Table 1.
HMGB1-targeting therapeutic strategies.
| Therapeutic strategies | Inhibition of HMGB1 | Animal type | Occlusion type | Treatment timing | Main outcome | References |
|---|---|---|---|---|---|---|
| Antibody | ||||||
| Anti-HMGB1 monoclonal antibody | Release | Mouse (male, C57BL/6) Rat (male, Wistar) Rat (male, Wistar) |
1. Permanent middle cerebral artery occlusion (MCAO) 2. 2 h transient MCAO 3. 2 h transient MCAO |
a)15 min before MCAO b) immediately and 6 h after reperfusion c) immediately and at 6 h after reperfusion |
1. Significantly reduced the infarct volume 2. Ameliorated brain infarction, significantly improved neurological deficits in locomotor function, inhibited the increased permeability of the blood-brain barrier, the activation of microglia, the expression of TNF-α and iNOS, and suppressed the activity of MMP-9 3. Reduced the blood-brain barrier permeability and inhibited the development of brain edema |
1. Muhammad et al., 2008 2. Liu et al., 2007 3. Zhang et al., 2011 |
| HMGB1-receptor and signaling pathway inhibition | ||||||
| Soluble RAGE | Inhibition of HMGB1-RAGE pathway | Mouse (male, C57BL/6) | Permanent MCAO | 15 min before MCAO plus 90 min after MCAO | Significantly reduced the infarct size and the inflammatory response | Muhammad et al., 2008 |
| Peptide and protein | ||||||
| A box | Activity | Rat (male, Sprague-Dawley) | 1h transient MCAO | at 1 h, 3 h, or 6 h after MCAO | Reduced infarct volumes, along with remarkable improvement of neurological deficits, suppressed proinflammatory cytokine inductions | Jin et al., 2011 |
| Fetuin-A | Release | Mouse (male, C57BL/6) Rat (male, Lewis) |
Permanent MCAO | at 15, 30, or 60 min after MCAO | Reduced brain infarct volume at 24 h after MCAO, effectively attenuated (i) ischemia-induced HMGB1 depletion from the ischemic core; (ii) activation of centrally (e.g., microglia) and peripherally derived immune cells (e.g., macrophage/monocytes); and (iii) TNF production in ischemic brain tissue | Wang et al., 2010aa |
| RNAi | ||||||
| HMGB1 siRNA | Expression | Rat (male, Sprague-Dawley) | 1 h transient MCAO | 24, 12, or 3 h prior to or 1, 3, or 6 h post-MCAO | Markedly suppressed infarct volume; recoveries from neurological and behavioral deficits | Kim I.D. et al., 2012 |
| HMGB1 shRNA | Expression | Rat (male, Sprague-Dawley) | 1 h transient MCAO | 24 h before the 1 h of MCAO | Suppressed infarct size, microglia activation, and proinflammatory marker induction | Kim et al., 2006 |
| Chemicals | ||||||
| Ethyl pyruvate (EP) | Release and expression | Rat (male, Sprague-Dawley) | 1 h transient MCAO | treatment with EP 30 min post-MCAO; delayed EP treatment from 4 days post-MCAO | Treatment with EP 30 min post-MCAO reduced ischemic infarct volume; delayed EP treatment from 4 days post-MCAO reduced HMGB1 accumulation in CSF at 7 day post-MCAO in the absence of accompanying amelioration of ischemic brain damage | Shin et al., 2014 |
| Glycyrrhizin (Gly) | Activity and release | Rat (Sprague-Dawley) Rat (T cell-deficient nude) Mouse (C57BL/6J) Mouse (SCID) |
100 min of transient MCAO in rats; 60 min of MCAO in mice |
immediately before MCAO and 2 h after reperfusion; immediately post-reperfusion and 3.5 h after reperfusion; immediately post-reperfusion. | Reduced infarctions and neuroinflammation in wild-type animals; did not offer protection in nude rats and severe combined immunodeficient (SCID) mice who had no T cells, while Gly reduced infarction in both nude rats and SCID mice whose T cells were reconstituted; attenuated gene expression of IFNγ, but not IL-4 and IL-10 in CD4 T cells. |
Xiong et al., 2016 |
| Physical method | ||||||
| Molecular hydrogen | Release | Rat (male, Sprague-Dawley) | Permanent MCAO | at 5 min after MCAO followed by hydrogen-rich saline injections at 6 h, 12 h, and 24 h | Significantly reduced infarct volume and improved neurobehavioral outcomes; dose-dependently increased the activities of endogenous antioxidant enzymes (SOD and CAT) as well as decreased the levels of oxidative products (8-iso-PGF2a and MDA) and inflammatory cytokines (TNF-a and HMGB1) in injured ipsilateral brain tissues | Li et al., 2012 |
| Clinical drugs | ||||||
| Atorvastatin | Expression | Rat (male, Sprague-Dawley) | Permanent MCAO | Immediately after MCAO | Dramatically improved neurological deficits, reduced brain water contents and infarct sizes at 24 h after stroke and attenuated the over-expression of HMGB1, RAGE, TLR4, and NF-κB induced by ischemia | Wang et al., 2010a |
| Fluorocitrate | Release | Mouse (male, ddY) | 4h transient MCAO | 5 days after stroke onset | A significant decrease in HMGB1-positive reactive astrocytes and neurovascular remodeling, as well as a corresponding worsening of behavioral recovery | Hayakawa et al., 2010 |
| Parecoxib | Release | Rat (male, Sprague-Dawley) | Permanent MCAO | 15 min before ischemia and again 12 h after inchemia | Significantly improved neurological deficit scores, reduced infarct volume, and decreased HMGB1 and TNF-α levels | Wang et al., 2011 |