TY - JOUR
T1 - High-mobility group box 1-mediated hippocampal microglial activation induces cognitive impairment in mice with neuropathic pain
AU - Hisaoka-Nakashima, Kazue
AU - Ohata, Kazuto
AU - Yoshimoto, Natsuki
AU - Tokuda, Shintarou
AU - Yoshii, Nanako
AU - Nakamura, Yoki
AU - Wang, Dengli
AU - Liu, Keyue
AU - Wake, Hidenori
AU - Yoshida, Takayuki
AU - Ago, Yukio
AU - Hashimoto, Kouichi
AU - Nishibori, Masahiro
AU - Morioka, Norimitsu
N1 - Funding Information:
This work was supported in part by JSPS KAKENHI Grant Number 20K07291 .
Funding Information:
This work was supported in part by JSPS KAKENHI Grant Number 20K07291.We wish to thank the Analysis Center of Life Science and the Natural Science Center for Basic Research and Development, Hiroshima University for the use of their facilities. We also thank Dr. Aldric Hama for his careful editing of the manuscript.
Publisher Copyright:
© 2022 Elsevier Inc.
PY - 2022/9
Y1 - 2022/9
N2 - Clinical evidence indicates that cognitive impairment is a common comorbidity of chronic pain, including neuropathic pain, but the mechanism underlying cognitive impairment remains unclear. Neuroinflammation plays a critical role in the development of both neuropathic pain and cognitive impairment. High-mobility group box 1 (HMGB1) is a proinflammatory molecule and could be involved in neuroinflammation-mediated cognitive impairment in the neuropathic pain state. Hippocampal microglial activation in mice has been associated with cognitive impairment. Thus, the current study examined a potential role of HMGB1 and microglial activation in cognitive impairment in mice with neuropathic pain due to a partial sciatic nerve ligation (PSNL). Mice developed cognitive impairment over two weeks, but not one week, after nerve injury. Nerve-injured mice demonstrated decreased nuclear fraction HMGB1, suggesting increased extracellular release of HMGB1. Furthermore, two weeks after PSNL, significant microglia activation was observed in hippocampus. Inhibition of microglial activation with minocycline, local hippocampal microglia depletion with clodronate liposome, or blockade of HMGB1 with either glycyrrhizic acid (GZA) or anti-HMGB1 antibody in PSNL mice reduced hippocampal microglia activation and ameliorated cognitive impairment. Other changes in the hippocampus of PSNL mice potentially related to cognitive impairment, including decreased hippocampal neuron dendrite length and spine densities and decreased α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptor (AMPAR) subunits, were prevented with anti-HMGB1 antibody treatment. The current findings suggest that neuro-inflammation involves a number of cellular-level changes and microglial activation. Blocking neuro-inflammation, particularly through blocking HMGB1 could be a novel approach to reducing co-morbidities such as cognitive impairment associated with neuropathic pain.
AB - Clinical evidence indicates that cognitive impairment is a common comorbidity of chronic pain, including neuropathic pain, but the mechanism underlying cognitive impairment remains unclear. Neuroinflammation plays a critical role in the development of both neuropathic pain and cognitive impairment. High-mobility group box 1 (HMGB1) is a proinflammatory molecule and could be involved in neuroinflammation-mediated cognitive impairment in the neuropathic pain state. Hippocampal microglial activation in mice has been associated with cognitive impairment. Thus, the current study examined a potential role of HMGB1 and microglial activation in cognitive impairment in mice with neuropathic pain due to a partial sciatic nerve ligation (PSNL). Mice developed cognitive impairment over two weeks, but not one week, after nerve injury. Nerve-injured mice demonstrated decreased nuclear fraction HMGB1, suggesting increased extracellular release of HMGB1. Furthermore, two weeks after PSNL, significant microglia activation was observed in hippocampus. Inhibition of microglial activation with minocycline, local hippocampal microglia depletion with clodronate liposome, or blockade of HMGB1 with either glycyrrhizic acid (GZA) or anti-HMGB1 antibody in PSNL mice reduced hippocampal microglia activation and ameliorated cognitive impairment. Other changes in the hippocampus of PSNL mice potentially related to cognitive impairment, including decreased hippocampal neuron dendrite length and spine densities and decreased α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptor (AMPAR) subunits, were prevented with anti-HMGB1 antibody treatment. The current findings suggest that neuro-inflammation involves a number of cellular-level changes and microglial activation. Blocking neuro-inflammation, particularly through blocking HMGB1 could be a novel approach to reducing co-morbidities such as cognitive impairment associated with neuropathic pain.
KW - Cognitive impairment
KW - HMGB1
KW - Microglia
KW - Neural plasticity
KW - Neuro-inflammation
KW - Neuropathic pain
KW - Novel object recognition
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U2 - 10.1016/j.expneurol.2022.114146
DO - 10.1016/j.expneurol.2022.114146
M3 - Article
AN - SCOPUS:85132530377
VL - 355
JO - Neurodegeneration
JF - Neurodegeneration
SN - 0014-4886
M1 - 114146
ER -