Dev Neurobiol. 2026 Oct;86(4):e70067. doi: 10.1002/dneu.70067.
ABSTRACT
Neonatal hypoxic-ischemic brain damage (HIBD) is the leading cause of neonatal death and long-term neurological dysfunction. Dexmedetomidine (DEX) has been shown to have neuroprotective effects, but its mechanisms in HIBD remain incompletely understood. This study aimed to explore whether DEX inhibits neuroinflammation and pyroptosis via activating adenosine monophosphate-activated protein kinase (AMPK)/sirtuin 1 (SIRT1) axis, thereby reducing HIBD. A HIBD model was established. Histological staining observed the pathological changes and neuronal survival. Primary cortical neurons were cultured to establish an oxygen-glucose deprivation/reoxygenation (OGD/R) model. DEX was used for intervene, and siAMPK was transfected to knock down AMPK expression. Inflammatory and oxidative stress indicators within brain tissue and neuronal cells were measured using enzyme-linked immunosorbent assay (ELISA) and biochemical kits. The AMPK/SIRT1 pathway and pyroptosis protein expressions were evaluated using fluorescence staining and Western blot. DEX dose-dependently reduced cerebral infarction volume, improved cerebral cortex pathological damage, enhanced neuronal nuclei (NeuN) positive neurons, decreased interleukin (IL)-6 and malondialdehyde (MDA) contents, enhanced superoxide dismutase (SOD) activity, and inhibited terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)/cleaved Caspase-1 double positive cells and N-terminal domain of Gasdermin D (GSDMD-N) protein expressions. DEX significantly upregulated p-AMPK and SIRT1 expression, whereas the AMPK inhibitor Compound C reversed the neuroprotective effect of DEX. In vitro experiments confirmed that DEX increased neuronal cell viability, reduced lactate dehydrogenase (LDH) release and propidium iodide (PI)-positive cell rate, reduced oxidative stress, and inhibited inflammatory factor release and pyroptosis-related protein expression. AMPK knockdown significantly reversed this axis activation by DEX and attenuated the neuroprotective effect of DEX. In conclusion, DEX improved neurological function in HIBD rats via the activating AMPK/SIRT1 pathway, reducing neuroinflammation and inhibiting neuronal pyroptosis.
PMID:42834580 | DOI:10.1002/dneu.70067