鼠尾草酸对慢性不可预见性轻度应激诱导的抑郁大鼠的抗抑郁作用及其SIRT1/ERS调控机制

doi:10.13481/j.1671-587X.20230212

Abstract

Abstract:

Objective To investigate the effect of carnosic acid （CA） on the endoplasmic reticulum stress （ERS） in the depression rats induced by chronic unpredictable mild stress （CUMS）， and to elucidate its antidepressant mechanism. Methods Twelve SD rats were randomly selected as control group from 66 SD rats by random number table method， and the remaining 54 rats were induced to establish depression model by CUMS combined with solitary feeding， and 48 rats were randomly divided into model group， fluoxetine（3.17 mg·kg^－1） group， CA （40 mg·kg^－1） group， CA （40 mg·kg^－1）+ EX527 silence information regulator 1 （SIRT1） inhibitor （5 mg·kg^－1） group， and there were 12 rats in each group. After corresponding drug intervention， the total exercise distance and intermediate residence time of the rats were measured by open field test （OFT）； the immobility time of the rats during forced swimming was observed by forced swimming test （FST）； the surge water perference of the rats in various groups were observed by sugar water preference test （SPT）； the percentages of the TUNEL positive cells in hippocampus tissue of the rats in various groups were detected by TUNEL method； immunofluorescence method was used to detect the positive expression intensities of C/EBP-homologous protein （CHOP） and glucose regulated protein 78 （GRP78） in hippocampus tissue of the rats in various groups； real-time fluorescence quantitative PCR（RT-qPCR） method was used to detect the expression levels of SIRT1， GRP78， CHOP， and Caspase-12 mRNA in hippocampus tissue of the rats in various groups； Western blotting method was used to detect the expression levels of SIRT1， GRP78， CHOP Caspase-12， and cleaved Caspase-12 （cleaved Caspase-12） proteins in CA1 region in hippocampus tissue in brain of the rats in various groups. Results Compared with control group， the total exercise distance， intermediate residence time， sugar water preference in OFT， and expression levels of SIRT1 protein and mRNA in CA1 region in hippocampus tissue in brain of the rats in model group were significantly decreased （P<0.05）， the immobility time during forced swimming， percentage of TUNEL positive cells，expression levels of GRP78， CHOP，Caspase-12， and cleaved Caspase-12 proteins were significantly increased （P<0.05）.Compared with model group， the total exercise distance， intermediate residence time，sugar water preference in OFT，and expression levels of SIRT1 protein and mRNA in hippocampus tissue of the rats in fluoxetine group and CA group were significantly increased （P<0.05）， the immobility time during forced swimming， percentage of TUNEL positive cells， expression levels of GRP78， CHOP，Caspase-12， and cleaved Caspase-12 proteins were significantly decreased （P<0.05）；compared with CA group， the total exercise distance， intermediate residence time，sugar water preference in OFT， and expression levels of SIRT1 protein and mRNA in CA1 region in hippocampus tissue in brain of the rats in CA+EX527 group were significantly decreased （P<0.05）， the immobility time during forced swimming， percentage of TUNEL positive cells， expression levels of GRP78， CHOP，Caspase-12， and cleaved Caspase-12 proteins were significantly increased （P<0.05）. Conclusion CA can alleviate the depression-like behaviors of the rats caused by CUMS， and its antidepressant mechanism may be related to the inhibition of ERS mediated by SIRT1.

Key words: Carnosic acid, Depression, Endoplasmic reticulum stress, Silent information regulator 1

CLC Number:

R966

Dongming TAN,Hongying YIN,Xiangmin DENG,Xu DING. Antidepressant effect of carnosic acid on chronic unpredictable mild stress-induced depression in rats and its SIRT1/ERS regulatory mechanism[J].Journal of Jilin University(Medicine Edition), 2023, 49(2): 360-368.

Figures/Tables 9

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References 26

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Gene	Forward primer (5'－3')	Reverse primer (5'－3')
SIRT1	GTTGTGTGCCTTCGTTTTGGA	AGGCCGGTTTGGGCTTATACA
GRP78	ACACTTGGTATTGAAACTGTGGGAG	CTTGATTGTTACGGTGGGCTG
CHOP	TCTTCATACACCACCACACCTG	CTTCGTTTCCTGGGGATGAGA
Caspase-12	TTGGATACTCAGTGGTGATAAAGGA	GGATGCCGTGGGACATAAAGA
β-actin	GTTGTCTCCTGCGACTTCA	GCCCCTCCTGTTATTATGG

Group	Total exercisedistance (l/m)	Intermediate residence time (t/s)	Immobility time during forced swimming (t/s)	Sugar water preference (η/%)
Control	10.45±1.37	68.39±9.26	20.30±3.48	67.80±7.24
Model	5.12±0.86^*	32.27±5.40^*	76.74±5.19^*	25.31±4.69^*
CA	7.33±0.91^*△	49.58±6.35^*△	45.29±4.62^*△	43.54±5.81^*△
Fluoxetine	7.84±1.15^*△	56.42±8.16^*△	39.61±5.07^*△	52.72±6.35^*△
CA+EX527	5.50±0.76^*#	35.07±6.24^*#	70.43±6.25^*△#	27.43±4.06^*#

Group	Percentage of TUNEL positive cells
Control	7.25±1.10
Model	21.34±2.06^*
Fluoxetine	10.39±1.28^*△
CA	14.60±1.75^*△
CA+EX527	18.52±1.91^*△#

Group	CHOP	GRP78
Control	7.25±2.07	2.30±0.26
Model	42.81±4.13^*	16.17±2.09^*
Fluoxetine	19.40±2.65^*△	5.09±0.72^*△
CA	23.36±3.29^*△	8.28±1.35^*△
CA+EX527	35.78±4.02^*△#	12.75±1.46^*△#

Group	SIRT1 mRNA	GRP78 mRNA	CHOP mRNA	Caspase-12 mRNA
Control	1.01±0.12	0.98±0.10	1.02±0.14	1.00±0.09
Model	0.35±0.05^*	2.43±0.28^*	2.18±0.25^*	2.05±0.22^*
Fluoxetine	0.79±0.08^*△	1.57±0.21^*△	1.45±0.18^*△	1.33±0.15^*△
CA	0.64±0.07^*△	1.81±0.25^*△	1.59±0.20^*△	1.46±0.19^*△
CA+ EX527	0.45±0.06^*#	2.26±0.29^*#	1.92±0.23^*#	1.80±0.20^*#

Antidepressant effect of carnosic acid on chronic unpredictable mild stress-induced depression in rats and its SIRT1/ERS regulatory mechanism

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Group	SIRT1	GRP78	CHOP	Caspase-12	cleaved Caspase-12
Control	0.56±0.07	0.24±0.04	0.49±0.07	0.57±0.06	0.10±0.02
Model	0.21±0.04^*	0.61±0.08^*	1.05±0.12^*	1.14±0.13^*	0.37±0.05^*
CA	0.34±0.05^*△	0.50±0.07^*△	0.78±0.09^*△	0.83±0.11^*△	0.25±0.04^*△
Fluoxetine	0.46±0.06^*△	0.38±0.05^*△	0.70±0.08^*△	0.75±0.08^*△	0.16±0.03^△
CA+EX527	0.29±0.04^*#	0.55±0.06^*#	0.92±0.11^*#	1.03±0.12^*#	0.31±0.05^*#

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