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Biomedicines
Von Wang L und Li Z.
Inhalt auf Englisch
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Hypoxic-ischemic brain injury triggers persistent microglial hyperactivation, which drives progressive secondary neuroinflammation and subsequent neurological deficits. Nicotinamide mononucleotide (NMN), a key nicotinamide adenine dinucleotide (NAD+) precursor, confers neuroprotective effects in neonatal hypoxic-ischemic injury models. Nevertheless, the molecular landscape linking NMN treatment to metabolic and inflammatory reprogramming in microglia remains incompletely characterized.
Primary mouse microglia were subjected to oxygen-glucose deprivation/reoxygenation (OGD/R) insult. Three experimental groups were established: a Control, OGD/R, and OGD/R + NMN. We combined mitochondrial ultrastructural and functional assessments, DESeq2-based transcriptomic profiling for unbiased molecular screening, followed by RT-qPCR and supernatant-based ELISA for target-oriented validation.
OGD/R exposure induced severe mitochondrial structural damage, intracellular depletion of NAD+ and ATP, and excessive reactive oxygen species (ROS) generation; these pathological phenotypes were partially attenuated by NMN supplementation. Transcriptomic profiling identified co-regulated gene subsets in which OGD/R-dependent expression alterations showed opposing changes after NMN intervention. Transcriptomic analysis pinpointed two core molecular signatures: the Nlrp3-Casp1 inflammasome cascade and lipid-droplet-associated molecular markers, including Hilpda and Plin2. Multi-level molecular validation demonstrated that NMN treatment was associated with reduced transcript levels of Nlrp3, Casp1, Hilpda, and Plin2, accompanied by reduced secretion of mature IL-1β and TNF-α.
Collectively, this correlative transcriptomic study shows that NMN treatment correlates with mitigation of OGD/R-provoked pro-inflammatory remodeling in microglia, alongside partial restoration of mitochondrial homeostasis and attenuated transcript levels of NLRP3 inflammasome and lipid-droplet-associated markers. These findings identify NMN-associated molecular responses that warrant further mechanistic investigation and in vivo validation under hypoxic-ischemic brain-injury conditions. Genetic manipulation and in vivo animal experiments are essential before drawing any therapeutic conclusions.
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