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

Abstract

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 H2S donors in ischemic stroke displays conflicting and ambiguous results. In this study we assess the neuroprotective attributes of AP39, a mitochondria-targeted H2S 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.