Leucine–Histidine Dipeptide Attenuates Microglial Activation and Emotional Disturbances Induced by Brain Inflammation and Repeated Social Defeat Stress
Abstract
:1. Introduction
2. Materials and Methods
2.1. Peptides
2.2. Animals
2.3. Culture of Primary Mouse Microglia
2.4. LPS Induction of Neuronal Inflammation
2.5. TST
2.6. OFT
2.7. Repeated SDS (R-SDS)
2.8. Social Interaction Test (SIT)
2.9. Elevated Plus Maze (EPM) Test
2.10. Pharmacokinetics of the 14C-LH Peptide
2.11. Statistical Analysis
3. Results
3.1. Effects of the LH Dipeptide on Primary Microglia
3.2. Penetration of the LH Dipeptide through the Blood–Brain Barrier
3.3. Effects of the LH Dipeptide on Inflammation in the Brain
3.4. Effects of the LH Dipeptide on Depression-Associated Emotional Disturbances
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Conflicts of Interest
References
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LPS(−) | LPS(+) | LPS(+) | LPS(+) | |
---|---|---|---|---|
LH | 0 μM | 0 μM | 10 μM | 30 μM |
Mean ± SE | Mean ± SE | Mean ± SE | Mean ± SE | |
IL-1α | 10.85±0.41 | 33.92 ± 4.52 ## | 27.80 ± 0.35* | 21.03 ± 2.76 * |
IL-1β | N.D. | 461.90 ± 22.31 | 370.28 ± 7.15* | 232.69 ± 65.04 * |
IL-2 | 0.49±0.16 | 5.11 ± 0.85 ## | 3.83 ± 0.68 | 1.96 ± 1.20 * |
IL-4 | 11.03±1.87 | 21.10 ± 7.26 | 16.87 ± 2.39 | 10.92 ± 2.53 |
IL-5 | N.D. | 70.64 ± 6.00 | 59.81 ± 3.63 | 34.33 ± 2.96 * |
IL-6 | 1.49 ± 0.17 | 1115.34 ± 291.93 ## | 868.39 ± 63.81 | 40.64 ± 4.66 ** |
IL-9 | N.D. | 0.97 ± 0.51 | 0.95 ± 0.48 | N.D. |
IL-10 | 4.42 ± 0.88 | 46.67 ± 4.41 ## | 32.60 ± 2.41 | 9.81 ± 6.38 * |
IL-12p40 | 3.67 ± 0.05 | 2814.93 ± 1672.56 ## | 1285.46 ± 64.50 | 26.13 ± 6.46 ** |
IL-12p70 | 31.41 ± 7.59 | 274.67 ± 70.58 ## | 255.40 ± 20.96 | 114.16 ± 48.49 |
IFN-γ | N.D. | 203.20 ± 43.29 | 200.09 ± 13.56 | 205.37 ± 11.01 |
KC | 249.36 ± 21.45 | 608.00 ± 325.53 | 617.92 ± 54.11 | 164.15 ± 15.42 * |
G-CSF | 14.82 ± 0.89 | 2553.57 ± 858.49 # | 1526.14 ± 213.37 | 35.49 ± 7.38 ** |
GM-CSF | 3.24 ± 0.70 | 12.48 ± 3.77 # | 15.78 ± 1.46 | 6.10 ± 1.73 |
Eotaxin | N.D. | 115.55 ± 114.07 | 5.41 ± 2.50 | N.D. |
MCP-1 | 341.31 ± 2.31 | 6309.88 ± 874.11 # | 4575.50 ± 224.07 * | 245.64 ± 48.90 ** |
MIP-1α | 1456.73 ± 57.27 | 7558.73 ± 441.63 ## | 4338.73 ± 1422.37 ** | 1167.67 ± 273.58 ** |
MIP-1β | 1750.02 ± 82.41 | 34440.79 ± 4285.71 ## | 22361.34 ± 2599.65 * | 1674.58 ± 42.01 ** |
RANTES | 211.50 ± 3.28 | 13515.62 ± 6828.57 ## | 18915.28 ± 1333.45 | 3393.04 ± 1229.12 |
TNF-α | N.D. | 4239.37 ± 688.90 | 758.51 ± 115.39 ** | 369.73 ± 84.86 ** |
Time | Radioactivity (ng/mL) | |
---|---|---|
Mean | SE | |
2 min | 229.7 | 89.0 |
5 min | 568.5 | 126.0 |
10 min | 1424.0 | 167.3 |
30 min | 2006.7 | 179.4 |
1 h | 3839.5 | 389.2 |
2 h | 3915.3 | 292.4 |
4 h | 3860.1 | 313.9 |
6 h | 3360.5 | 362.1 |
8 h | 3000.5 | 215.5 |
10 h | 2776.0 | 164.2 |
24 h | 1704.9 | 147.8 |
48 h | 1151.0 | 89.9 |
72 h | 867.6 | 37.5 |
120 h | 543.2 | 17.5 |
168 h | 364.0 | 20.1 |
Cmax (ng eq./mL) | 3955.6 | 574.3 |
Tmax(h) | 1.67 | 0.58 |
T1/2(h) | 76.37 | 1.91 |
Tissue | Radioactivity Concentration (ng eq. of LH /g or mL) | ||
---|---|---|---|
Mean | SE | Ratio | |
Plasma | 3770.7 | 728.7 | 1.00 |
Cerebrospinal fluid | 34.4 | 1.9 | 0.01 |
Cerebrum | 703.7 | 64.3 | 0.19 |
Cerebral cortex | 788.9 | 32.4 | 0.21 |
Hippocampus | 722.4 | 38.7 | 0.19 |
Striatum | 661.7 | 21.1 | 0.18 |
Thalamus | 702.4 | 63.1 | 0.19 |
Hypothalamus | 710.0 | 130.1 | 0.19 |
Midbrain | 812.7 | 42.4 | 0.22 |
Cerebellum | 704.9 | 293.5 | 0.19 |
Spinal cord | 553.1 | 29.8 | 0.15 |
Liver | 8207.5 | 561.5 | 2.18 |
Kidney | 4023.0 | 168.2 | 1.07 |
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Ano, Y.; Kita, M.; Kitaoka, S.; Furuyashiki, T. Leucine–Histidine Dipeptide Attenuates Microglial Activation and Emotional Disturbances Induced by Brain Inflammation and Repeated Social Defeat Stress. Nutrients 2019, 11, 2161. https://doi.org/10.3390/nu11092161
Ano Y, Kita M, Kitaoka S, Furuyashiki T. Leucine–Histidine Dipeptide Attenuates Microglial Activation and Emotional Disturbances Induced by Brain Inflammation and Repeated Social Defeat Stress. Nutrients. 2019; 11(9):2161. https://doi.org/10.3390/nu11092161
Chicago/Turabian StyleAno, Yasuhisa, Masahiro Kita, Shiho Kitaoka, and Tomoyuki Furuyashiki. 2019. "Leucine–Histidine Dipeptide Attenuates Microglial Activation and Emotional Disturbances Induced by Brain Inflammation and Repeated Social Defeat Stress" Nutrients 11, no. 9: 2161. https://doi.org/10.3390/nu11092161