Related Experiment Video
Updated: Jul 14, 2025
Analysis of Learning and Memory Ability in an Alzheimer's Disease Mouse Model using the Morris Water Maze
Published on: October 29, 2019
Mitochondrial dysfunction following repeated administration of alprazolam causes attenuation of hippocampus-dependent
Siqing Zhu1, Jingjing Shi1, Qian Jin1
1State Key Laboratory of NBC Protection for Civilian, Changping, Beijing 102205, China.
Abstract:
The frequently repeated administration of alprazolam (Alp), a highly effective benzodiazepine sedative-hypnotic agent, in anxiety, insomnia, and other diseases is closely related to many negative adverse reactions that are mainly manifested as memory impairment. However, the exact molecular mechanisms underlying these events are poorly understood. Therefore, we conducted a proteomic analysis on the hippocampus in mice that received repeated administration of Alp for 24 days. A total of 439 significantly differentially expressed proteins (DEPs) were identified in mice with repeated administration of Alp compared to the control group, and the GO and KEGG analysis revealed the enrichment of terms related to mitochondrial function, cycle, mitophagy and cognition. In vitro experiments have shown that Alp may affect the cell cycle, reduce the mitochondrial membrane potential (MMP) to induce apoptosis in HT22 cells, and affect the progress of mitochondrial energy metabolism and morphology in the hippocampal neurons. Furthermore, in vivo behavioral experiments including IntelliCage System (ICS) and nover object recognition (NOR), hippocampal neuronal pathological changes with HE staining, and the expression levels of brain-deprived neuron factor (BDNF) with immunohistochemistry showed a significant decrease in memory consolidation in mice with repeated administration of Alp, which could be rescued by the co-administration of the mitochondrial protector NSI-189. To the best of our knowledge, this is the first study to identify a link between repeated administration of Alp and mitochondrial dysfunction and that mitochondrial impairment directly causes the attenuation of memory consolidation in mice.
Insights
Repeated alprazolam (Alp) use impairs memory by causing mitochondrial dysfunction in the hippocampus. This memory deficit in mice was reversed by a mitochondrial protector, NSI-189.
Area of Science:
- Neuroscience
- Molecular Biology
- Pharmacology
Background:
- Repeated alprazolam (Alp) administration is linked to memory impairment.
- The molecular mechanisms behind Alp-induced memory deficits remain unclear.
Purpose of the Study:
- To investigate the molecular mechanisms of Alp-induced memory impairment.
- To explore the role of mitochondrial dysfunction in Alp's adverse effects.
Main Methods:
- Proteomic analysis of mouse hippocampus after 24-day Alp administration.
- In vitro studies on HT22 cells and hippocampal neurons.
- In vivo behavioral tests (IntelliCage System, NOR) and histological analysis.
Main Results:
- Identified 439 differentially expressed proteins, enriched in mitochondrial function and cognition pathways.
- Alp reduced mitochondrial membrane potential, induced apoptosis, and altered mitochondrial metabolism and morphology.
- Alp significantly impaired memory consolidation, which was rescued by NSI-189.
Conclusions:
- This study establishes a link between repeated alprazolam use and mitochondrial dysfunction.
- Mitochondrial impairment directly contributes to memory consolidation deficits.
- NSI-189 shows potential as a therapeutic agent to mitigate Alp-induced cognitive side effects.
