A comparative analysis to determine the optimum histone deacetylase inhibitors and administration route for improving survival and organ injury in rats after hemorrhagic shock

Objective: Histone deacetylase inhibitors (HDACIs) have been reported to improve survival in rats with hemorrhagic shock (HS). However, no consensus exists on the most effective HDACIs and their administration routes. We herein aimed to determine the optimal HDACIs and administration route in rats with HS.

Methods: Survival analysis: In experiment I, male Sprague-Dawley rats were subjected to HS (mean arterial pressure [MAP] was maintained at 30 to 40 mm Hg for 20 min), and intravenously injected with the following agents (n = 8 per group): 1) no treatment, 2) vehicle (VEH), 3) entinostat (MS-275), 4) [N-((6-(Hydroxyamino)-6-oxohexyl)oxy)-3,5-dimethylbenzamide] (LMK-235), 5) tubastatin A, 6) trichostatin A (TSA), and 7) sirtinol. In experiment II, rats were intraperitoneally injected with TSA. Mechanism research: In experiments I and II, rats were observed for 3 h, after which blood samples and liver, heart, and lung tissues were harvested.

Results: In experiment I, 75% rats in the VEH group but only 25% rats in the LMK-235 and sirtinol groups died within ≤5 h of treatment, whereas the survival of rats in the MS-275, tubastatin A, and TSA groups was significantly prolonged. MS-275, LMK-235, tubastatin A, and TSA significantly reduced histopathological scores, apoptosis cell numbers, and inflammatory cytokine levels. In experiment II, the survival was longer after i.v. TSA treatment than after i.p. TSA treatment, and the IL-6 levels in the heart were significantly lower in rat who received i.p. TSA treatment than in those who received i.v. TSA treatment.

Conclusions: The i.v. effect was superior to the i.p. effect, while nonselective and isoform-specific classes I and IIb HDACIs had similar effects.

 

Comments:

The study aimed to determine the optimal histone deacetylase inhibitors (HDACIs) and administration route in rats with hemorrhagic shock (HS). The researchers conducted two experiments involving male Sprague-Dawley rats subjected to HS and administered various HDACIs through different routes. The following findings were reported:

Experiment I: 

Rats were intravenously injected with different agents: no treatment, vehicle (VEH), entinostat (MS-275), [N-((6-(Hydroxyamino)-6-oxohexyl)oxy)-3,5-dimethylbenzamide] (LMK-235), tubastatin A, trichostatin A (TSA), and sirtinol.

The survival rate within 5 hours of treatment was 75% in the VEH group, but only 25% in the LMK-235 and sirtinol groups.

Rats treated with MS-275, tubastatin A, and TSA showed significantly prolonged survival.

MS-275, LMK-235, tubastatin A, and TSA reduced histopathological scores, apoptosis cell numbers, and inflammatory cytokine levels.

Experiment II:

Rats were intraperitoneally injected with TSA.

Intravenous (i.v.) administration of TSA resulted in longer survival compared to intraperitoneal (i.p.) administration.

Rats treated with i.p. TSA showed significantly lower levels of IL-6 in the heart compared to those treated with i.v. TSA.

Conclusions:

The intravenous (i.v.) administration route was found to be more effective than intraperitoneal (i.p.) administration.

Both nonselective and isoform-specific classes I and IIb HDACIs showed similar effects.

MS-275, LMK-235, tubastatin A, and TSA demonstrated improved survival rates, reduced histopathological scores, apoptosis cell numbers, and inflammatory cytokine levels in rats with hemorrhagic shock.

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