Pharmacological suppression of lactate mitigates postoperative cognitive dysfunction

Hippocampal metabolic reprogramming from Oxidative Phosphorylation to glycolysis is a pathological feature in postoperative cognitive dysfunction (POCD). However, the relationship between elevated lactate levels and cognitive deficits following surgical trauma needs to be further illuminated. The lactate dehydrogenase-A (LDHA) inhibitor oxamate (OXA) and the lactate transporter inhibitor α-cyano-4-hydroxycinnamate (4-CIN) were delivered by intraperitoneal administration before POCD modeling. Recombinant adeno-associated virus 9 (AAV9)-Syn to knockdown Synaptosomal-associated protein 25 (SNAP25) was used to investigate whether neuronal-specific SNAP25 ablation blunts OXA-mediated phenotypes. Lactate accumulates in the hippocampus and hippocampal neurons after isoflurane anesthesia and aseptic laparotomy. Both OXA and 4-CIN attenuated cognitive impairment arising from anesthesia and surgery, enhanced SNAP25, PINK1, and LC3B protein, increased dendritic spine density and thickness of the postsynaptic densities, and attenuated pyroptosis-pertinent elements including cleaved Caspase-3, N-GSDME, IL-1β and IL-18. SNAP25 knockdown counteracted the favorable effects of OXA on cognitive function, as confirmed by impaired synaptic plasticity, insufficient PINK1-mediated Mitophagy, and activation of Caspase-3/GSDME-mediated Pyroptosis. Our findings suggest that pharmacological inhibition of lactate may be considered as a novel neuroprotective strategy for POCD.