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

Document Type: Research article

Authors

1 Department of Physiology and Pharmacology, Pasteur Institute of Iran, Tehran, Iran.

2 Department of Biology, Faculty of Sciences, University of Zanjan, Zanjan, Iran.

3 Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

4 Department of Neuroscience, College of Medicine and McKnight Brain Institute, University of Florida, Gainesville, FL, USA.

5 Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

Abstract

Entorhinal cortex (EC) is one of the first Entorhinal cortex (EC) is one of the first cerebral regions affected in Alzheimer’s
disease (AD). The pathology propagates to neighboring cerebral regions through a prion-like
mechanism. In AD, intracellular calcium dyshomeostasis is associated with endoplasmic
reticulum (ER) stress. This study was designed to examine hippocampal ER stress following
EC amyloidopathy. Aβ1-42 was bilaterally microinjected into the EC under stereotaxic surgery.
Rats were daily treated with 30 μg of isradipine, nimodipine, or placebo over one week.
Passive avoidance and novel object recognition (NOR) tasks were performed using shuttle box
and NOR test, respectively. GRP78/BiP and CHOP levels were measured in the hippocampal
dentate gyrus (DG) by western blot technique. The glutathione (GSH) level and PDI activity
were also assessed in the hippocampus by colorimetric spectrophotometer. Aβ 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 GSH level in the hippocampus decreased in the Aβ 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.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. Aβ1-42 was bilaterally microinjected into the EC under stereotaxic surgery. Rats were daily treated with 30 μg 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. Aβ 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 Aβ 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.

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