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High mobility group box 1 (HMGB1) inhibition attenuates lipopolysaccharide-induced cognitive dysfunction and sickness-like behavior in mice

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Abstract

Cognitive dysfunction, sickness-like behavior, for instance, anxiety, and depression are common aspects of neuropsychiatry often associated with neurodegenerative disorders. Growing evidence suggests that high mobility group box 1 (HMGB1) may act as a proinflammatory cytokine that aggravates neurobehavioral dysfunction. However, the detailed underlying mechanism is still elusive. Here we focus on determining the relationship between lipopolysaccharide (LPS)-induced neuroinflammation (in both in vitro and in vivo models), cognitive dysfunction, sickness-like behavior and thus decode the impact of HMGB1 inhibition (using Glycyrrhizin; Gcy as an antagonist). Using a mice model of repeated LPS (1 mg/kg, i.p. for 4 days) injections, we found that LPS induced neurobehavioral deficit and a strong proinflammatory response with increased proinflammatory markers, including tumor necrosis factor-α (TNF-α), interleukin-1 beta (IL-1β), interleukin-6 (IL-6) and iNOS (inducible nitric oxide synthase) at 7 days after the final dose of LPS compared to control animals. Our findings suggest that neurobehavioral dysfunction strongly correlates with the proinflammatory immune response following LPS stimulation. In vitro Gcy pretreatment to LPS-activated BV2 microglia cells significantly reduced nitrite and reactive oxygen species production, along with diminished expression of classical proinflammatory cytokines (TNF-α, IL-1β, IL-6, iNOS). These key proinflammatory changes with LPS and Gcy treatment are also found in vivo mice model and correlate with improved cognitive function and reduced anxiety/depression. Together, these results show that blocking HMGB1 using Gcy abrogated the cognitive dysfunction, sickness-like behavior of anxiety and depression induced by LPS which can be a promising avenue for crucial neurobehavioral dysfunction.

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Funding

This study was supported by the Department of Biotechnology, Government of India (BT/RLF/13/2014), and SGPGI intramural research grant (A-18-PGI/IMP/80/2019) to AK.

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Authors and Affiliations

  1. Amity Institute of Biotechnology, Amity University Uttar Pradesh, Lucknow Campus, Gomti Nagar Extension, Lucknow, 226028, Uttar Pradesh, India

    Devlina Ghosh & Aditi Singh

  2. Centre of Biomedical Research, Sanjay Gandhi Postgraduate Institute of Medical Sciences Campus, Raibareli Road, Lucknow, 226014, Uttar Pradesh, India

    Devlina Ghosh & Neeraj Sinha

  3. Department of Molecular Medicine and Biotechnology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, 226014, Uttar Pradesh, India

    Alok Kumar

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  1. Devlina Ghosh
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Contributions

D.G. designed the research and contributed to conceptualizing. D.G, A.K. helped in experimenting and data analysis. D.G., A.S., A.K., N.S. contributed to drafting the article, edited, revised and gave final approval of the version to be published.

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Correspondence to Devlina Ghosh or Neeraj Sinha.

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Ghosh, D., Singh, A., Kumar, A. et al. High mobility group box 1 (HMGB1) inhibition attenuates lipopolysaccharide-induced cognitive dysfunction and sickness-like behavior in mice. Immunol Res 70, 633–643 (2022). https://doi.org/10.1007/s12026-022-09295-8

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