title: Memantine prevents cognitive impairment and reduces Bcl-2 and caspase 8 immunoreactivity in rats injected with amyloid β1-40.
abstract: 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.
authors: Department of Psychiatry and Human Behavior, University of Mississippi Medical Center, 2500 N. State Street, Box 127, Jackson, MS 39216, USA. jmiguel-hidalgo@umc.edu
authors: José Javier
authors: JJ
authors: Miguel-Hidalgo
authors: Ian A
authors: IA
authors: Paul
authors: Valerie
authors: V
authors: Wanzo
authors: Pradeep K
authors: PK
authors: Banerjee
mesh_terms: D016229:Amyloid beta-Peptides / Q000008:administration & dosage* / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D053181:Caspase 8 / Q000378:metabolism*; D003072:Cognition Disorders / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D005260:Female; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D007267:Injections; D008559:Memantine / Q000494:pharmacology*; D008568:Memory / Q000187:drug effects; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010446:Peptide Fragments / Q000008:administration & dosage* / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D016229:Amyloid beta-Peptides; D018696:Neuroprotective Agents; D010446:Peptide Fragments; D019253:Proto-Oncogene Proteins c-bcl-2; C078592:amyloid beta-protein (1-40); D053181:Caspase 8; D008559:Memantine