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Blocking Brain Myeloid Differentiation Factor 2-Toll-like Receptor 4 Signaling Improves Cognition by Diminishing
Thura Tun Oo1,2, Natticha Sumneang1,2, Titikorn Chunchai1,2
1Neurophysiology Unit, Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand.
Abstract:
The myeloid differentiation factor 2 (MD-2)-toll-like receptor 4 (TLR4) signaling pathway has been linked to cognitive decline in obese rats. However, more research is required to fully understand the mechanistic role of MD-2-TLR4 signalling pathway in obese-related cognitive impairment. In this study, we used two novel MD-2 inhibitors-MAC28 (a mono-carbonyl analogue of curcumin 28) and 2i-10 (a cinnamamide-derivative compound)-to better comprehend the mechanistic role of the MD-2-TLR4 signalling pathway in obese-related cognitive impairment. A normal diet (ND) (n = 16) and a high-fat diet (HFD) (n = 64) were given to randomly divided groups of male Wistar rats for 16-weeks. At week 13, 2 types of vehicles were randomly administered to ND-fed and HFD-fed rats, whereas MAC28 (3-doses) and 2i-10 (3-doses) were randomly given to HFD-fed rats until week 16. HFD-fed rats developed obesity with metabolic disturbances, a variety of brain pathologies and cognitive decline. In obese rats, blocking the brain MD-2-TLR4 signalling pathway with MAC28 or 2i-10 improved cognition via reducing brain inflammation, neurodegeneration, microglial activation, dendritic spine loss, brain oxidative stress, as well as preserving adult hippocampal neurogenesis. Our findings highlight to better understand the role of MD-2-TLR4 signaling pathway in obese-related cognitive decline, and MD-2 could be a potential therapeutic target for brain pathologies and cognitive decline in obesity.
Insights
Blocking the myeloid differentiation factor 2 (MD-2)-toll-like receptor 4 (TLR4) pathway with novel inhibitors improved cognition in obese rats. This suggests MD-2 is a therapeutic target for obesity-related cognitive decline and brain pathologies.
Area of Science:
- Neuroscience
- Immunology
- Metabolic Disorders
Background:
- The myeloid differentiation factor 2 (MD-2)-toll-like receptor 4 (TLR4) pathway is implicated in cognitive decline associated with obesity.
- Further research is needed to elucidate the precise role of this pathway in obesity-related cognitive impairment.
Purpose of the Study:
- To investigate the mechanistic role of the MD-2-TLR4 signaling pathway in obesity-related cognitive impairment.
- To evaluate the efficacy of novel MD-2 inhibitors, MAC28 and 2i-10, in mitigating these impairments.
Main Methods:
- Male Wistar rats were fed a normal diet (ND) or a high-fat diet (HFD) for 16 weeks.
- Obese rats received either vehicle, MAC28, or 2i-10 from week 13 to 16.
- Cognitive function, brain inflammation, neurodegeneration, microglial activation, dendritic spine loss, oxidative stress, and hippocampal neurogenesis were assessed.
Main Results:
- HFD-induced obesity in rats led to metabolic disturbances, brain pathologies, and cognitive decline.
- Treatment with MAC28 or 2i-10 significantly improved cognitive function in obese rats.
- Inhibitors reduced brain inflammation, neurodegeneration, microglial activation, dendritic spine loss, and oxidative stress, while preserving adult hippocampal neurogenesis.
Conclusions:
- Blocking the MD-2-TLR4 signaling pathway ameliorates cognitive deficits in obese rats.
- MD-2 represents a potential therapeutic target for addressing brain pathologies and cognitive decline associated with obesity.
