Neuroprotective effects of dexmedetomidine on intracerebral hemorrhage of rats by Nrf2-GPX4 mediated iron death pathway

doi:10.11958/20212825

Abstract

Abstract:

Objective To explore the mechanism of Nrf2-GPX4-mediated iron death pathway in the neuroprotective effect of dexmedetomidine (Dex) on intracerebral hemorrhage (ICH) in rats. Methods A total of 100 rats were randomly divided into the sham group, the ICH group (model group), the Dex-L group (Dex 50 μg/kg), the Dex-H group (Dex 100 μg/kg) and the Dex-H+ML385 group (Nrf2 inhibitor ML385, 30 mg/kg), with 20 rats in each group. Except for the sham group, ICH model was established by autologous blood injection in the other groups. In the Dex-L group, the Dex-H group and the Dex-H+ML385 group, the corresponding Dex or ML385 was injected intraperitoneally 30 minutes before operation, and the sham group and the ICH group were injected with the same amount of normal saline. Zea Longa 5 scoring method was used to evaluate rat nerve function damage. The contents of glutathione (GSH), malondialdehyde (MDA) and iron ions in brain tissue around the hematoma were detected by the kit. The brain water content around the hematoma was measured. HE staining, Nissl staining and Prussian blue staining were used to observe the pathology, nerve cell damage and iron deposition around the hematoma. Western blot assay was used to detect the expression levels of GPX4, cystine/glutamate antiporter system light chain (xCT) and Nrf2 in brain tissue. Results Compared with the sham group, the neurological deficit score, MDA, iron content, brain water content, brain tissue pathological damage and iron deposition were significantly increased in the ICH group, while the GSH content, nerve cell number, GPX4, xCT and Nrf2 expression levels were significantly decreased in the ICH group (P<0.05). Compared with the ICH group, the neurological deficit score, MDA, iron content, brain water content, brain tissue pathological damage and iron deposition were significantly reduced in turn in the Dex-L group and the Dex-H group, and the GSH content, nerve cell number, GPX4, xCT and Nrf2 expression levels were significantly increased (P<0.05). ML385 reversed improvements in neurological function, iron deposition and brain damage caused by Dex-H. Conclusion Dexmedetomidine inhibits iron death by activating the Nrf2-GPX4 pathway, thereby exerting a neuroprotective effect on ICH rats.

Key words: NF-E2-related factor 2, cerebral hemorrhage, glutathione peroxidase, dexmedetomidine, iron death

CLC Number:

R329.21

Figures/Tables 6

References 20

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组别	MDA（µmol/g）	铁离子（μg/g）	GSH（mg/g）
Sham组	5.01±0.65	40.28±3.22	3.49±0.33
ICH组	16.95±1.03^a	93.50±4.29^a	0.84±0.26^a
Dex-L组	10.73±0.82^b	76.84±4.03^b	1.92±0.30^b
Dex-H组	7.12±0.68^bc	58.08±3.69^bc	2.80±0.35^bc
Dex-H+ML385组	12.87±1.10^d	81.23±4.22^d	1.12±0.28^d
F	145.026^＊＊	143.132^＊＊	66.601^＊＊

组别	MDA（µmol/g）	铁离子（μg/g）	GSH（mg/g）
Sham组	5.01±0.65	40.28±3.22	3.49±0.33
ICH组	16.95±1.03^a	93.50±4.29^a	0.84±0.26^a
Dex-L组	10.73±0.82^b	76.84±4.03^b	1.92±0.30^b
Dex-H组	7.12±0.68^bc	58.08±3.69^bc	2.80±0.35^bc
Dex-H+ML385组	12.87±1.10^d	81.23±4.22^d	1.12±0.28^d
F	145.026^＊＊	143.132^＊＊	66.601^＊＊

组别	GPX4/β-actin	xCT/β-actin	Nrf2/β-actin
Sham组	1.67±0.25	1.08±0.10	1.40±0.21
ICH组	0.44±0.07^a	0.25±0.06^a	0.61±0.08^a
Dex-L组	0.83±0.11^b	0.56±0.07^b	0.94±0.10^b
Dex-H组	1.32±0.19^bc	0.83±0.09^bc	1.23±0.14^bc
Dex-H+ML385组	0.70±0.09^d	0.45±0.08^d	0.82±0.09^d
F	49.691^＊＊	80.326^＊＊	28.416^＊＊

组别	GPX4/β-actin	xCT/β-actin	Nrf2/β-actin
Sham组	1.67±0.25	1.08±0.10	1.40±0.21
ICH组	0.44±0.07^a	0.25±0.06^a	0.61±0.08^a
Dex-L组	0.83±0.11^b	0.56±0.07^b	0.94±0.10^b
Dex-H组	1.32±0.19^bc	0.83±0.09^bc	1.23±0.14^bc
Dex-H+ML385组	0.70±0.09^d	0.45±0.08^d	0.82±0.09^d
F	49.691^＊＊	80.326^＊＊	28.416^＊＊