米诺环素活化孤束核相关网络减轻脂多糖诱发的神经炎症

doi:10.24920/003954

摘要/Abstract

摘要：

目的研究米诺环素减轻脂多糖（LPS）诱导的神经炎症的神经解剖基础。
方法将40只C57BL/6雄性小鼠随机分为8组。连续三天,四组小鼠服用生理盐水,其他四组服用米诺环素。在第三天服用生理盐水或米诺环素后,两组小鼠立即额外注射生理盐水,另外两组小鼠注射LPS。最后一次注射后6或24小时,处死小鼠,取出大脑。对整个大脑进行免疫组织化学染色,通过Iba1检测小胶质细胞激活情况,通过c-Fos检测神经元的活化。通过Image Pro Premier 3D分析小胶质细胞的形态和c-Fos阳性神经元的数量。采用单因素方差分析和Fisher最小显著性差异进行统计分析。
结果米诺环素可减轻LPS诱导的神经炎症,其表现为多个脑区小胶质细胞的激活减少,包括伏隔核的壳亚区、下丘脑室旁核（PVN）、中央杏仁核、蓝斑（LC）和孤束核（NTS）。米诺环素显著增加LPS注射后NTS和极后区中c-Fos阳性神经元的数量。此外,在NTS相关的脑区,包括LC、臂旁外侧核、中脑导水管周围灰质、中缝背核、杏仁核、PVN和终纹床核,米诺环素也显著增加了LPS注射后c-Fos阳性神经元的数量。
结论米诺环素可减轻脂多糖诱导的多个脑区神经炎症,这种效应可能是由于孤束核相关网络中神经元的激活增加所致。

关键词: 神经炎症, 脂多糖, 抑郁症, 孤束核, 小胶质细胞

Abstract:

Objective To examine the neuroanatomical substrates underlying the effects of minocycline in alleviating lipopolysaccharide (LPS)-induced neuroinflammation.
Methods Forty C57BL/6 male mice were randomly and equally divided into eight groups. Over three conse-cutive days, saline was administered to four groups of mice and minocycline to the other four groups. Immediately after the administration of saline or minocycline on the third day, two groups of mice were additionally injected with saline and the other two groups were injected with LPS. Six or 24 hours after the last injection, mice were sacrificed and the brains were removed. Immunohistochemical staining across the whole brain was performed to detect microglia activation via Iba1 and neuronal activation via c-Fos. Morphology of microglia and the number of c-Fo-positive neurons were analyzed by Image-Pro Premier 3D. One-way ANOVA and Fisher’s least-significant differences were employed for statistical analyses.
Results Minocycline alleviated LPS-induced neuroinflammation as evidenced by reduced activation of microglia in multiple brain regions, including the shell part of the nucleus accumbens (Acbs), paraventricular nucleus (PVN) of the hypothalamus, central nucleus of the amygdala (CeA), locus coeruleus (LC), and nucleus tractus solitarius (NTS). Minocycline significantly increased the number of c-Fo-positive neurons in NTS and area postrema (AP) after LPS treatment. Furthermore, in NTS-associated brain areas, including LC, lateral parabrachial nucleus (LPB), periaqueductal gray (PAG), dorsal raphe nucleus (DR), amygdala, PVN, and bed nucleus of the stria terminali (BNST), minocycline also significantly increased the number of c-Fo-positive neurons after LPS administration.
Conclusion Minocycline alleviates LPS-induced neuroinflammation in multiple brain regions, possibly due to increased activation of neurons in the NTS-associated network.

Key words: neuroinflammation, lipopolysaccharide, depression, nucleus tractus solitaries, microglia

基金资助: 国家自然科学基金(81625008);国家自然科学基金(81930104);国家自然科学基金(31970952);国家重点研发计划(2016YFC1306700)

Jianbo Xiu, Lanlan Li, Qi Xu. Minocycline Activates the Nucleus of the Solitary Tract-Associated Network to Alleviate Lipopolysaccharide-Induced Neuroinflammation[J].Chinese Medical Sciences Journal, 2022, 37(1): 1-14.

图/表 8

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Brain Region	number of microglia cells	cell body areas of microglia (μm²) of the group
Brain Region	number of microglia cells	S3S6	S3L6	M3S6	M3L6	S3S24	S3L24	M3S24	M3L24
Acbs	850	29.5±1.4	48.3±2.8^†††	33.8±1.7	34.7±1.8^***	31.0±1.7	31.2±1.7	34.2±1.6	41.2±1.9^###
BNSTd	1077	31.3±1.6	41.2±2.2^††	37.3±2.0	35.7±2.3	31.9±1.9	40.0±2.3	35.7±2.0	49.7±2.8^##
PVN	698	28.8±1.4	43.0±4.1^†††	29.7±1.4	32.6±3.1^*	30.5±1.3	38.5±2.4^‡	32.9±1.5	40.8±2.4
CeA	1461	32.9±1.8	49.4±2.2^†††	38.0±1.2	39.8±2.7^***	32.4±1.2	39.5±1.7^‡‡	37.6±1.3	47.5±2.0^###
DG	1405	35.7±1.4	49.9±2.5^†††	38.1±2.0	44.7±2.2	34.7±1.4	49.4±2.3^‡‡	39.9±1.5	45.6±2.0
LPB	846	33.9±1.9	44.9±3.1^††	35.4±1.6	41.0±2.6	30.0±1.5	43±2.2^‡‡‡	35.4±1.6	38.3±2.2
LC	590	31.7±1.5	43.8±3.2^†††	36.6±1.8	37.2±2.0^*	32.8±1.6	38.7±1.9^‡	35.6±3.9	36.8±2.9
NTS	927	30.8±1.7	50.7±3.1^†††	37.2±2.2	35.9±2.1^***	33.2±1.9	38.9±2.1	35.1±1.9	40.8±2.4
AP	1061	46.2±4.5	54.8±3.2	55.3±3.3	58.5±4.8	48.9±3.2	57.9±2.5	47.0±3.5	54.2±3.2

Brain Region	number of c-Fos immunocreative neurons of the group (n)
Brain Region	S3S6	S3L6	M3S6	M3L6	S3S24	S3L24	M3S24	M3L24
Acbc	0	0	0	0	0	35.4±6.8^‡‡‡	0	30.2± 2.5
Acbs	0	37.8±2.5^†	8.6±2.2	23.0±5.7	0	59.0±11.9	41.8±15.7	87.6±18.1
BNSTd	0	29.0±4.9^†††	4.4±2.9	68.3±11.6^***	0	7.2±2.8^‡‡	4.4±2.77	12.4±3.9
BNSTv	5.0±3.5	46.0±7.3^†††	2±2	123.0±17.2^***	0	16.8±2.4^‡‡	5.8±2.7	27.4±8.3^#
PVN	0.8±0.8	174±19.8^†††	6±1.1	240.0±3.6^***	15.4±7.4	36.4±6.2^‡‡‡	17.2±4.3	90.8±21.9^##
CeA	0	28.0±3^†††	6.8±2	52.6±7.8^***	2.0±2.0	13.6±4.2^‡	11.6±3.2	45.0±5.8^###
BLA	0	25.3±2^†††	6±0.8	9.4±3.0^*	3.2±3.2	7.8±3.4^‡	9.8±4.7	47.2±9.3^###
DG	0	0	0	0	5.0±1.4	39.4±6.8^‡‡‡	16.2±4.3	36.2±2.5
VTA	0	0	0	0	0	0	0	0
DR	1.0±1.0	65.0±7.9^††	12.4±3.5	121.6±21.0^**	11.8±8.9	60.4±19.6	29.2±4.1	83.4±10.6
PAG	7.0±1.2	14.0±1.8	9.0±1.9	51.0±8.3^***	8.0±5.8	18±5.7	25.4±6.7	103.0±9.5^###
LPB	3.0±1.8	36.0±12^†††	5.8±2.9	101.0±8.5^***	2.0±2.0	21.0±4.3	1.8±1.1	38.0±5.6^#
LC	4.3±3.3	34.0±2.1^†	6.4±4.7	70.4±8.1^**	14.6±9.0	24.6±5.9	52.8±7.4	58.2±10.8^##
NTS	0	104.8±8.2^†††	0	204.8±13.5^***	13.8±7.8	106.8±35.9	11.6±1.3	97.4±9.4
AP	0	72.0±8.6^†††	0	170.6±22.1^***	0	4.3±4.3^‡‡‡	0	3.0±2.1

[1]	李冉,吕占云,李燕新,李维,郝延磊. 酪氨酸蛋白激酶结合蛋白缺乏对携带PSEN1 p.G378E突变的阿尔茨海默病小鼠模型神经炎症的影响[J]. Chinese Medical Sciences Journal, 2022, 37(4): 320-330.
[2]	潘艳芳, 贾晓涛, 宋二飞, 彭小忠. 黄芪甲苷拮抗Aβ1-42所致大鼠氧化应激,神经炎症和认知功能损伤[J]. Chinese Medical Sciences Journal, 2018, 33(1): 29-37.

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