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Primary cultures from the hypothalamus/thalamus/septum/midbrain (HTSM) region of 1-day-old mice were used to investigate the effects of angiotensin on NMDA excitotoxicity. Cell viability was determined following exposure to 1-10 mM glutamate or 0.01-10 mM NMDA. Cells exposed to 1 mM glutamate or 1 mM NMDA for 24 h showed a significant increase in cell death as determined by propidium iodide staining. HTSM cultures treated with 0.1 mM NMDA revealed both DNA laddering and positive staining for TUNEL, suggesting apoptosis as the primary mechanism for the cell death. We also determined whether angiotensin II (Ang II) modulated NMDA-induced cell death in HTSM-cultured neurons. Cells pre-treated with 10 nM Ang II showed a decrease in NMDA-induced cytotoxicity, TUNEL staining and DNA laddering. NMDA-induced cell death was also reduced when cells were pre-treated with the AT1 receptor antagonist losartan. In this study, we have shown that NMDA and glutamate induce cell death through the NMDA receptor, and that Ang II, acting primarily through the AT2 receptor, can attenuate this response.