Intranasal delivery of HMGB1-binding heptamer peptide confers a robust neuroprotection in the postischemic brain

Kim, Il‐Doo; Shin, Jong-Gye; Lee, Hyekyung; Jin, Young–Joo; Lee, Ja-Kyeong

doi:10.1016/j.neulet.2012.07.040

Cited by 33 publications

(26 citation statements)

References 19 publications

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“…Interestingly, NMDAR activation also causes HMGB1 cytoplasmic translocation and release. Cytosolic HMGB1 can bind to Beclin-1 to limit death by upregulated autophagy (Perez-Carrion and Cena, 2013), whereas extracellular HMGB1 plays both negative and positive roles in the regulation of neuronal cell death (Kim et al, 2010a; Kim et al, 2012c; Kim et al, 2006; Kim et al, 2012d; Kim et al, 2011b). A recent coimmunoprecipitation study demonstrated that HMGB1 physiologically interacts with GluN1 and GluN2B subunits of NMDAR via a specific region of HMGB1 localized in the B box upstream from the RAGE and downstream from the TLR4 binding sites (Pedrazzi et al, 2012).…”

Section: Hmgb1 Receptors (Figure 7)mentioning

confidence: 99%

HMGB1 in health and disease

Kang

Chen

Zhang

et al. 2014

Molecular Aspects of Medicine

801

828

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Complex genetic and physiological variations as well as environmental factors that drive emergence of chromosomal instability, development of unscheduled cell death, skewed differentiation, and altered metabolism are central to the pathogenesis of human diseases and disorders. Understanding the molecular bases for these processes is important for the development of new diagnostic biomarkers, and for identifying new therapeutic targets. In 1973, a group of non-histone nuclear proteins with high electrophoretic mobility was discovered and termed High-Mobility Group (HMG) proteins. The HMG proteins include three superfamilies termed HMGB, HMGN, and HMGA. High-mobility group box 1 (HMGB1), the most abundant and well-studied HMG protein, senses and coordinates the cellular stress response and plays a critical role not only inside of the cell as a DNA chaperone, chromosome guardian, autophagy sustainer, and protector from apoptotic cell death, but also outside the cell as the prototypic damage associated molecular pattern molecule (DAMP). This DAMP, in conjunction with other factors, thus has cytokine, chemokine, and growth factor activity, orchestrating the inflammatory and immune response. All of these characteristics make HMGB1 a critical molecular target in multiple human diseases including infectious diseases, ischemia, immune disorders, neurodegenerative diseases, metabolic disorders, and cancer. Indeed, a number of emergent strategies have been used to inhibit HMGB1 expression, release, and activity in vitro and in vivo. These include antibodies, peptide inhbitiors, RNAi, anti-coagulants, endogenous hormones, various chemical compounds, HMGB1-receptor and signaling pathway inhibition, artificial DNAs, physical strategies including vagus nerve stimulation and other surgical approaches. Future work further investigating the details of HMGB1 localizationtion, structure, post-translational modification, and identifccation of additional partners will undoubtedly uncover additional secrets regarding HMGB1’s multiple functions.

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Section: Hmgb1 Receptors (Figure 7)mentioning

confidence: 99%

HMGB1 in health and disease

Kang

Chen

Zhang

et al. 2014

Molecular Aspects of Medicine

801

828

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“…Also, this nose to brain route bypasses the BBB and avoids drug elimination by the liver and gastrointestinal tract and filtration through the kidney [44,45]. Especially, we demonstrated the potency of the intranasal approach using siRNA or protein-containing nanoparticles in post-ischemic brain [41,46,47]. Therefore, we estimated the possibility of the NCs for ATP delivery via an intranasal administration route.…”

Section: Basementioning

confidence: 89%

Enhanced cell survival of pH-sensitive bioenergetic nucleotide nanoparticles in energy/oxygen-depleted cells and their intranasal delivery for reduced brain infarction

et al. 2016

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“…Furthermore, the study provides evidence that HBHP suppresses LCM-induced microglial activation, and that this is achieved by its direct binding to HMGB1 A box. In a previous report, we found that intranasal delivered HBHP ameliorates neuronal damage in the postischemic rat brain, and that HBHP confers neuroprotection to NMDA- or Zn 2+ -treated primary cortical cultures, wherein HBHP interacts with accumulated HMGB1 in NMDA-conditioned media [19]. Under pathological conditions, including that of the postischemic brain, where HMGB1 might be released from neurons after an excitotoxic insult [3] or secreted from activated microglia (Figs.…”

Section: Discussionmentioning

confidence: 99%

“…In a previous study, we found that a HMGB1-binding heptamer peptide (HBHP) with the HMSKPVQ sequence, which directly binds with HMGB1 under cell free conditions and in NMDA-conditioned media (MCM), exerted a neuroprotective effect in the rat postischemic brain [19]. Moreover, intranasally delivered HBHP suppressed infarct formation in the rat brain after MCAO and ameliorated neurological deficits [19]. In the present study, we investigated whether HBHP confers anti-inflammatory effects on cultured primary microglia, and whether its effects are attributable to direct binding to HMGB1.…”

Section: Introductionmentioning

confidence: 99%

HMGB1-Binding Heptamer Confers Anti-Inflammatory Effects in Primary Microglia Culture

Kim

Lee

2013

Exp Neurobiol

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High mobility group box 1 (HMGB1) is an endogenous danger signal molecule. In the postischemic brain, HMGB1 is massively released during NMDA-induced acute damage and triggers inflammatory processes. In a previous study, we demonstrated that intranasally delivered HMGB1 binding heptamer peptide (HBHP; HMSKPVQ) affords robust neuroprotective effects in the ischemic brain after middle cerebral artery occlusion (MCAO, 60 minutes). In the present study, we investigated HBHP-induced anti-inflammatory effects on microglia activation. In LPS-treated primary microglia culture, HMGB1 was rapidly released and accumulated in culture media. Furthermore, LPS-conditioned media collected from primary microglia cultures (LCM) activated naïve microglia and markedly induced NO and proinflammatory cytokines. However, the suppression of HMGB1 by siRNA-HMGB1, HMGB1 A box, or anti-HMGB1 antibody significantly attenuated LCM-induced microglial activation, suggesting that HMGB1 plays a critical role in this process. A pull-down assay using biotin-labeled HBHP showed that HBHP binds directly to HMGB1 (more specifically to HMGB1 A box) in LCM. In addition, HBHP consistently inhibited LCM-induced microglial activation and suppressed the inductions of iNOS and proinflammatory cytokines. Together these results suggest that HBHP confers anti-inflammatory effects in activated microglia cultures by forming a complex with HMGB1.

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Intranasal delivery of HMGB1-binding heptamer peptide confers a robust neuroprotection in the postischemic brain

Cited by 33 publications

References 19 publications

HMGB1 in health and disease

HMGB1 in health and disease

Enhanced cell survival of pH-sensitive bioenergetic nucleotide nanoparticles in energy/oxygen-depleted cells and their intranasal delivery for reduced brain infarction

HMGB1-Binding Heptamer Confers Anti-Inflammatory Effects in Primary Microglia Culture

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