Role of histone deacetylases and sirtuins in the ischaemic stroke: a systematic review and meta-analysis of animal studies.

Abstract

Background: Treatment of ischaemic stroke requires exploration of novel neuroprotective strategies owing to the constraints of thrombolytic therapy. Recent research implies that modulation of histone deacetylases (HDAC) or sirtuins (SIRT) could be beneficial in achieving this goal.

Methods: This systematic review and meta-analysis evaluates the effectiveness of HDAC/SIRT enzyme modulation in treating acute ischaemic stroke. It includes relevant studies but excludes human and in vitro research and non-primary studies. An electronic search was conducted across databases PubMed, Web of Science and Scopus until 20 March 2025. The methodological quality was assessed using a modified SYRCLE risk of bias tool. Infarct volume and neurological responses were extracted as key outcomes, and a random-effects meta-analysis of infarct volume was conducted for studies directly targeting HDAC/SIRT enzymes.

Results: A review of 71 studies involving over 1600 animals focused on ischaemic stroke treatments, predominantly using male rodents in a transient middle cerebral artery occlusion model. Most treatments were administered intraperitoneally, starting from the inception of ischaemia until 5 days afterwards. Non-selective HDAC inhibitors and SIRT1 modulators were targeted most frequently. The meta-analysis on infarct volume with 95% CI showed an overall effect estimate of -1.529 and suggested that non-selective HDAC inhibitors exhibit the most promise in reducing infarct size. Additionally, agonists of SIRT3/7, SIRT6, SIRT1 and HDAC1, along with inhibitors of SIRT5, HDAC6 and HDAC3, may play a significant role in the treatment of ischaemic stroke. Importantly, neuroprotective treatments have been found to be most effective in reducing infarct volume when administered within 24 hours following ischaemia.

Discussion: This study highlights the most promising neuroprotective trials for ischaemic stroke by focusing on infarct volume as a key outcome. However, relying exclusively on infarct volume may not fully capture the effectiveness of these treatments.