Glutathione-protected Au22 Nanoclusters Ameliorates Hypoxic-Ischemic Brain Damage in Neonatal Rats via Sirt3/SOD2 Signaling Pathway.

Hypoxic-ischemic brain damage (HIBD) arises from perinatal hypoxia, a leading cause of neonatal mortality during the perinatal period, as well as subsequent disabilities beyond the neonatal stage. While there is currently no unified and comprehensive treatment approach for hypoxic-ischemic encephalopathy (HIE), hypothermia therapy represents the only recognized clinical intervention. Nevertheless, the efficacy of hypothermia therapy remains limited. Recently, atomically precise metal nanoclusters (NCs), an emerging class of nanomaterials, has displayed promising potential in biomedical field. This study aimed to assess whether glutathione-protected Au22 nanoclusters (GSH-Au22 NCs) could mitigate brain damage induced by hypoxic-ischemic (HI) injury in rats and oxygen-glucose deprivation (OGD) in cortical primary neurons while exploring the underlying protective mechanisms. In vitro findings revealed that GSH-Au22 NCs enhanced cell activity, mitigated inflammatory reactions, and reduced oxidative stress induced by oxygen-glucose deprivation in cortical primary neurons. In vivo, GSH-Au22 NCs significantly diminished cerebral infarction volume, alleviated inflammatory responses, reduced oxidative stress, facilitated tissue structure recovery, attenuated apoptosis resulting from HIE, and enhanced long-term learning and memory abilities following HI injury. Mechanistically, GSH-Au22 NCs ameliorated the Sirt3/SOD2 signaling pathway, thereby exerting a protective effect against HIBD. Furthermore, the protective impact of GSH-Au22 NCs was reversed upon knocking down SOD2. In conclusion, our findings demonstrate that GSH-Au22 NCs modulate the Sirt3/SOD2 signaling pathway, thereby mitigating HI brain damage.