Calcium Channel Blockade Ameliorates Endoplasmic Reticulum Stress in the Hippocampus Induced by Amyloidopathy in the Entorhinal Cortex

摘要

Entorhinal cortex (EC) is one of the first Entorhinal cortex (EC) is one of the first cerebral regions affected in Alzheimera??sdisease (AD). The pathology propagates to neighboring cerebral regions through a prion-likemechanism. In AD, intracellular calcium dyshomeostasis is associated with endoplasmicreticulum (ER) stress. This study was designed to examine hippocampal ER stress followingEC amyloidopathy. A?21-42 was bilaterally microinjected into the EC under stereotaxic surgery.Rats were daily treated with 30 ??g of isradipine, nimodipine, or placebo over one week.Passive avoidance and novel object recognition (NOR) tasks were performed using shuttle boxand NOR test, respectively. GRP78/BiP and CHOP levels were measured in the hippocampaldentate gyrus (DG) by western blot technique. The glutathione (GSH) level and PDI activitywere also assessed in the hippocampus by colorimetric spectrophotometer. A?2 treated groupdeveloped passive avoidance and novel recognition memory deficit compared to the controlgroup. However, treatment with calcium channel blockers reversed the impairment. BiP andCHOP level increased in the hippocampus following amyloidopathy in the EC. PDI activityand GSH level in the hippocampus decreased in the A?2 treated group, but calcium channelblockers restored them toward the control level. In conclusion, memory impairment due to ECamyloidopathy is associated with ER stress related bio-molecular changes in the hippocampus,and treatment with L-type calcium channel blockers may prevent the changes and ultimatelyimprove cognitive performance.cerebral regions affected in AD. Intracellular calcium buffering capacity is disrupted in the dentate gyrus (DG) following EC amyloidopathy. This study was designed to examine hippocampal endoplasmic reticulum (ER) stress following EC amyloidopathy. A?21-42 was bilaterally microinjected into the EC under stereotaxic surgery. Rats were daily treated with 30 ??g of isradipine, nimodipine or placebo over one week. Passive avoidance and novel object recognition (NOR) tests were performed. GRP78/BiP and CHOP levels were measured in the hippocampal DG. The glutathione (GSH) level and PDI activity were also assessed in the hippocampus. A?2 treated group developed passive avoidance and novel recognition memory deficit compared to the control group. However, treatment with calcium channel blockers reversed the impairment. BiP and CHOP level increased in the hippocampus following amyloidopathy in the EC. PDI activity and GDH level in the hippocampus were decreased in the A?2 treated group, but calcium channel blockers restored them toward the control level. In conclusion, memory impairment due to EC amyloidopathy is associated with ER stress related bio-molecular changes in the hippocampus, and treatment with L-type calcium channel blockers may prevent the changes and ultimately improve cognitive performance.