Memantine inhibits the expression of caspase‐8 and improves learning in rats injected with [beta]‐amyloid (A[beta] 1–40 )

Abstract

To determine a possible mechanism for the anti-apoptotic effect of memantine, immunohistochemistry was used to measure the expression of various caspases (3, 6, 8, and 9) in the hippocampus of memantine-treated rats injected with Aβ1–40. Additionally, the performance of Aβ-injected rats pretreated with memantine was tested in an active avoidance task. Sprague-Dawley rats were administered vehicle or memantine (30 mg/ml, s.c.) for 8 days. On day 3, all rats received bilateral intrahippocampal injections of Aβ1–40 (1.5 μM in 2 μL/side). Three days after the Aβ injections, one group of Aβ-injected rats was sacrificed and 30 μm coronal brain sections were processed for caspase immunostaining. Another group of Aβ-injected rats was tested in an active avoidance paradigm starting on the third day after Aβ injection. In Aβ-treated rats, there was a selective increase in the expression of caspase 8 in the CA1 subfield and dentate gyrus, whereas the expression of other caspases (3, 6 and 9) did not change significantly from control. The Aβ-treated rats also demonstrated poor performance on the active avoidance task compared to control rats. In contrast, memantine pretreatment significantly decreased Aβ-induced caspase 8 immunoreactivity in the CA1 and dentate gyrus and also significantly improved the performance of Aβ-injected rats on the active avoidance task. These data suggest that memantine can improve performance in memory-impaired animals, and that its anti-apoptotic activity may be mediated by caspase 8.