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

Highlight

Minocycline is a tetracycline derivative with good permeability through blood-brain barrier and exerts a variety of neuroprotective effects by inhibiting microglia activation. However, how minocycline exerts its effects across the whole brain remains unclear. The authors examined the Lipopolysaccharide (LPS)-induced activation of microglia and expression of c-Fos by immunohistochemistry throughout the mouse brain at 6 hours and 24 hours after treatment. They also investigated with minocycline pretreatment to identify which brain regions can suppress activation of microglia and which brain network may be involved in the antidepressant effects of minocycline. It was found that minocycline may attenuate LPS-induced neuroinflammation by activating the NTS-associated network.

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

Funding:

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.

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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

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Minocycline Activates the Nucleus of the Solitary Tract-Associated Network to Alleviate Lipopolysaccharide-Induced Neuroinflammation

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