L6H21 protects against cognitive impairment and brain pathologies via toll‐like receptor 4–myeloid differentiation factor 2 signalling in prediabetic rats

Chronic high-fat diet (HFD) intake instigates prediabetes and brain pathologies, which include cognitive decline and neuroinflammation. The myeloid differentiation factor 2 (MD-2)/toll-like receptor 4 (TLR4) complex plays a pivotal role in neuroinflammation. The MD-2 inhibitor (L6H21) reduces systemic inflammation and metabolic disturbances in HFD-induced prediabetes. However, the potential role of L6H21, and its comparison with metformin, on brain pathologies in HFD-induced prediabetes has never been investigated.Male Wistar rats were given either a normal diet (ND) (n = 8) or a HFD (n = 104) for 16 weeks. At the 13th week, ND-fed rats were given a vehicle, whereas HFD-fed rats were randomly divided into 13 subgroups. Each subgroup was given vehicle, L6H21 (three doses) or metformin (300-mg·kg-1 ·day-1 ) for 1, 2 or 4 weeks. Metabolic parameters, cognitive function, brain mitochondrial function, brain TLR4-MD-2 signalling, microglial morphology, brain oxidative stress, brain cell death and dendritic spine density were investigated.HFD-fed rats developed prediabetes, neuroinflammation, brain pathologies and cognitive impairment. All doses of L6H21 and metformin given to HFD-fed rats at 2 and 4 weeks attenuated metabolic disturbance.In rats, L6H21 and metformin restored cognition and attenuated brain pathologies dose and time-dependently. These results indicate a neuroprotective role of MD-2 inhibitor in a model of prediabetes.