雷帕霉素对核苷类逆转录酶抑制剂治疗人类免疫缺陷病毒感染并发神经病理性痛的影响

doi:10.3877/cma.j.issn.1674-1358.2021.04.006

目的

探讨雷帕霉素对核苷类逆转录酶抑制剂（NRTIs）类药物治疗人类免疫缺陷病毒（HIV）感染并发神经病理性痛的影响。

方法

40只健康雄性昆明小鼠随机分为对照组、司他夫定组、雷帕霉素+司他夫定组和羧甲基纤维素钠（CMC-Na）组（每组各10只）。司他夫定组和雷帕霉素+司他夫定组小鼠每隔24 h灌胃给予相应剂量的药物，对照组和CMC-Na组分别给予同等剂量的生理盐水和0.5% CMC-Na。分别于给药后7、14、21、28、35和42 d测定小鼠机械缩足反应阈和热缩足潜伏期，应用Western blot蛋白印迹检测小鼠脊髓组织中哺乳动物雷帕霉素靶蛋白（mTOR）的表达。

结果

给予司他夫定后7、14、21、28、35和42 d小鼠的机械/热痛阈值均显著下降（P均< 0.01）。与司他夫定组小鼠相比，雷帕霉素+司他夫定组小鼠在给药后7、14、21、28、35和42 d机械/热痛阈值均显著增加（P均< 0.05），其中给药后42 d，雷帕霉素缓解司他夫定所致小鼠机械痛敏[（8.41 ± 0.17） vs. （7.40 ± 0.13），t = 4.89、P = 0.034]和热痛敏[（6.25 ± 0.16） vs. （4.43 ± 0.21），t = 13.32、P < 0.001）的效应达到最大，差异有统计学意义。Western blot蛋白印迹结果显示，雷帕霉素+司他夫定组小鼠与司他夫定组小鼠相比，雷帕霉素可显著逆转司他夫定所致小鼠脊髓组织中磷酸化mTOR蛋白表达增加[（0.72 ± 0.04） vs. （0.86 ± 0.03），t = 4.24、P = 0.045）]。

结论

雷帕霉素可能通过抑制mTOR蛋白磷酸化而缓解NRTIs类药物治疗HIV感染并发的神经病理性痛。

关键词: 雷帕霉素, 核苷类逆转录酶抑制剂, 人类免疫缺陷病毒, 神经病理性痛, 哺乳动物雷帕霉素靶蛋白

Objective

To investigate the effect of rapamycin on neuropathic pain complicated with nucleoside reverse transcriptase inhibitors (NRTIs) treatment of human immunodeficiency virus (HIV) infection.

Methods

Forty male mice were divided into control group, stavudine group, rapamycin + stavudine group and sodium carboxymethyl cellulose (CMC-Na) group (n = 10), randomly. Mice in sastavidine group and rapamycin + stavidine group were intragastrically administered corresponding dose of drug every 24 h, and equivalent dose of saline and 0.5% CMC-Na were given to mice of control and CMC-Na groups, respectively. Behavioral tests were conducted at 7, 14, 21, 28, 35 and 42 days after drug administration, and the expression of mammalian target of rapamycin (mTOR) in spinal cord of mice was detected by Western blot.

Results

The mechanical sensitivity and dramatic thermal hyperalgesia to noxious plantar heat stimulation decreased significantly in mice at 7, 14, 21, 28, 35 and 42 days after stetafudine administration (all P < 0.01). The mechanical threshold in mice was significantly increased and thermal hyperalgesia was reversed in rapamycin + stavudine group at 7, 14, 21, 28, 35, 42 days after stetafudine administration compared with stavudine group (all P < 0.05); among which, on the 42nd day after stetafudine administration, the effect of rapamycin on mechanical allodynia [(8.41 ± 0.17) vs. (7.40 ± 0.13); t = 4.89, P = 0.034] and thermal hyperalgesia [(6.25 ± 0.16) vs. (4.43 ± 0.21); t = 13.32, P < 0.001] in mice were both at the maximum level, with significant differences. Western blot result showed that rapamycin significantly reversed the increased expression of phospho-mTOR in the spinal cord of mice caused by stavudine compared with stavudine group [0.72 ± 0.04) vs. (0.86 ± 0.03); t = 4.24, P = 0.045].

Conclusion

Rapamycin could relieve the neuropathic pain associated with NRTIs treatment of HIV by inhibiting the phosphorylation of mTOR.

Key words: Rapamycin, Nucleoside reverse transcriptase inhibitors, Human immunodeficiency virus, Neuropathic pain, Mammalian target of rapamycin

图1 雷帕霉素对小鼠机械痛敏和热痛敏的影响

表1 雷帕霉素对小鼠机械痛敏和热痛敏的影响（± s）

指标		只数	给药前	给药后7 d	给药后14 d	给药后21 d	给药后28天	给药后35天	给药后42天
PWMT（g）
对照组		10	15.93 ± 0.53	15.63 ± 0.52	15.37 ± 0.46	15.68 ± 0.39	15.42 ± 0.36	15.38 ± 0.42	15.62 ± 0.33
	CMC-Na组	10	15.55 ± 0.29	15.44 ± 0.35	15.45 ± 0.34	15.36 ± 1.53	15.52 ± 0.35	15.50 ± 0.38	15.68 ± 0.34
	雷帕霉素+司他夫定组	10	15.49 ± 0.40	13.44 ± 0.25	10.51 ± 0.27	10.12 ± 0.29	9.51 ± 0.20	8.69 ± 0.20	8.41 ± 0.17
	司他夫定组	10	15.45 ± 0.30	12.35 ± 0.36	9.98 ± 0.50	9.16 ± 1.39	8.54 ± 0.22	7.64 ± 1.03	7.40 ± 0.13
F值			1.45	20.63	34.68	35.76	22.56	18.96	29.18
P值			0.180	0.008	0.004	0.003	0.007	0.008	0.005
t_{对照组 vs. CMC-Na组}			0.48	1.21	0.56	0.89	0.79	1.16	1.23
P_{对照组 vs. CMC-Na组}			0.640	0.28	0.59	0.42	0.56	0.31	0.23
t_{对照组 vs.雷帕霉素+司他夫定组}			0.85	17.16	24.61	32.16	37.18	30.12	19.21
P_{对照组 vs.雷帕霉素+司他夫定组}			0.490	0.009	0.007	0.004	0.003	0.005	0.008
t_{对照组 vs.司他夫定组}			1.12	28.17	34.24	25.12	38.12	22.23	35.17
P_{对照组 vs.司他夫定组}			0.380	0.006	0.004	0.007	0.003	0.007	0.003
t_{CMC-Na组 vs.司他夫定组}			1.25	32.23	33.17	17.73	29.16	37.69	38.69
P_{CMC-Na组 vs.司他夫定组}			0.210	0.004	0.004	0.009	0.005	0.003	0.002
t_{CMC-Na组 vs.雷帕霉素+司他夫定组}			0.63	21.12	27.16	36.21	31.16	18.61	23.14
P_{CMC-Na组 vs.雷帕霉素+司他夫定组}			0.580	0.008	0.006	0.003	0.005	0.009	0.007
t_{司他夫定组 vs.雷帕霉素+司他夫定组}			1.56	5.71	1.64	4.12	4.36	5.06	4.89
P_{司他夫定组 vs.雷帕霉素+司他夫定组}			0.190	0.026	0.12	0.046	0.042	0.031	0.034
PWTL（s）
	对照组	10	10.14 ± 0.17	10.28 ± 0.18	10.15 ± 0.23	10.18 ± 0.20	10.27 ± 0.20	10.21 ± 0.33	10.25 ± 0.21
	CMC-Na组	10	10.59 ± 1.43	10.36 ± 0.14	10.43 ± 0.15	10.44 ± 0.20	10.39 ± 0.14	10.35 ± 0.24	10.39 ± 0.16
	雷帕霉素+司他夫定组	10	10.31 ± 0.17	8.56 ± 0.23	8.29 ± 0.14	7.88 ± 0.19	7.27 ± 0.11	6.90 ± 0.14	6.25 ± 0.16
	司他夫定组	10	10.39 ± 0.16	7.56 ± 0.35	7.12 ± 0.32	6.54 ± 0.20	5.89 ± 0.16	5.26 ± 0.23	4.43 ± 0.21
F值			1.66	20.63	33.96	25.63	18.83	30.28	24.71
P值			0.150	0.008	0.004	0.006	0.008	0.005	0.007
t_{对照组 vs. CMC-Na组}			0.98	0.64	0.96	1.24	1.36	1.07	0.52
P_{对照组 vs. CMC-Na组}			0.470	0.57	0.45	0.26	0.21	0.41	0.62
t_{对照组 vs.雷帕霉素+司他夫定组}			0.86	18.72	23.17	28.81	22.18	33.69	31.21
P_{对照组 vs.雷帕霉素+司他夫定组}			0.510	0.008	0.007	0.006	0.007	0.004	0.005
t_{对照组 vs.司他夫定组}			1.18	29.12	27.18	32.38	19.23	21.17	35.56
P_{对照组 vs.司他夫定组}			0.360	0.005	0.006	0.004	0.008	0.008	0.003
t_{CMC-Na组 vs.司他夫定组}			1.28	30.16	34.71	28.63	22.32	18.12	25.07
P_{CMC-Na组 vs.司他夫定组}			0.240	0.005	0.004	0.006	0.007	0.009	0.007
t_{CMC-Na组 vs.雷帕霉素+司他夫定组}			1.61	31.12	26.18	20.26	15.71	21.21	24.16
P_{CMC-Na组 vs.雷帕霉素+司他夫定组}			0.170	0.005	0.007	0.008	0.009	0.008	0.007
t_{司他夫定组 vs.雷帕霉素+司他夫定组}			0.81	4.57	5.92	6.23	6.68	15.79	16.68
P_{司他夫定组 vs.雷帕霉素+司他夫定组}			0.530	0.039	0.023	0.017	0.013	0.009	0.009

表1 雷帕霉素对小鼠机械痛敏和热痛敏的影响（± s）

指标		只数	给药前	给药后7 d	给药后14 d	给药后21 d	给药后28天	给药后35天	给药后42天
PWMT（g）
对照组		10	15.93 ± 0.53	15.63 ± 0.52	15.37 ± 0.46	15.68 ± 0.39	15.42 ± 0.36	15.38 ± 0.42	15.62 ± 0.33
	CMC-Na组	10	15.55 ± 0.29	15.44 ± 0.35	15.45 ± 0.34	15.36 ± 1.53	15.52 ± 0.35	15.50 ± 0.38	15.68 ± 0.34
	雷帕霉素+司他夫定组	10	15.49 ± 0.40	13.44 ± 0.25	10.51 ± 0.27	10.12 ± 0.29	9.51 ± 0.20	8.69 ± 0.20	8.41 ± 0.17
	司他夫定组	10	15.45 ± 0.30	12.35 ± 0.36	9.98 ± 0.50	9.16 ± 1.39	8.54 ± 0.22	7.64 ± 1.03	7.40 ± 0.13
F值			1.45	20.63	34.68	35.76	22.56	18.96	29.18
P值			0.180	0.008	0.004	0.003	0.007	0.008	0.005
t_{对照组 vs. CMC-Na组}			0.48	1.21	0.56	0.89	0.79	1.16	1.23
P_{对照组 vs. CMC-Na组}			0.640	0.28	0.59	0.42	0.56	0.31	0.23
t_{对照组 vs.雷帕霉素+司他夫定组}			0.85	17.16	24.61	32.16	37.18	30.12	19.21
P_{对照组 vs.雷帕霉素+司他夫定组}			0.490	0.009	0.007	0.004	0.003	0.005	0.008
t_{对照组 vs.司他夫定组}			1.12	28.17	34.24	25.12	38.12	22.23	35.17
P_{对照组 vs.司他夫定组}			0.380	0.006	0.004	0.007	0.003	0.007	0.003
t_{CMC-Na组 vs.司他夫定组}			1.25	32.23	33.17	17.73	29.16	37.69	38.69
P_{CMC-Na组 vs.司他夫定组}			0.210	0.004	0.004	0.009	0.005	0.003	0.002
t_{CMC-Na组 vs.雷帕霉素+司他夫定组}			0.63	21.12	27.16	36.21	31.16	18.61	23.14
P_{CMC-Na组 vs.雷帕霉素+司他夫定组}			0.580	0.008	0.006	0.003	0.005	0.009	0.007
t_{司他夫定组 vs.雷帕霉素+司他夫定组}			1.56	5.71	1.64	4.12	4.36	5.06	4.89
P_{司他夫定组 vs.雷帕霉素+司他夫定组}			0.190	0.026	0.12	0.046	0.042	0.031	0.034
PWTL（s）
	对照组	10	10.14 ± 0.17	10.28 ± 0.18	10.15 ± 0.23	10.18 ± 0.20	10.27 ± 0.20	10.21 ± 0.33	10.25 ± 0.21
	CMC-Na组	10	10.59 ± 1.43	10.36 ± 0.14	10.43 ± 0.15	10.44 ± 0.20	10.39 ± 0.14	10.35 ± 0.24	10.39 ± 0.16
	雷帕霉素+司他夫定组	10	10.31 ± 0.17	8.56 ± 0.23	8.29 ± 0.14	7.88 ± 0.19	7.27 ± 0.11	6.90 ± 0.14	6.25 ± 0.16
	司他夫定组	10	10.39 ± 0.16	7.56 ± 0.35	7.12 ± 0.32	6.54 ± 0.20	5.89 ± 0.16	5.26 ± 0.23	4.43 ± 0.21
F值			1.66	20.63	33.96	25.63	18.83	30.28	24.71
P值			0.150	0.008	0.004	0.006	0.008	0.005	0.007
t_{对照组 vs. CMC-Na组}			0.98	0.64	0.96	1.24	1.36	1.07	0.52
P_{对照组 vs. CMC-Na组}			0.470	0.57	0.45	0.26	0.21	0.41	0.62
t_{对照组 vs.雷帕霉素+司他夫定组}			0.86	18.72	23.17	28.81	22.18	33.69	31.21
P_{对照组 vs.雷帕霉素+司他夫定组}			0.510	0.008	0.007	0.006	0.007	0.004	0.005
t_{对照组 vs.司他夫定组}			1.18	29.12	27.18	32.38	19.23	21.17	35.56
P_{对照组 vs.司他夫定组}			0.360	0.005	0.006	0.004	0.008	0.008	0.003
t_{CMC-Na组 vs.司他夫定组}			1.28	30.16	34.71	28.63	22.32	18.12	25.07
P_{CMC-Na组 vs.司他夫定组}			0.240	0.005	0.004	0.006	0.007	0.009	0.007
t_{CMC-Na组 vs.雷帕霉素+司他夫定组}			1.61	31.12	26.18	20.26	15.71	21.21	24.16
P_{CMC-Na组 vs.雷帕霉素+司他夫定组}			0.170	0.005	0.007	0.008	0.009	0.008	0.007
t_{司他夫定组 vs.雷帕霉素+司他夫定组}			0.81	4.57	5.92	6.23	6.68	15.79	16.68
P_{司他夫定组 vs.雷帕霉素+司他夫定组}			0.530	0.039	0.023	0.017	0.013	0.009	0.009

图2 雷帕霉素对小鼠脊髓组织中磷酸化mTOR蛋白表达的影响

表2 雷帕霉素对小鼠脊髓组织中磷酸化mTOR蛋白表达的影响（± s）

组别	只数	phospho-mTOR/β-actin
对照组	10	0.58 ± 0.03
CMC-Na组	10	0.61 ± 0.01
雷帕霉素+司他夫定组	10	0.72 ± 0.04
司他夫定组	10	0.86 ± 0.03
F值		6.19
P值		0.018
t_{对照组 vs. CMC-Na组}		1.75
P_{对照组 vs. CMC-Na组}		0.120
t_{对照组 vs.雷帕霉素+司他夫定组}		6.05
P_{对照组 vs.雷帕霉素+司他夫定组}		0.021
t_{对照组 vs.司他夫定组}		12.13
P_{对照组 vs.司他夫定组}		0.008
t_{CMC-Na组 vs.司他夫定组}		13.25
P_{CMC-Na组 vs.司他夫定组}		0.006
t_{CMC-Na组 vs.雷帕霉素+司他夫定组}		7.12
P_{CMC-Na组 vs.雷帕霉素+司他夫定组}		0.018
t_{司他夫定组 vs.雷帕霉素+司他夫定组}		4.24
P_{司他夫定组 vs.雷帕霉素+司他夫定组}		0.045

表2 雷帕霉素对小鼠脊髓组织中磷酸化mTOR蛋白表达的影响（± s）

组别	只数	phospho-mTOR/β-actin
对照组	10	0.58 ± 0.03
CMC-Na组	10	0.61 ± 0.01
雷帕霉素+司他夫定组	10	0.72 ± 0.04
司他夫定组	10	0.86 ± 0.03
F值		6.19
P值		0.018
t_{对照组 vs. CMC-Na组}		1.75
P_{对照组 vs. CMC-Na组}		0.120
t_{对照组 vs.雷帕霉素+司他夫定组}		6.05
P_{对照组 vs.雷帕霉素+司他夫定组}		0.021
t_{对照组 vs.司他夫定组}		12.13
P_{对照组 vs.司他夫定组}		0.008
t_{CMC-Na组 vs.司他夫定组}		13.25
P_{CMC-Na组 vs.司他夫定组}		0.006
t_{CMC-Na组 vs.雷帕霉素+司他夫定组}		7.12
P_{CMC-Na组 vs.雷帕霉素+司他夫定组}		0.018
t_{司他夫定组 vs.雷帕霉素+司他夫定组}		4.24
P_{司他夫定组 vs.雷帕霉素+司他夫定组}		0.045

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Effects of rapamycin on the neuropathic pain complicated with nucleoside reverse transcriptase inhibitors treatment of human immunodeficiency virus infection

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Effects of rapamycin on the neuropathic pain complicated with nucleoside reverse transcriptase inhibitors treatment of human immunodeficiency virus infection