Blocking myeloid differentiation factor 2 improves cognitive function via reducing microglia activation, neuroinflammation, brain mitochondrial dysfunction and dendritic spine loss in obese insulin-resistant rats.

BACKGROUND: Chronic high fat diet (HFD) consumption induces not only low-grade systemic inflammation and obese-insulin resistance, but also initiates neuroinflammation via activating myeloid differentiation factor 2 (MD-2)/toll-like receptor 4 (TLR4) complex, resulting in brain pathologies and cognitive impairment. Recently, MD-2 inhibitor (L6H21) has been shown to alleviate systemic inflammation. However, the effect of L6H21 on the cognitive function and brain pathologies of HFD-induced obese insulin-resistant condition has not been investigated.

METHOD: Male Wistar rats were fed either a normal diet (ND; n=8) or HFD (n=40) for 16 weeks. After 12th week of dietary periods, HFD-fed rats were divided into 5 groups (n=8/group). Each group was orally administered either vehicle, 10 mg/kg/day of L6H21, 20 mg/kg/day of L6H21, 40 mg/kg/day of L6H21, or 300 mg/kg/day of metformin for 4 weeks. For ND-fed rats, animals were orally administered vehicle for 4 weeks. At the end of experimental protocol, the novel object location (NOL) test was examined in each animal. Then, blood was collected before animals were sacrificed. Brains were rapidly removed to determine microglial activity, dendritic spine density, inflammatory cytokines, mitochondrial function, and insulin signaling.

RESULT: HFD-fed rats showed peripheral and brain insulin resistance, as indicated by impaired glucose tolerance and reduced brain insulin receptor substrate (IRS) level. In addition, HFD-fed rats developed brain pathologies, and cognitive impairment, as indicated by increased brain TNF-α level, increased microglial hyperactivity, increased mitochondrial reactive oxygen species (ROS), increased Bax/Bcl2 level, reduced dendritic spine density, and reduced preference indexes of NOL phase. Although L6H21 (20mg/kg/day, 40 mg/kg/day) and metformin alleviated HFD-induced brain pathologies and cognitive impairment, L6H21 at 40mg/kg/day and metformin had the highest efficacy for the neuroprotection in obese insulin-resistant rats through inhibiting neuroinflammation, oxidative stress, microglial activation, neuronal apoptosis and improving dendritic spine density, resulting in restoring cognitive function (p<0.05, Figure 1).

CONCLUSION: These findings suggest that MD-2 inhibitor may be the other drug of choice for improving brain function in the obese-insulin resistant condition.