TLR4 inhibitor TAK-242 attenuates the adverse neural effects of diet-induced obesity

Abstract

BackgroundObesity exerts negative effects on brain health, including decreased neurogenesis, impaired learning and memory, and increased risk for Alzheimer’s disease and related dementias. Because obesity promotes glial activation, chronic neuroinflammation, and neural injury, microglia are implicated in the deleterious effects of obesity. One pathway that is particularly important in mediating the effects of obesity in peripheral tissues is toll-like receptor 4 (TLR4) signaling. The potential contribution of TLR4 pathways in mediating adverse neural outcomes of obesity has not been well addressed. To investigate this possibility, we examined how pharmacological inhibition of TLR4 affects the peripheral and neural outcomes of diet-induced obesity.MethodsMale C57BL6/J mice were maintained on either a control or high-fat diet for 12 weeks in the presence or absence of the specific TLR4 signaling inhibitor TAK-242. Outcomes examined included metabolic indices, a range of behavioral assessments, microglial activation, systemic and neuroinflammation, and neural health endpoints.ResultsPeripherally, TAK-242 treatment was associated with partial inhibition of inflammation in the adipose tissue but exerted no significant effects on body weight, adiposity, and a range of metabolic measures. In the brain, obese mice treated with TAK-242 exhibited a significant reduction in microglial activation, improved levels of neurogenesis, and inhibition of Alzheimer-related amyloidogenic pathways. High-fat diet and TAK-242 were associated with only very modest effects on a range of behavioral measures.ConclusionsThese results demonstrate a significant protective effect of TLR4 inhibition on neural consequences of obesity, findings that further define the role of microglia in obesity-mediated outcomes and identify a strategy for improving brain health in obese individuals.Electronic supplementary materialThe online version of this article (10.1186/s12974-018-1340-0) contains supplementary material, which is available to authorized users.

Investigation of toll-like receptor (TLR) 4 inhibitor TAK-242 as a new potential anti-rheumatoid arthritis drug

“…These things indicate that NF-κB and AP-1 are important factors in arthritis induction in the AIA rat model, and TAK-242 effectively decreased the expression of both transcription factors. The treatment dose of TAK-242 (3 or 5 mg/kg) was decided based on the previous studies [27,28].…”

Toll-like receptor 4/nuclear factor-kappa B pathway is involved in radicular pain by encouraging spinal microglia activation and inflammatory response in a rat model of lumbar disc herniation

“…TLR4 antagonist ethyl (6R)-6-[N-(2-chloro-4-fluorophenyl) sulfamoyl]-cyclohex-1-ene-1-carboxylate (TAK242, cat no. HY-11109; MedChemExpress, South Brunswick, NJ), which can effectively pass through the blood-brain barrier, was freshly prepared in saline with 5% dimethyl sulfoxide and 5% Tween 80, administered intraperitoneally 1 hour before surgery, and then once daily for 5 days with concentration based on previous studies [ 13 ].…”

The melanocortin pathway and control of appetite-progress and therapeutic implications

“…Conversely, knockdown of TLR4 in the arcuate nucleus of obese rats fed high-fat diet, improves glucose homeostasis, attenuates insulin resistance, and reduces hepatic steatosis and adipocyte hypertrophy (Zhao et al 2017). Moreover, TAK-242, a TLR4 signaling inhibitor, decreases microglial activation and improves neurogenesis in mice fed fat diet (Moser et al 2018). These data indicate that, in the hypothalamus of obese mice, activation of TLR4 in microglia by excess circulating saturated fatty acids plays a major role to regulate hypothalamic inflammation by initiating the NF-κB pathway to alter glucose metabolism, to induce insulin resistance and to promote feeding.…”