SIRT1 activation alleviates paclitaxel induced neuropathic pain by inhibiting mitochondrial damage in the dorsal root ganglion neurons
10.3760/cma.j.cn115354-20240913-00569
- VernacularTitle:激活SIRT1可通过抑制背根神经节神经元线粒体损伤缓解紫杉醇诱导的神经病理性疼痛
- Author:
Yanyan ZENG
1
;
Li LIN
;
Mengyu YAO
;
Wen WU
;
Huai HUANG
Author Information
1. 解放军南部战区总医院高压氧康复科（重症康复中心），广州 510010
- Keywords:
Neuropathic pain;
SIRT1;
Paclitaxel;
Mitochondria;
Oxidative stress
- From:
Chinese Journal of Neuromedicine
2024;23(10):983-991
- CountryChina
- Language:Chinese
-
Abstract:
Objective:To investigate whether silencing information regulator 1 (SIRT1) activation can relieve paclitaxel-induced neuropathic pain by inhibiting mitochondrial damage in dorsal root ganglion neurons.Methods:Forty-eight healthy male SD rats were randomly divided into solvent control group, paclitaxel group, paclitaxel+SIRT1 inhibitor group and paclitaxel+SIRT1 agonist group ( n=12). Neuropathic pain model in the later 3 groups was prepared by intraperitoneal injection of paclitaxel at 8 mg/kg on the 1 st, 4 th and 7 th d of experiment, respectively; rats in the paclitaxel+SIRT1 inhibitor group and paclitaxel+SIRT1 agonist group were respectively injected with SIRT1 inhibitor EX527 or agonist SRT1720 30 min before the first injection of paclitaxel. In addition, neuropathic pain model was established in 12 rats (model group) by the same method and SIRT1 expression in the dorsal root ganglion tissues was detected by Western blotting 1 d before experiment and on the 3 rd, 7 th and 14 th d of experiment, respectively. Von-Frey filament was used to detect the 50% paw withdrawal mechanical threshold (PWMT), and thermal radiation thermal pain detector was used to evaluate the paw withdraw thermal latency (PWTL) 1 d before experiment and on the 3 rd, 7 th and 14 th d of experiment. On the 7 th d of experiment, 6 rats in each group were sacrificed with excessive anesthesia after PWMT and PWTL detection; L 4-L 6 dorsal root ganglion tissues were rapidly isolated and primary neurons were cultured; Western blotting was used to detect SIRT1 expression in the dorsal root ganglion tissues, JC-1 mitochondrial membrane potential detection kit was used to detect mitochondrial membrane potential (ratio of orange-red fluorescence to green fluorescence), hydrogen peroxide (H 2O 2) detection kit was used to detect H 2O 2 concentration, and mitochondrial superoxide detection kit and mitochondrial green fluorescence probe kit were used to detect mitochondrial superoxide expression. Results:In the model group, SIRT1 expression in the dorsal root ganglion tissues one d before experiment was significantly decreased compared with that on the 3 rd, 7 th and 14 th d of the experiment ( P<0.05). On 3 rd, 7 th and 14 th d of experiment, compared with the solvent control group, the paclitaxel group had significantly decreased 50% PWMT ([6.37±2.27] g, [5.47±2.42] g and [5.34±1.74] g), and PWTL ([9.38±1.27] s, [9.70±1.97] s and [9.12±1.21] s, P<0.05); compared with the paclitaxel group, the paclitaxel+SIRT1 agonist group had significantly increased 50% PWMT ([13.86±3.72] g, [11.87±3.10] g and [12.39±2.94] g) and PWTL ([14.25±2.63] s, [13.29±2.94] s and [14.43±3.91] s), and the paclitaxel+SIRT1 inhibitor group had significantly decreased 50% PWMT [(2.20±1.43] g, [2.43±1.44] g and [2.21±1.56] g) and PWTL ([4.47±1.66] s, [3.65±1.80] s and [3.14±1.59] s, P<0.05). On the 7 th d of experiment, the paclitaxel group had significantly decreased SIRT1 protein expression (53.95±7.37) and ratio of orange-red fluorescence to green fluorescence (48.74±14.57), and significantly increased H 2O 2 concentration ([4.86±0.69] μmol/L) and mitochondrial superoxide expression (180.17±12.08) in the dorsal root ganglion tissues compared with the solvent control group ( P<0.05); compared with the paclitaxel group, the paclitaxel+SIRT1 agonist group had significantly increased SIRT1 expression (97.51±10.09) and ratio of orange-red fluorescence to green fluorescence (83.52±8.60) and decreased H 2O 2 concentration ([2.30±0.39] μmol/L) and mitochondrial superoxide expression (90.17±18.84) in the dorsal root ganglion tissues ( P<0.05); compared with the paclitaxel group, the paclitaxel+SIRT1 inhibitor group had significantly decreased SIRT1 expression (30.80±6.31) and ratio of orange-red fluorescence to green fluorescence (24.60±6.19) and increased H 2O 2 concentration ([10.67±1.85] μmol/L) and mitochondrial superoxide expression (294.52±26.94) in the dorsal root ganglion tissues ( P<0.05). Conclusion:SIRT1 activation can alleviate paclitaxel-induced neuropathic pain by inhibiting mitochondrial damage in dorsal root ganglion neurons.
