The mitochondria-targeted hydrogen sulfide donor AP39 reduces cortical stroke volume and improves motor function in a photothrombotic stroke model in mice in a sex-dependent manner.

Despite many years of research, the treatment for patients affected by ischemic stroke remains very limited and insufficient. Currently, new neuroprotective treatment strategies are being sought to reduce brain tissue damage in the penumbra zone. One of these strategies involves the use of a hydrogen sulfide donor, the compound AP39, which mitochondria-targeted and, in very low concentrations, has shown a favorable action profile in preclinical studies across various disease models. In this study, we evaluated whether the administration of AP39, given 10 min after photothrombotic focal cerebral stroke, affects motor performance in a skilled reaching task in both female mice and male mice. We also assessed cerebral blood flow using laser speckle contrast analysis, stroke volume via MRI at 24 h, 3 days, and 6 days post-stroke, as well as the expression of mitochondrial proteins TOMM20, COX4, PINK1 and Parkin as markers of mitophagy in cells. Our results showed significant improvement in motor function, increased blood flow and noticeably lower stroke volume, and TOMM20 and COX4 expression with concomitant upregulation of PINK1 and Parkin expression at day 6 in male mice treated with AP39 after focal cortical stroke. In females, the beneficial effect was limited, with only a slight reduction in stroke volume observed, without any impact on skilled task performance. These results indicate that AP39 has neuroprotective potential, but it is sex dependent.