Table 1.
Summary of pre-clinical studies investigating the therapeutic potential of various HDACi inhibitors.
| Inhibitor | Target | Study | HDACi dose | Sepsis model | Animal model | Effect |
|---|---|---|---|---|---|---|
| Valproic acid (VPA) | HDAC1 HDAC2 |
(100) | 50 mg/kg | LPS | Beagles | Significant reduction in TNF-α and IL-6 mRNA in PBMCs 3 and 6 h post-treatment. No difference in clinical symptoms between treated and untreated groups. |
| (101) | 300 mg/kg | CLP | C57Bl/6J mice | Reduced TNF-α, IL-1β, and IL-6 in peripheral blood, reduced histopathological events, and oxidative damage in renal tissue. No comment on survival. | ||
| (102) | Prophylactic and therapeutic doses given. | CLP | Sprague-Dawley rats | Improves survival of treated mice, inhibits transcription of TNF-α and IL-6, reduced oxidative burst. Reduced acute lung injury All animals were exposed to haemorrhagic shock 24 h prior to CLP. |
||
| (103) | Prophylactic and therapeutic doses given. | CLP | BALB/c mice | Anti-apoptotic effect in lung and spleen tissue. No effect on serum cytokine levels or inflammation in lungs. No controls used. | ||
| (104) | 100 mg/kg | CLP | C57BL/6 mice | No significant difference in survival between treated and untreated mice. Hippocampal IL-1β levels were reduced in VPA group, Spatial learning ameliorated in treated mice. | ||
| Tubastatin A (Tub-A) | HDAC6 | (105) | 70 mg/kg | CLP | C57Bl/6J mice | Improved survival, inhibits transcription of TNF-α and IL-6, reduced oxidative burst. All animals were exposed to haemorrhagic shock 24 h prior to CLP. |
| (106) | 70 mg/kg | CLP | C57BL/6J mice | Improved survival, reduced TNF-α and IL-6 in peritoneal fluid and plasma, reduced lung injury, and macrophage apoptosis. | ||
| Trichostatin A (TSA) | HDAC1 HDAC2 |
(107) | 1 mg/g (co-administered with DNA methyltransferase inhibitor, Aza) | LPS | C57BL/6J mice | Reduced apoptosis in lung tissue, reduced pro-apoptotic gene expression in lung. |
| (108) | 1 μg/g (administered alone or DNA methyltransferase inhibitor, Aza) | LPS | C57BL/6J mice | Treatment with both epigenetic modifiers had synergistic effect. Increased M2 macrophages in lungs, reduced pro-inflammatory cytokines in plasma, increased acetylation of STAT3 promotor in BMDMs, increased STAT3–Bcl2 signaling, reduced p38MAPK activation. |
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| (109) | 3.3 μmol/L/kg (administered alone or DNA methyltransferase inhibitor, Aza) Co-administered with 4.4 μmol/L/kg Aza | LPS | C57BL/6 mice | Treatment with both epigenetic modifiers had synergistic effect. Reduced inflammation in lung Reduced pulmonary microvascular permeability Reduced apoptosis of lung cells |
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| (110) | 10 mg/kg | CLP | Male Sprague–Dawley rats | Daily treatment for 7 days reduced neuronal cell death and improved spatial learning and memory defects induced by sepsis. | ||
| (111) | 10 mg/kg | CLP | Sprague-Dawley rats | HDAC inhibition increased skeletal muscle catabolism 4 h after sepsis induction, atrogin-1 expression is upregulated. | ||
| Suberoylanilide hydroxamic acid (SAHA or Vorinostat) | Pan-inhibitor | (112) | 50 mg/kg | CLP | C57BL/6J mice | Improved survival, ameliorated coagulation disturbances at 48 h post-sepsis induction. |
| (113) | 50 mg/kg | CLP | C57BL/6J mice | Improved survival, reduced cytokine levels in peritoneal fluid and blood, reduced acute liver injury. | ||
| (114) | Prophylactic and therapeutic doses given. | LPS | C57B1/6J mice | Reduced phosphorylation of MAP kinase proteins at 3 h post-induction, reduced neutrophil, and macrophage activity in the liver, reduced pro-inflammatory cytokine levels in liver tissue. | ||
| (115) | 50 mg/kg | LPS | C57BL/6J mice | Improved survival, reduced MyD88 gene expression, reduced TNF-α and IL-6 production. | ||
| (116) | Prophylactic and therapeutic doses given. | LPS | C57BL/6J mice | Improved survival, reduced inflammatory infiltration into lungs and spleen, increased histone acetylation, reduced TNF-α in blood, reduced pro-inflammatory gene expression in lung. | ||
| Sodium butyrate | HDAC1 HDAC2 |
(117) | 500 mg/kg (2 doses) | CLP | Wister rat | Improved survival 6 days post-sepsis, protective effect on liver, kidney, and lung |
| Cambinol | SIRT1 SIRT2 |
(118) | Prophylactic and therapeutic doses given. | LPS | BALB/c mice | Improved survival, lowered TNFα levels and bacteraemia, blocked phosphorylation of MAPKs. |
| EX-527 | SIRT1 | (119) | 47 mg/kg | CLP | C57BL/6J mice | Improved survival, reduced TNF-α and IL-6 levels, attenuated bone marrow atrophy. |