Amyloid-beta peptides (Aβ) can trigger apoptotic cascades in neurons. We found previously that memantine, an uncompetitive antagonist of N-methyl-D-aspartate (NMDA) receptors approved for the treatment of moderate to severe Alzheimer's disease, can prevent neurodegeneration induced by intracranial Aβ(1-40) injection. In this study, we tested the hypothesis that memantine prevents Aβ(1-40)-mediated cognitive impairment, neurodegeneration, and apoptosis of hippocampal neurons in rats. In addition, we hypothesized that Aβ(1-40) injection would induce changes in the levels of one or more apoptosis-related proteins, and that these changes would be attenuated by memantine treatment. Female Sprague-Dawley rats were administered memantine (continuous subcutaneous application, 9.6-14.4mg/kg/day; n=8) or vehicle (water; n=8) for 9 days. Two days after treatment initiation, the animals were bilaterally injected with Aβ(1-40) into the CA1/DG region of the hippocampus, subjected to active avoidance testing for 7 days, and sacrificed for immunohistochemical examination of four caspases (3, 6, 8, and 9) and three proteins of the Bcl-2 family (Bcl-2, Bax, and Bad). Injection of Aβ resulted in neurodegeneration, DNA fragmentation, increased Bcl-2 immunostaining, and significantly impaired performance in an active avoidance task, all which were significantly attenuated in rats treated with memantine. No differences in immunoreactivity of caspases 3, 6, 8, and 9 were discovered between groups after 7 days. Additional experiments demonstrated that an increase in caspase 8 immunostaining, observed 3 days after Aβ(1-40) injection, was significantly attenuated in memantine-treated rats. These data suggest that, in rats, memantine can prevent amyloid-triggered expression of apoptosis-related markers and concomitant cognitive deficits.