Pharmacokinetics and Acute Toxicity of a Histone Deacetylase Inhibitor, Scriptaid, and its Neuroprotective Effects in Mice After Intracranial Hemorrhage

Abstract

Background & Objective: The pharmacokinetics and acute toxicity of a histone deacetylase inhibitor, Scriptaid, was unknown in the mouse. The aim of this study was to determine the pharmacokinetics, acute toxicity, and tissue distribution of Scriptaid, a new histone deacetylase inhibitor, in mice, and its neuroprotective efficacy in a mouse intracranial hemorrhage (ICH) model. Methods: The pharmacokinetics, acute toxicity, and tissue distribution were determined in C57BL/6 male and female mice after the intraperitoneal administration of a single dose. Behavioral tests, as well as investigations of brain atrophy and white matter injury, were used to evaluate the neuroprotective effect of Scriptaid after ICH. Western blotting was used to investigate if Scriptaid could offer antiinflammatory benefits after ICH. Results: No significant differences were observed in body weight or brain histopathology between the group that received Scriptaid at 50 mg/kg and the group that received dimethyl sulfoxide (control). The pharmacokinetics of Scriptaid in mice was nonlinear, and it was cleared rapidly at low doses and slowly at higher doses. Consistent with the pharmacokinetic data, Scriptaid was found to distribute in several tissues, including the spleen and kidneys. In the ICH model, we found that Scriptaid could reduce neurological deficits, brain atrophy, and white matter injury in a dose-dependent manner. Western blotting results demonstrated that Scriptaid could decrease the expression of pro-inflammatory cytokines IL1β and TNFα, as well as iNOS, after ICH. Conclusion: These findings indicate that Scriptaid is safe and can alleviate brain injury after ICH, thereby providing a foundation for the pharmacological action of Scriptaid in the treatment of brain injury after ICH.