Exploration of Neuroprotective Therapy

Table 1

Involvement of the TLR4 pathway and related mediators in stress response, neuroinflammation, and behavioral effects in animal models

Animal (strain, sex, size/age)	Stress model	Behavioral assessment	Major findings	Modulation of TLR4 pathway	Reference
C3H/HeN mice, male adult	Immobilization stress (1 eCB/7 days)	None	Stress induces ↑COX-2, ↑iNOS, and ↑lipid peroxidation in HeN but not in HeJ animals	C3H/HeJ mice	Caso et al., 2008 [126]
C57BL/6N mice, male 6–12 weeks old	Single or repeated social defeat stress (4 or 10 days)	Social interaction test, EPM	Repeated stress induces microglia activation, ↑IL-1α, ↑TNF-α, and social avoidance, all absent in TLR2/4 double KO mice	TLR2/4 KO mice	Nie et al., 2018 [129]
C57Bl/6 mice, male 8–12 weeks old	Footshock stress (one or two sessions of 180 inescapable footshocks, 0.3 mA duration of 6 s)	Learned helplessness; number of failures to scape footshocks	Stress in WT animals but not TLR4 KO promotes ↑HMGB1, ↑TNF-α, ↑IL-6, ↑IL-1β, ↑TLR4, and ↑NLRP3 in PFC TLR4 KO animals display resistance to learned helplessness depression-like behavior	TLR4 KO mice	Cheng et al., 2016 [100]
ICR mice, male Weighing 18–22 g	CUMS (8 weeks) LPS (5 days, 0,83 mg/kg, i.p./day)	SPT, OFT, TST, FST	Stress: ↑TNF-α, ↑IL-6, ↑IL-1β, and ↑TLR4 in hippocampus and depressive-like behavior Stress effects were reversed by TAK-242 and baicalin	TAK-242 (3 mg/kg, i.p.) and baicalin (60 or 30 mg/kg, i.g.)	Guo et al., 2019 [96]
C57Bl/6 mice, male 8–10 weeks old	CUMS (6 weeks)	FST, TST, OFT, SPT	Stress ↑HMGB1, ↑Iba-1, ↑TNF-α, ↑TNFR1, ↑GM-CSF, ↑IL-1β, ↑IL-5, ↑IL-6, ↑IL-7, ↑IL-9, ↑IL-13, ↑IFNγ, ↑NO, ↑IDO, ↓dopamine, ↓5-HT, ↑TLR4, ↑MyD88, ↑p-IkBα, and ↑p-NFκB p65 in PFC. Stress induced depressive-like behavior in WT but not TLR4 KO mice Stress effects were reversed by drug treatment	TLR4 KO mice and arctigenin (25, 50, or 100 mg/kg, i.p.)	Xu et al., 2020 [101]
C57Bl/6J mice, male 8 weeks old	LPS (1 mg/kg, i.p.)	TST, SPT, FST	LPS ↑IL-1β, ↑Iba-1, ↑RANTES, and ↑MCP-1 in PFC	None	He et al., 2020 [74]
ICR mice, male weighing 18–22 g	CUMS (6 weeks)	SPT, TST, OFT, FST	Stress ↓5-HT, ↓NE, ↑TNF-α, ↑IL-6, ↑IL-1β, ↑TLR4, ↑p-NFκB, ↑p-p38, ↑NLRP3, and ↑caspase-1 in PFC and hippocampus Stress ↓SOD, ↓GPx, and ↓MDA in the serum Stress promotes depressive-like behavior prevented by Cli-095	TAK-242 (referred as Cli-095 in this paper) (3 mg/kg, i.g.)	Fu et al., 2019 [110]
BALB/c mice, male 8 weeks old	CUMS (4 weeks); i.c.v. administration of fr-HMGB1 or non-oxid HMGB	SPT, TST, OFT	Stress ↑HMGB1 (serum and cortex) and depressive like behavior fr-HMGB1, but not non-oxid HMGB1, induced depressive-like behavior, ↑TNF-α, and ↓ MBP in hippocampus, which was reversed by TAK-242	TAK-242 (3 mg/kg, i.p.)	Lian et al., 2017 [117]
C57Bl/6 mice and ob/ob mice, male 7–8 weeks old	CUMS (3 weeks)	SPT, OFT, Morris water maze	Stress induced depressive-like behavior and alterations in target quadrant in Morris water maze Stress ↑TNF-α, ↑IL-6, and ↑IL-1β in hippocampus and frontal cortex TAK-242 reversed the depressive-like behavior in c57 and ob/ob mice Also, reversed stress effects in TNF-α, IL-6, and IL-1β levels in the brain	TAK-242 (3 mg/kg, i.p.)	Wang et al., 2018 [43]
ICR mice, male 6–8 weeks old	LPS (0,83 mg/kg, i.p.)	OFT, TST, FST, SPT	LPS induced ↑TNF-α, ↑IL-6, ↑IL-1β, ↑CD89, ↑TLR4, ↑p-IkBα, ↑NFκB p65, and ↑HMGB1 in hippocampus LPS also induced depressive-like behavior reversed by the drug used	Saikosaponin-d (1 mg/kg, i.g.)	Su et al., 2020 [112]
ICR mice, male 8–10 weeks old	LPS (1 mg/kg, i.p.)	FST, SPT, NSFT	LPS induced ↑Iba-1, ↑GFAP, ↑TNF-α, ↑IL-6, ↑IL-1β, ↑TLR4, ↑p-NFκB, ↑MyD88, ↓BDNF in hippocampus, and depressive- like behavior These effects are reversed by the pre-treatment with fast green FCF	Molecular docking simulation indicates possible interaction between TLR4 and fast green FCF (100 mg/kg, i.p.)	Yang et al., 2019 [73]
NMRI mice, male Adult Weighing20–25 g	LPS (0,83 mg/kg, i.p.)	OFT, FST	LPS induced ↑expression of TLR4, p-NFκB, and IDO in mice hippocampus and depressive-like behavior GM-CSF inhibited the LPS effects	Modulation of TLR4 pathway with GM- CSF (30 μg/kg, i.p.)	Hemmati et al., 2019 [111]
Wistar rats, male Weighing 150–180 g	CRS (6 eCB/day, 28 days)	SPT, OFT, FST, social interaction test	CRS induced ↑TNF-α, ↑IL-6, ↑IL-1β, and ↓BDNF in rat hippocampus and PFC. CRS also induced alterations in neurotransmitters, ↓GABA, ↑glutamate, and ↓GAD in hippocampus and PFC CRS also promoted depressive-like behavior and ↓social interaction All effects were reversed in a dose-dependent manner by eritoran	TLR4 antagonist, eritoran (5 mg/kg, i.p.)	Aboul-Fotouh et al., 2018 [98]
Wistar rats, male adult Weighing 250–300g	LPS (20 μg or 80 μg, i.c.v.)	OFT, EPM, FST, Morris water maze	LPS induced ↑TNF-α, ↑IL-1β LPS induced depressive- and anxiety-like behaviors and cognitive impairments in Morris water maze	None	Na et al., 2021 [131]
Wistar Hannover rats, male Weighing 200–225g	CMS (21 days)	FST, SPT, splash test, EPM	CMS induces bacterial translocation, ↑plasma LPS and depressive-like behavior	None	Martín-Hernández et al., 2016 [130]
Offspring of C57BL/6 mice, male and female	MIA (single dose of LPS on embryonic day 12, 50 μg/kg, i.p.)	None	Pro-inflammatory profile of cytokines and ↑TLR4 in amygdala of MIA offspring	None	O’Loughlin et al., 2017 [114]

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↑: increase; ↓: decrease; EPM: elevated plus-maze; WT: wild-type; SPT: sucrose preference test; OFT: open field test; TST: tail suspension test; FST: forced swim test; Iba-1: ionized calcium binding adaptor molecule 1; TNFR1: tumor necrosis factor receptor 1; GM-CSF: granulocyte-macrophage colony-stimulating factor; NO: nitric oxide; 5-HT: 5-hydroxytriptamine; p-NFκB: phosphorylated NFκB; RANTES: regulated on activation, normal T cell expressed and secreted; MCP-1: monocyte chemoattractant protein-1; NE: norepinephrine; p-p38: phosphorylated p38; SOD: superoxide dismutase; GPx: glutathione peroxidase; MDA: malondialdehyde; MBP: myelin basic protein; NSFT: novelty suppressed feeding test; GFAP: Glial fibrillary acidic protein; GABA: γ-aminobutyric acid; GAD: glutamate decarboxylase; CMS: chronic mild stress; MIA: maternal immune activation