High-Mobility Group Box 1 Neutralization Prevents Chronic Cerebral Hypoperfusion-Induced Optic Tract Injuries in the White Matter Associated with Down-regulation of Inflammatory Responses
Chronic cerebral hypoperfusion (CCH)-induced white matter lesions (WMLs) are region-specific with the optic tract (OT) displaying the most severe damages and leading to visual-based behavioral impairment. Previously we have demonstrated that anti-high-mobility group box 1 (HMGB1) neutralizing antibody (Ab) prevents CCH-induced hippocampal damages via inhibition of neuroinflammation. Here we tested the protective role of the Ab on CCH-induced OT injuries. Rats were treated with permanent occlusion of common carotid arteries (2-VO) or a sham surgery, and then administered with PBS, anti-HMGB1 Ab, or paired control Ab. Pupillary light reflex examination, visual water maze, and tapered beam-walking were performed 28 days post-surgery to investigate the behavioral deficits. Meanwhile, WMLs were measured by Klüver-Barrera (KB) and H&E staining, and glial activation was further assessed to evaluate inflammatory responses in OT. Results revealed that anti-HMGB1 Ab ameliorated the morphological damages (grade scores, vacuoles, and thickness) in OT area and preserved visual abilities. Additionally, the increased levels of inflammatory responses and expressions of TLR4 and NF-κB p65 and phosphorylated NF-κB p65 (p-p65) in OT area were partly down-regulated after anti-HMGB1 treatment. Taken together, these findings suggested that HMGB1 neutralization could ease OT injuries and visual-guided behavioral deficits via suppressing inflammatory responses.
KeywordsHMGB1 neutralization Chronic cerebral hypoperfusion Optic tract Glial activation NF-κB
Informed consent was obtained from all individual participants included in the study. Besides, we wish to thank Xiaoyan Chen for technical support.
YH and XZ performed the experiments, RC and YZ wrote the manuscript, DG and WL designed the experiments, and WL is responsible for the final version. All authors read and approved the final manuscript.
This research was supported by Natural Science Foundation of China (No. 81627806).
Compliance with Ethical Standards
Conflict of interest
No conflict of interest was declared.
National Institutes of Health Ethic Committee gave permission to the animal experiments, which were conducted in accordance with the National Experimental Animals Guidelines.
- Festoff BW, Sajja RK, van Dreden P, Cucullo L (2016) HMGB1 and thrombin mediate the blood-brain barrier dysfunction acting as biomarkers of neuroinflammation and progression to neurodegeneration in Alzheimer’s disease. J Neuroinflamm 13:194. https://doi.org/10.1186/s12974-016-0670-z CrossRefGoogle Scholar
- Hei Y, Chen R, Yi X, Long Q, Gao D, Liu W (2018) HMGB1 neutralization attenuates hippocampal neuronal death and cognitive impairment in rats with chronic cerebral hypoperfusion via suppressing inflammatory responses and oxidative stress. Neuroscience 383:150–159. https://doi.org/10.1016/j.neuroscience.2018.05.010 CrossRefGoogle Scholar
- Kim SK, Cho KO, Kim SY (2008) White matter damage and hippocampal neurodegeneration induced by permanent bilateral occlusion of common carotid artery in the rat: comparison between Wistar and Sprague-Dawley strain. Korean J Physiol Pharmacol 12:89–94. https://doi.org/10.4196/kjpp.2008.12.3.89 CrossRefGoogle Scholar
- Lee JH, Park SY, Shin YW, Hong KW, Kim CD, Sung SM et al (2006) Neuroprotection by cilostazol, a phosphodiesterase type 3 inhibitor, against apoptotic white matter changes in rat after chronic cerebral hypoperfusion. Brain Res 1082:182–191. https://doi.org/10.1016/j.brainres.2006.01.088 CrossRefGoogle Scholar
- Lee KM, Bang J, Kim BY, Lee IS, Han JS, Hwang BY et al (2015) Fructus mume alleviates chronic cerebral hypoperfusion-induced white matter and hippocampal damage via inhibition of inflammation and downregulation of TLR4 and p38 MAPK signaling. BMC Complement Altern Med 15:125. https://doi.org/10.1186/s12906-015-0652-1 CrossRefGoogle Scholar
- Takizawa S, Fukuyama N, Hirabayashi H, Kohara S, Kazahari S, Shinohara Y et al (2003) Quercetin, a natural flavonoid, attenuates vacuolar formation in the optic tract in rat chronic cerebral hypoperfusion model. Brain Res 980:156–160. https://doi.org/10.1016/S0006-8993(03)03009-9 CrossRefGoogle Scholar