Abstract
High mobility group box-1 (HMGB1) is a ubiquitous non-histone nuclear protein that plays a key role as a transcriptional activator, with its extracellular release provoking inflammation. Inflammatory responses are essential in methamphetamine (METH)-induced acute dopaminergic neurotoxicity. In the present study, we examined the effects of neutralizing anti-HMGB1 monoclonal antibody (mAb) on METH-induced dopaminergic neurotoxicity in mice. BALB/c mice received a single intravenous administration of anti-HMGB1 mAb prior to intraperitoneal injections of METH (4 mg/kg × 2, at 2-h intervals). METH injections induced hyperthermia, an increase in plasma HMGB1 concentration, degeneration of dopaminergic nerve terminals, accumulation of microglia, and extracellular release of neuronal HMGB1 in the striatum. These METH-induced changes were significantly inhibited by intravenous administration of anti-HMGB1 mAb. In contrast, blood–brain barrier disruption occurred by METH injections was not suppressed. Our findings demonstrated the neuroprotective effects of anti-HMGB1 mAb against METH-induced dopaminergic neurotoxicity, suggesting that HMGB1 could play an initially important role in METH toxicity.
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Abbreviations
- ANOVA:
-
Analysis of variance
- BBB:
-
Blood-brain barrier
- DAMP:
-
Damage-associated-molecular-pattern
- DAT:
-
Dopamine transporter
- DMSO:
-
Dimethylsulphoxide
- GFAP:
-
Glial fibrillary acidic protein
- HMGB1:
-
High mobility group box-1
- Iba1:
-
Ionized calcium binding adaptor molecule 1
- IFN-γ:
-
Interferon-γ
- IL:
-
Interleukin
- mAb:
-
Monoclonal antibody
- METH:
-
Methamphetamine
- NF-κB:
-
Nuclear factor κB
- NSAID:
-
Nonsteroidal anti-inflammatory drugs
- PPARγ:
-
Peroxisome proliferator-activated receptor γ
- PB:
-
Phosphate buffer
- PBS-T:
-
Phosphate buffered saline with 0.2% Triton X-100
- RAGE:
-
Receptor for advanced glycation end products
- ROS:
-
Reactive oxygen species
- RT:
-
Room temperature
- TH:
-
Tyrosine hydroxylase
- TLR:
-
Toll-like receptor
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Acknowledgements
The authors would like to thank Dr. Yu Okuma for his technical assistance with measuring plasma HMGB1 level.
Funding
This work was supported by Health and Labour Sciences Research Grants for Research on Regulatory Science of Pharmaceuticals and Medical Devices (H30-IYAKU-IPPAN-004 to M.A.) from the Japanese Ministry of Health, Labour, and Welfare, and by Grants-in-Aid for Scientific Research (C) (KAKENHI #25461279 to I.M.) and Grants-in-Aid for Scientific Research (B) (KAKENHI #19H03408 to M.N.) from the Japan Society for the Promotion of Science, by a Grant-in-Aid for Scientific Research on Innovative Areas “Brain Environment” (KAKENHI #24111533 to M.A.) from the Japanese Ministry of Education, Culture, Sports, Science, and Technology, and by a Research Grant from the Okayama Medical Foundation (to I.M.).
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M.A. and I.M. designed the experiment. K.M., K.K., N.I., R.K., S.M., D.W., K.L., S.K., and I.M. performed experiment and data analysis. K.M. and M.A. wrote the main manuscript text and prepared all figures. M.N. and M.A. supervised this study. All authors read and approved the manuscript.
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All animal procedures described in our experiments were in strict accordance with the NIH Guide for the Care and Use of Experimental Animals and the Policy on the Care and Use of the Laboratory Animals of Okayama University and were approved by the Animal Care and Use Committee of Okayama University (approval reference number OKU-2017131 and OKU-2020008, approved on April 1, 2017, and April 1, 2020, respectively). All experiments were conducted in compliance with the ARRIVE guidelines.
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Masai, K., Kuroda, K., Isooka, N. et al. Neuroprotective Effects of Anti-high Mobility Group Box-1 Monoclonal Antibody Against Methamphetamine-Induced Dopaminergic Neurotoxicity. Neurotox Res 39, 1511–1523 (2021). https://doi.org/10.1007/s12640-021-00402-5
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DOI: https://doi.org/10.1007/s12640-021-00402-5