Anti-high mobility group box-1 (HMGB1) antibody inhibits hemorrhage-induced brain injury and improved neurological deficits in rats

Abstract

As one of the most lethal stroke subtypes, intracerebral hemorrhage (ICH) is acknowledged as a serious clinical problem lacking effective treatment. Available evidence from preclinical and clinical studies suggests that inflammatory mechanisms are involved in the progression of ICH-induced secondary brain injury. High mobility group box-1 (HMGB1) is a ubiquitous and abundant nonhistone DNA-binding protein, and is also an important proinflammatory molecule once released into the extracellular space from the nuclei. Here, we show that treatment with neutralizing anti-HMGB1 mAb (1 mg/kg, i.v. twice) remarkably ameliorated ICH-injury induced by local injection of collagenase IV in the striatum of rats. Administration of anti-HMGB1 mAb inhibited the release of HMGB1 into the extracellular space in the peri-hematomal region, reduced serum HMGB1 levels and decreased brain edema by protecting blood-brain barrier integrity, in association with decreased activated microglia and the expression of inflammation-related factors at 24 h after ICH. Consequently, anti-HMGB1 mAb reduced the oxidative stress and improved the behavioral performance of rats. These results strongly indicate that HMGB1 plays a critical role in the development of ICH-induced secondary injury through the amplification of plural inflammatory responses. Intravenous injection of neutralizing anti-HMGB1 mAb has potential as a novel therapeutic strategy for ICH.

HMGB1 a-Box Reverses Brain Edema and Deterioration of Neurological Function in a Traumatic Brain Injury Mouse Model

“…Encouraging results, that have been obtained with HMGB1 antibodies, peptides, natural or synthetic molecules, suggest therapeutic effects of HMGB1 on TBI [27]. HMGB1-specific antibodies have been shown to reduce brain edema, decrease cell apoptosis and improve functional outcomes in intracerebral hemorrhage and TBI rat models [8, 30]. Consistently, pharmacological inhibitors of HMGB1, glycyrrhizin and ethyl pyruvate, have beneficial effects in brain trauma models [31, 32].…”

“…For instance, increased cerebrospinal fluid levels of the pro-inflammatory cytokines, including interleukin (IL)-1β, IL-6 and tumor necrosis factor (TNF)-α, correlate with cerebral edema and neurological deterioration after TBI [5]. Moreover, various inhibitors of these pro-inflammatory factors have been evaluated for their potential effects in TBI [6-8]. …”

Targeting Inflammation Driven by HMGB1

“…The antibody, termed #10-22, recognizes an epitope in the repetitive Cterminal sequence. Successful therapeutic interventions are reported in a number of experimental neuro-inflammatory conditions, including stroke (70), traumatic brain injury (71), cognitive dysfunction after traumatic brain injury (72), spinal cord injury (73), epilepsy (74,75), blood brain barrier dysfunction after CNS ischemia (76), hemorrhageinduced brain injury (77), neuropathic pain (78)(79)(80)(81)(82)(83), and neuropathic pain-related depressive behavior (84). The antibody has also demonstrated beneficial effects in severe mouse influenza models (85,86).…”

Leukocyte-derived High-mobility group box 1 controls innate immune responses against Listeria monocytogenes

“…In light of the reported beneficial effects of HMGB1-targeted interventions during LPS-induced shock and polymicrobial abdominal sepsis (11,12), we aimed to assess the consequences of antibody-mediated neutralization of extracellular HMGB1 during murine infection with Listeria monocytogenes , a paradigmatic mouse model of bloodstream gram-positive bacterial infection (19). Daily administrations of well-established HMGB1-neutralizing antibodies (10,20,21), but not isotype-matched controls, failed to confer protection from systemic listeriosis, but instead impaired bacterial clearance, resulting in significantly higher hepatic bacterial burden 72 hours after infection ( Fig. 1A-B ).…”