated hippocampal neurons of mice were divided into eight groups as control, A beta, Hcy, MEM, A beta + Hcy, A beta + Hcy + MEM, A beta + MEM and Hcy + MEM. The neurons were exposed to incubated with A beta (20 mu M for 24 h), Hcy (250 mu M for 30 min) and MEM (10 mu M for 24 h). TRPA1, TRPM2 and TRPV1 of the eight groups were further stimulated by cinnamaldehyde, cumene hydyroperoxide and capsaicin, respectively although they were further inhibited by AP-18, N-(p-Amylcinnamoyl) anthranilic acid (ACA) and capsazepine (CPZ). The [Ca2+] concentration, apoptosis, caspase 3, caspase 9 activations, mitochondrial membrane depolarization and intracellular ROS production values in the neurons were higher in A beta and Hcy groups than in control although they were lower in the MEM group than in A beta and Hcy groups. The values were further decreased by MEM + AP-18, MEM + CPZ and MEM + ACA treatments as compared to MEM only. A beta and Hcy-induced decrease of cell viability level was increased by MEM treatment although A beta and Hcy-induced increase of caspase 3, caspase 9, PARP1, TRPA1, TRPM2 and TRPV1 expression levels were decreased by MEM treatments. In conclusion, TRPA1, TRPM2 and TRPV1 channels are involved in A beta and Hcy-induced neuronal death, and modulation of the activity of these channels by MEM treatment may account for their neuroprotective activity against apoptosis, excessive ROS production, and Ca(2+)entry.