Effect of curcumin regulating NMDAR/Ca2+/CaMKⅡ signaling pathway on postoperative cognitive dysfunction induced by isoflurane in young mice

doi:10.11958/20221719

Abstract

Abstract:

Objective To investigate the effect of curcumin (Cur) regulating N-methyl-D-aspartate receptor (NMDAR)/calcium ion (Ca²⁺)/calmodulin dependent protein kinase Ⅱ (CaMKⅡ) signaling pathway on isoflurane (ISO) -induced postoperative cognitive dysfunction (POCD) in young mice. Methods Seventy-two C57BL/6J mice were separated into the control group, the ISO group, the low-dose Cur group (Cur-L group, 50 mg/kg), the medium-dose Cur group (Cur-M group, 100 mg/kg), the high-dose Cur group (Cur-H group, 200 mg/kg) and the Cur-H+NMDA (NMDAR activator) group (200 mg/kg+8 mg/kg), with 12 animals in each group. After 30 min of corresponding drug treatment, the mice in the control group inhaled a mixed gas containing 30% oxygen and air for 2 hours, and mice in the other groups inhaled 2% ISO for 2 hours, once a day for 14 days. Twenty-four hours after the last treatment, Morris water maze test was used to detect the learning and spatial memory abilities of mice. HE staining was used to detect the pathological changes in hippocampal CA1 area. Immunofluorescence staining was used to detect the positive expression of neuron specific nucleoprotein (NeuN) in hippocampus CA1 region of mice. TUNEL staining was used to detect neuronal apoptosis. Enzyme linked immunosorbent assay was used to detect levels of interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) in hippocampal CA1 tissue. Western blot assay was used to detect NMDAR1 and CaMKⅡ protein expression in mouse hippocampal CA1 tissue. Intracellular Ca²⁺ concentration in hippocampal CA1 region was detected by fluorescence probe. Results Compared with the control group, the pathological damage of hippocampal CA1 region of mice was severe in the ISO group, and the escape latency was prolonged. The apoptosis rate of neural cells, levels of IL-1β and TNF-α, expression levels of NMDAR1 and CaMKⅡ protein, and the concentration of Ca²⁺ in hippocampal CA1 region were increased (P<0.05). Times of crossing platform and the number of NeuN positive cells were decreased in the ISO group (P<0.05). Compared with the ISO group, pathological damages of hippocampal CA1 region of mice were alleviated in the Cur-L group, the Cur-M group and the Cur-H group, the escape latency was shortened, and the apoptosis rate of neural cells, levels of IL-1β and TNF-α, expression levels of NMDAR1 and CaMKⅡ protein, and the concentration of Ca²⁺ in hippocampal CA1 region were decreased (P<0.05). Times of crossing platform and the number of NeuN positive cells were increased (P<0.05), which was dose-dependent. NMDA attenuated the improvement effect of high-dose Cur on ISO induced POCD in mice (P<0.05). Conclusion Curcumin may improve ISO-induced POCD in mice by inhibiting NMDAR/Ca²⁺/CaMKⅡ signaling pathway.

Key words: curcumin, receptors, N-methyl-D-aspartate, calcium channels, calcium-calmodulin-dependent protein kinase type 2, cognitive dysfunction, postoperative cognitive complications, isoflurane

CLC Number:

R285.5，R614.2

Figures/Tables 8

References 22

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组别	逃避潜伏期/s	穿越平台次数/次
对照组	10.27±1.02	8.83±0.79
ISO组	58.45±7.34^a	1.73±0.12^a
Cur-L组	49.33±5.15^b	2.67±0.21^b
Cur-M组	38.82±2.77^bc	4.03±0.32^bc
Cur-H组	24.48±2.51^bcd	6.93±0.53^bcd
Cur-H+NMDA组	41.97±4.86^e	3.22±0.27^e
F	182.808^＊＊	474.270^＊＊

组别	逃避潜伏期/s	穿越平台次数/次
对照组	10.27±1.02	8.83±0.79
ISO组	58.45±7.34^a	1.73±0.12^a
Cur-L组	49.33±5.15^b	2.67±0.21^b
Cur-M组	38.82±2.77^bc	4.03±0.32^bc
Cur-H组	24.48±2.51^bcd	6.93±0.53^bcd
Cur-H+NMDA组	41.97±4.86^e	3.22±0.27^e
F	182.808^＊＊	474.270^＊＊

组别	NeuN阳性细胞数/（个/视野）	细胞凋亡率/%
对照组	58.45±3.34	2.45±0.11
ISO组	10.27±1.02^a	18.62±1.21^a
Cur-L组	24.48±2.51^b	15.41±1.02^b
Cur-M组	35.82±2.77^bc	10.96±0.75^bc
Cur-H组	49.33±3.15^bcd	5.62±0.37^bcd
Cur-H+NMDA组	28.97±2.86^e	13.34±1.26^e
F	492.239^＊＊	554.614^＊＊

组别	NeuN阳性细胞数/（个/视野）	细胞凋亡率/%
对照组	58.45±3.34	2.45±0.11
ISO组	10.27±1.02^a	18.62±1.21^a
Cur-L组	24.48±2.51^b	15.41±1.02^b
Cur-M组	35.82±2.77^bc	10.96±0.75^bc
Cur-H组	49.33±3.15^bcd	5.62±0.37^bcd
Cur-H+NMDA组	28.97±2.86^e	13.34±1.26^e
F	492.239^＊＊	554.614^＊＊

组别	IL-1β	TNF-α
对照组	1.35±0.12	1.17±0.10
ISO组	12.28±1.02^a	8.45±0.62^a
Cur-L组	9.46±0.64^b	6.52±0.43^b
Cur-M组	6.82±0.47^bc	4.67±0.21^bc
Cur-H组	3.45±0.22^bcd	2.58±0.20^bcd
Cur-H+NMDA组	7.66±0.43^e	5.57±0.31^e
F	591.153^＊＊	663.438^＊＊

Effect of curcumin regulating NMDAR/Ca²⁺/CaMKⅡ signaling pathway on postoperative cognitive dysfunction induced by isoflurane in young mice

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组别	NMDAR1/ β-actin	CaMKⅡ/ β-actin	Ca²⁺/ （nmol/L）
对照组	0.31±0.02	0.23±0.02	68.52±3.16
ISO组	1.36±0.11^a	0.97±0.08^a	157.73±11.34^a
Cur-L组	1.05±0.08^b	0.72±0.08^b	129.24±9.62^b
Cur-M组	0.71±0.07^bc	0.49±0.04^bc	105.56±6.33^bc
Cur-H组	0.39±0.03^bcd	0.27±0.03^bcd	79.73±4.26^bcd
Cur-H+NMDA组	0.82±0.07^e	0.66±0.04^e	117.58±6.24^e
F	383.611^＊＊	334.224^＊＊	235.201^＊＊

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