Neuroprotection by Post-Stroke Administration of the Slow-Releasing Hydrogen Sulfide (H2S) Delivery Molecule AP39: Novel Insight into Stroke Therapy.

Abstract Ischemic stroke represents a significant global health challenge and ranks as the third leading cause of mortality worldwide, contributing to approximately 12% of total deaths. Despite extensive research endeavors, effective pharmacotherapy options for the treatment of ischemic stroke remain limited. The existing body of evidence concerning the effects of H 2 S donors in ischemic stroke displays conflicting and ambiguous results. In this study we assess the neuroprotective attributes of AP39, a mitochondria-targeted H 2 S delivery molecule with a slow-releasing mechanism, in the context of brain ischemia. To achieve this, we employed a rat model of 90-minute middle cerebral artery occlusion (MCAO). A single intravenous dose of AP39 (100 nmol/kg) was administered 10 minutes after reperfusion. Our investigation revealed that AP39 treatment yielded improvements, including a reduction in neurological deficits and infarct volume, but also preserved the integrity of the blood-brain barrier (BBB). Notably, AP39 exhibited pronounced anti-inflammatory activity, as evidenced by a decrease in the levels and mRNA expression of pro-inflammatory cytokines such as Il-1β, Il-6, TNFα, and IP10. Additionally, AP39 administration resulted in an upregulation of mRNA expression of neurotrophic factors Bdnf and Ngf , while concurrently reducing the ratios of proBDNF/BDNF and proNGF/NGF. Furthermore, AP39 treatment demonstrated an inhibitory effect on the activation of poly(ADP-ribose) polymerase 1 (PARP1), a key mediator of cellular death pathways. Collectively, our findings provide substantial evidence supporting the therapeutic potential of AP39 when administered post-ischemia, thereby highlighting its efficacy in mitigating the detrimental consequences of ischemic stroke.