Pharmacological suppression of lactate mitigates postoperative cognitive dysfunction

Area of Science:

• Neuroscience
• Metabolic Neuroscience
• Cellular Biology

Background:

• Postoperative cognitive dysfunction (POCD) is linked to metabolic shifts in the hippocampus, specifically from oxidative phosphorylation to glycolysis.
• Elevated lactate levels in the hippocampus are observed following surgical trauma, but their direct role in cognitive deficits requires further elucidation.

Purpose of the Study:

• To investigate the neuroprotective potential of inhibiting lactate accumulation in the hippocampus for treating POCD.
• To explore the underlying mechanisms, including synaptic plasticity and pyroptosis, affected by lactate modulation in POCD.

Main Methods:

• Administered lactate dehydrogenase-A (LDHA) inhibitor oxamate (OXA) and lactate transporter inhibitor α-cyano-4-hydroxycinnamate (4-CIN) intraperitoneally before POCD modeling.
• Utilized recombinant adeno-associated virus 9 (AAV9)-Syn to knockdown Synaptosomal-associated protein 25 (SNAP25) for investigating neuronal-specific effects.
• Assessed cognitive function, protein levels (SNAP25, PINK1, LC3B), dendritic spine density, postsynaptic density thickness, and pyroptosis markers (cleaved caspase-3, N-GSDME, IL-1β, IL-18).

Main Results:

• Lactate accumulated in the hippocampus and neurons after anesthesia and surgery.
• Both OXA and 4-CIN treatment attenuated cognitive impairment, enhanced synaptic proteins (SNAP25, PINK1, LC3B), increased dendritic spine density, and reduced pyroptosis.
• SNAP25 knockdown reversed the beneficial effects of OXA, impairing synaptic plasticity, mitophagy, and promoting pyroptosis.

Conclusions:

• Pharmacological inhibition of lactate accumulation demonstrates neuroprotective effects against POCD.
• Modulating lactate levels impacts synaptic plasticity, mitophagy, and pyroptosis, suggesting these pathways are crucial in POCD pathogenesis.
• Targeting lactate metabolism presents a potential novel therapeutic strategy for preventing and treating POCD.