TY - JOUR
T1 - Inhibition of Toll-Like Receptor-4 (TLR-4) Improves Neurobehavioral Outcomes After Acute Ischemic Stroke in Diabetic Rats
T2 - Possible Role of Vascular Endothelial TLR-4
AU - Abdul, Yasir
AU - Abdelsaid, Mohammed
AU - Li, Weiguo
AU - Webb, R Clinton
AU - Sullivan, Jennifer C.
AU - Dong, Guangkuo
AU - Ergul, Adviye
N1 - Funding Information:
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.
Funding Information:
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.
Publisher Copyright:
© 2018, Springer Science+Business Media, LLC, part of Springer Nature.
PY - 2019/3/1
Y1 - 2019/3/1
N2 - 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.
AB - 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.
KW - Brain vascular endothelial cells
KW - Diabetes
KW - Hemorrhagic transformation
KW - Inflammation
KW - Neurovascular injury
KW - Stroke
KW - TLR-4
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U2 - 10.1007/s12035-018-1184-8
DO - 10.1007/s12035-018-1184-8
M3 - Article
C2 - 29909454
AN - SCOPUS:85048577575
SN - 0893-7648
VL - 56
SP - 1607
EP - 1617
JO - Molecular Neurobiology
JF - Molecular Neurobiology
IS - 3
ER -