Translocator protein ligand, YL-IPA08, attenuates lipopolysaccharide-induced depression-like behavior by promoting neural regeneration

Abstract

Translocator protein has received attention for its involvement in the pathogenesis of depression. This study assessed the effects of the new translocator protein ligand, YL-IPA08, on alleviating inflammation-induced depression-like behavior in mice and investigated its mechanism of action. Mice were intracerebroventricularly injected with 1, 10, 100 or 1000 ng lipopolysaccharide. The tail-suspension test and the forced swimming test confirmed that 100 ng lipopolysaccharide induced depression-like behavior. A mouse model was then established by intraventricular injection of 100 ng lipopolysaccharide. On days 16-24 after model establishment, mice were intragastrically administered 3 mg/kg YL-IPA08 daily. Immunohistochemistry was used to determine BrdU and NeuN expression in the hippocampus. YL-IPA08 effectively reversed the depression-like behavior of lipopolysaccharide-treated mice, restored body mass, increased the number of BrdU-positive cells, and the number and proportion of BrdU and NeuN double-positive cells. These findings indicate that YL-IPA08 can attenuate lipopolysaccharide-induced depression-like behavior in mice by promoting the formation of hippocampal neurons.

Keywords: YL-IPA08; dentate gyrus; depression; hippocampus; lipopolysaccharide; nerve regeneration; neural regeneration; neuroinflammation; translocator protein.

Figure 1

Chemical structure of YL-IPA08.

Figure 2

Intracerebroventricular LPS induced depression-like behavior in mice. Twenty-four hours after a single intracerebroventricular injection of LPS, immobility was increased in the tail suspension test (A) and the forced swimming test (B). Effective doses were 100–1000 ng and 10–100 ng, respectively. Data are expressed as the mean ± SEM (n = 12; one-way analysis of variance followed by Dunnett's test). *P < 0.05, **P < 0.01, ***P < 0.001, vs. 0 ng LPS. LPS: Lipopolysaccharide.

Figure 3

YL-IPA08 attenuated 100 ng LPS-induced depression-like behavior and sickness response in mice. LPS was dissolved in aCSF. (A, B) Line crossings (A) and rearings (B) in the open field test were measured to estimate the effect of LPS and/or YL-IPA08 (a selective translocator protein ligand) on locomotor activity. (C, D) Duration of immobility in the tail suspension test (C) and forced swimming test (D) was determined 24 hours after LPS microinjection. LPS-treated mice spent more time immobile compared to vehicle-treated mice, while the duration of immobility in LPS-exposed mice was reduced by YL-IPA08. (E) Body weight was measured 24 hours after LPS injection. Data are expressed as the mean ± SEM (n = 15; two-way analysis of variance with Bonferroni test for multiple comparisons). *P < 0.05, **P < 0.01; #P < 0.05. LPS: Lipopolysaccharide; aCSF: artificial cerebrospinal fluid.

Figure 4

YL-IPA08 (a selective translocator protein ligand) attenuates the reduction in neurogenesis caused by 100 ng LPS. LPS was dissolved in aCSF. (A) BrdU cells are labeled red in the micrographs of the hippocampal dentate gyrus. Scale bar: 500 μm. (B) Confocal micrographs of NeuN⁺ (green) and BrdU⁺ (red) cells in the hippocampal dentate gyrus. Scale bar: 50 μm. (C–E) The number of BrdU-labeled (C), NeuN⁺/BrdU⁺ cells (D) and the percentage of BrdU⁺/NeuN⁺ cells to total BrdU⁺ cells (E) were reduced in the LPS group, but the reductions were reversed in the YL-IPA08 + LPS group. Data are expressed as the mean ± SEM (n = 5; two-way analysis of variance with Bonferroni test for multiple comparisons). **P < 0.01; #P < 0.05. LPS: Lipopolysaccharide; aCSF: artificial cerebrospinal fluid.