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Aluminum-induced "mixed" cell death in mice cerebral tissue and potential intervention
Yan-Xia Hao1,2, Mei-Qin Li1, Jing-Si Zhang1
1Department of Occupational Health, Key Laboratory of Environmental Hazard and Health of Shanxi Province, Key Laboratory of Cellular Physiology of Ministry of Education, Shanxi Medical University, Taiyuan, 030001, People's Republic of China.
Abstract:
The brain is one of organs vulnerable to aluminum insult. Aluminum toxicity is involved in neurobehavioral deficit, neuronal cell dysfunction, and death. The aim of this study are as follows: (1) to evaluate the repairing efficiency of Necrostatin-1 (Nec-1), a cell death inhibitor, and Z-VAD-FMK, a pan-caspase inhibitor, on Al-induced neurobehavioral deficit and neuronal cell death, in order to evidence the cell death inducing ability of aluminum, and (2) to primarily explore the possibility of treating neuronal cell loss-related disease, such as Alzheimer's disease, with Nec-1 and Z-VAD in Al-induced dementia animal model. We found Nec-1 and Z-VAD-FMK alone or in combination could reduce aluminum-induced learning and memory impairment in mice. Pathohistological results indicated that Nec-1 and Z-VAD-FMK can decrease Al-induced neuronal death cell. In addition, some cell death-associated proteins in cell death signal pathway were inhibited by Nec-1 and Z-VAD-FMK in Al-exposed mice. In conclusions, Nec-1 and Z-VAD-FMK can repair the injury of learning and memory induced by aluminum in mice. Furthermore, Nec-1 was more obvious to repair the injury of learning and memory function compared with Z-VAD-FMK. Nec-1 and Z-VAD-FMK can repair the Al-induced morphological injury of cell and reduce the amounts of dead cell, and repairing effects were more significant at higher doses. The effect of Nec-1 was stronger than Z-VAD-FMK, though their mechanism was different. The combination of them had the strongest effect. Our study evidenced Al-induced neuronal necroptosis and apoptosis existing in animal model and suggested potential therapeutic effects of Nec-1 and Z-VAD-FMK on neuronal cell death in neurodegenerative diseases.
Insights
Necrostatin-1 (Nec-1) and Z-VAD-FMK reduce aluminum-induced learning and memory deficits in mice by inhibiting neuronal cell death. These inhibitors show potential for treating neurodegenerative diseases like Alzheimer's.
Area of Science:
- Neuroscience
- Toxicology
- Pharmacology
Background:
- Aluminum toxicity poses a significant threat to brain health, leading to neurobehavioral deficits and neuronal cell death.
- Neurodegenerative diseases, such as Alzheimer's disease, are characterized by neuronal loss, highlighting the need for effective therapeutic strategies.
Purpose of the Study:
- To evaluate the efficacy of Necrostatin-1 (Nec-1), a necroptosis inhibitor, and Z-VAD-FMK, a pan-caspase inhibitor, in repairing aluminum-induced neurobehavioral deficits and neuronal cell death.
- To explore the therapeutic potential of Nec-1 and Z-VAD-FMK in an aluminum-induced dementia animal model, relevant to Alzheimer's disease treatment.
Main Methods:
- Administering Nec-1 and Z-VAD-FMK, alone or in combination, to mice exposed to aluminum.
- Assessing neurobehavioral changes, including learning and memory impairment.
- Conducting pathohistological examinations to evaluate neuronal cell death and associated protein expression in the brain.
Main Results:
- Both Nec-1 and Z-VAD-FMK significantly reduced learning and memory impairments caused by aluminum exposure.
- Pathohistological analysis confirmed that Nec-1 and Z-VAD-FMK decreased aluminum-induced neuronal death.
- Inhibition of cell death-associated proteins in the signaling pathway was observed following treatment with Nec-1 and Z-VAD-FMK.
Conclusions:
- Nec-1 and Z-VAD-FMK effectively repair learning and memory injuries induced by aluminum in mice.
- Nec-1 demonstrated a more pronounced effect on repairing cognitive function compared to Z-VAD-FMK.
- The study provides evidence for aluminum-induced necroptosis and apoptosis, suggesting Nec-1 and Z-VAD-FMK as potential therapeutic agents for neurodegenerative diseases involving neuronal cell death.
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