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Homocysteine (Hcy) is a neurotoxic amino acid that accumulates in several neurodegenerative disorders. We examined the consequences of treatment of cultured rat hippocampal neurons with Hcy and the effects of folate, S-adenosyl methionine (SAM) and MK-801 on Hcy-induced neuron apoptosis and the related molecular mechanisms were also observed. Primary hippocampal neurons were treated with 250 μM Hcy for 4 h resulted in apoptosis time-dependently. 100 μM S-adenosyl methionine (SAM) and 10 μM folate significantly repressed, although 1 μM MK-801, an NMDA receptor inhibitor did not, Hcy-induced neuron apoptosis. SAM and folate significantly repressed Hcy-induced neuron DNA damage. Hcy induced neuron calcium overload through activation of NMDA receptors. Hcy treatment also induced a significant increase in MDA level, but did not affect the neurons' total antioxidant capacity (T-AOC). Hcy (250 μM) significantly increased the expression of p53 and Bax while decreased the expression of Bcl-2. SAM and folate inhibited the changes of apoptosis-related protein expression induced by Hcy. These findings indicate that Hcy compromises neuronal homeostasis by not only DNA damage, but also neuron exitotoxicity, oxidative injury, apoptosis, and expression changes of apoptosis-related proteins. [ABSTRACT FROM AUTHOR]