Synergistic enhancing-memory effect of D-serine and RU360, a mitochondrial calcium uniporter blocker in rat model of Alzheimer's disease

Background: Although Amyloid beta (A beta) and N - methyl D- aspartate receptors (NMDARs are involved in Ca2+ neurotoxicity, the function of mitochondrial calcium uniporter in cognition deficit remain uncertain. Here, we examined the effect of mitochondrial calcium uniporter (MCU) blocker, together with NMDA receptor agonist Dcycloserine (DCS) on memory impairment in a rat model of AD. Methods: Forty adult male Wistar rats underwent stereotaxic cannulation for inducing AD by intracerebroventricular (ICV) injection of A beta(1-42) (5 mu g /8 mu l/rat). Then animals were divided into 5 groups of: Saline + Saline, A beta + Saline, A beta + RU360, A beta + DCS, A beta + RU360 + DCS. Two weeks after the treatments, Morris Water Maze (MWM) and step through passive avoidance learning (SPL) were undertaken for evaluating of spatial and associative memories, respectively. Hippocampal level of cyclic-AMP response element binding protein (CREB) and brain-derived neurotrophic factor (BDNF) were measured by western blot and ELISA. Results: Co - administration of RU360 and DCS significantly improved both acquisition and retrieval of spatial memory as evident by decreased escape latency and increased time spent in the target quadrant (TTS) in MWM, together with increase in step-through latency, but reduced time spent in the dark compartment in SPL. Furthermore, there was a significant rise in the hippocampal level of CREB and BDNF in comparison with A beta + Saline. Conclusion: The present study supports the idea that co- administration of RU360 and DCS ameliorate memory impairment induced by A beta (1-42) probably via CREB / BDNF signaling.

Automated summary

Co-administration of RU360 and DCS significantly improved spatial memory acquisition and retrieval, as shown by decreased escape latency, increased time spent in the target quadrant in the Morris Water Maze, and increased step-through latency in passive avoidance learning. Additionally, hippocampal levels of CREB and BDNF were significantly increased compared to A beta + Saline group.