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Inhibition of Toll-Like Receptor-4 (TLR-4) Improves Neurobehavioral Outcomes After Acute Ischemic Stroke in Diabetic Rats: Possible Role of Vascular Endothelial TLR-4

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Abstract

Diabetes increases the risk of occurrence and poor functional recovery after ischemic stroke injury. Previously, we have demonstrated greater hemorrhagic transformation (HT), edema, and more severe functional deficits after stroke in diabetic animals that also presented with cerebral vasoregression and endothelial cell death in the recovery period. Given that Toll-like receptor 4 (TLR-4) activation in microvascular endothelial cells triggers a robust inflammatory response, we hypothesized that inhibition of TLR-4 signaling prevents endothelial cell death and improves outcomes after stroke. Animals were treated with vehicle or TLR-4 inhibitor TAK242 (3 mg/kg; i.p.) following middle cerebral artery occlusion (MCAO). Neurobehavioral deficits were measured at baseline and day 3 after ischemic stroke. Primary brain microvascular endothelial cells (BMVECs) from diabetic animals were subjected to oxygen glucose deprivation re-oxygenation (OGDR) and treated with 0.1 mM iron(III)sulfate hydrate (iron) (to mimic the post-stroke bleeding) and TLR-4 inhibitors. Ischemic stroke increased the expression of TLR-4 in both hemispheres and in the microvasculature of diabetic animals. Cerebral infarct, edema, HT, and functional deficits were greater in diabetic compared to control animals. Inhibition of TLR-4 significantly reduced the neurovascular injury and improved functional outcomes. OGDR and iron reduced the cell viability and increased the expression of TLR-4 associated proteins (RIP3, MyD88, phospho-NF-kB, and release of IL-6) in BMVECs from diabetic animals. In conclusion, TLR-4 is highly upregulated in the microvasculature and that beneficial effects of TLR-4 inhibition are more profound in diabetes. This suggests that inhibition of vascular TLR-4 may provide therapeutic benefits for stroke recovery in diabetes.

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Acknowledgements

AE is a Research Career Scientist at the Charlie Norwood Veterans Affairs Medical Center in Augusta, GA. This work was supported in part by a Veterans Affairs (VA) Merit Award (BX000347), VA Research Career Scientist Award and National Institutes of Health (NIH) awards (R01NS083559) to AE and Program Project award (PO1HL128207) to RCW, JCS, and AE. The contents do not represent the views of the Department of Veterans Affairs or the US Government.

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Authors and Affiliations

  1. Charlie Norwood Veterans Administration Medical Center, Augusta, GA, USA

    Yasir Abdul, Weiguo Li, Guangkuo Dong & Adviye Ergul

  2. Department of Physiology, Augusta University, 1120 15th Street CA-2094, Augusta, GA, 30912, USA

    Yasir Abdul, Weiguo Li, R. Clinton Webb, Jennifer C. Sullivan, Guangkuo Dong & Adviye Ergul

  3. School of Medicine, Mercer University, Savannah, GA, USA

    Mohammed Abdelsaid

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Abdul, Y., Abdelsaid, M., Li, W. et al. Inhibition of Toll-Like Receptor-4 (TLR-4) Improves Neurobehavioral Outcomes After Acute Ischemic Stroke in Diabetic Rats: Possible Role of Vascular Endothelial TLR-4. Mol Neurobiol 56, 1607–1617 (2019). https://doi.org/10.1007/s12035-018-1184-8

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