Background and Purpose: Sodium butyrate (NaB) is recognized as a HDAC inhibitor exhibiting anti-inflammatory and neuroprotective effects in a rat ischemic model of stroke as well as a myocardial ischemia model. Although clinical evidence show that older women are at higher risk for stroke occurrence and greater stroke severity, no studies have evaluated the effectiveness of the HDAC inhibitor either in females or in aged animals. Additionally, few studies have used this treatment at a time point > 6 h following stroke, thus the effectiveness of delayed NaB administration is not well understood. Our present study specifically tested the HDAC’s neuroprotective effect on middle-aged female rats after ischemic damage.
Methods: Middle-aged Sprague-Dawley female rats (9-11 months old, constant diestrus) were used for all experiments. Middle cerebral artery occlusion (MCAo) was induced by intracerebral injection of endothelin-1 (600 pmol). Rats were treated with NaB (300 mg/kg, i.p.) at 6 h and 30 h following ET-1 injection. Animals were sacrificed at 5 days after MCAo. Brains were quickly removed and sectioned coronally at 2-mm thickness. The sections were immersed in 2% 2,3,5-triphenyltetrazolium chloride in DPBS for 30 min at 37°C and processed for imaging. Serum and brain lysates were also collected for biochemical analyses.
Results: Treatment with NaB, a fatty acid HDAC inhibitor, by i.p. injection 6 h after MCAo followed by another injection 30 h later reduced brain infarction determined at 5 day. The effect was consistent both in cortex and striatum with an approximately 40% and 60% decrease, respectively, in infarct volume (n=6-7; p<0.01). The protective effects of NaB against MCAo were associated with the anti-inflammatory effect of this HDAC inhibitor. Specifically, NaB treatment significantly suppressed MCAo-induced increase of IL-1beta, IL-17A, and IL-18 in brain lysates from the ischemic hemisphere. No significant alterations were observed in cytokines and chemokines in circulating serum level at 5 day post MCAo.
Conclusions: These findings support the HDAC inhibitor, NaB, exhibits neuroprotective effects against MCAo-induced brain damage. This is also the first report that NaB treatment post-stroke is neuroprotective in older female rats.