Scutellarin attenuates hypertension-induced expression of brain Toll-like receptor 4/nuclear factor kappa B - PubMed (original) (raw)

Scutellarin attenuates hypertension-induced expression of brain Toll-like receptor 4/nuclear factor kappa B

Xingyong Chen et al. Mediators Inflamm. 2013.

Abstract

Hypertension is associated with low-grade inflammation, and Toll-like receptor 4 (TLR4) has been shown to be linked to the development and maintenance of hypertension. This study aimed to investigate the effects of scutellarin (administered by oral gavage daily for 2 weeks) on brain TLR4/nuclear factor kappa B-(NF- κ B-) mediated inflammation and blood pressure in renovascular hypertensive (using the 2-kidney, 2-clip method) rats. Immunofluorescence and western immunoblot analyses revealed that hypertension contributed to the activation of TLR4 and NF- κ B, accompanied by significantly enhanced expression of proinflammatory mediators, such as tumor necrosis factor- α (TNF- α ), interleukin-1 β (IL-1 β ), and interleukin-18 (IL-18). Furthermore, expression of the antiapoptotic protein, myeloid cell leukemia-1 (Mcl1), was decreased, and the pro-apoptotic proteins, Bax and cleavedcaspase-3 p17 were increased in combined cerebral cortical/striatal soluble lysates. Scutellarin significantly lowered blood pressure and attenuated the number of activated microglia and macrophages in brains of hypertensive rats. Furthermore, scutellarin significantly reduced the expression of TLR4, NF- κ B p65, TNF- α , IL-1 β , IL-18, Bax and cleaved-caspase-3 p17, and increased the expression of Mcl1. Overall, these results revealed that scutellarin exhibits anti-inflammatory and anti-apoptotic properties and decreases blood pressure in hypertensive rats. Therefore, scutellarin may be a potential therapeutic agent in hypertension-associated diseases.

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Figures

Figure 1

Figure 1

Effect of scutellarin treatment on systolic blood pressure (SBP). Baseline systolic blood pressure (SBP) (mmHg) was similar among the four experimental groups. SBP was significantly increased in hypertensive groups compared with the sham-operated group. No significant difference in SBP was found in NS rats prior to treatment. However, SBP was significantly reduced with low- and high-dose scutellarin. *P < 0.001 versus sham group; # _P_ > 0.05, ▲ P < 0.001 versus NS group; _♦_ _P_ < 0.001, versus before treatment; ▼ _P_ > 0.05, & P < 0.001 versus low-dose group.

Figure 2

Figure 2

Scutellarin decreases the number of activated microglia in brain of hypertension. (a–d) Cluster of differentiation 11b (OX-42) immunostaining for microglia. (e) Quantification of OX-42-positive cells revealed that activated microglia were significantly increased in normal saline (NS) rats compared with the sham group, and treatment with scutellarin significantly reduced these numbers in a dose-dependent manner. *P < 0.001 versus sham group; ◆ P < 0.001 versus NS group; & P < 0.001 versus low-dose group. Scale bar = 100 __μ_m.

Figure 3

Figure 3

Scutellarin suppresses hypertension-induced expression of brain Toll-like receptor 4 (TLR4). (a) Chronic hypertension significantly enhanced the expression of TLR4 in the cerebral cortex. (b) Double immunofluorescence labeling indicated that the majority of TLR4 (red) was colabeled with OX-42-positive (green) cells and fewer with glial fibrillary acid protein- or Neuronal Nuclei-positive cells. (c) Western immunoblot analysis of brains of hypertensive rats showed that scutellarin dose-dependently suppressed the expression of TLR4. *P < 0.001 versus sham group; ◆ P < 0.001 versus NS group; & P < 0.001 versus low-dose group. (c) Scale bar = 200 _μ_m (a) and 50 _μ_m (b).

Figure 4

Figure 4

Scutellarin attenuates hypertension-induced brain expression of NF-κ_B, TNF-α, IL-1_β, and IL-18. Western immunoblot analysis for (a) NF-κ_B p65, (b) TNF-α, (c) IL-1_β, and (d) IL-18 in the rat cortex and striatum. Treatment with scutellarin significantly reduced the expression of these inflammatory markers in a dose-dependent manner. *P < 0.001 versus sham group; # P < 0.05, ◆ P < 0.001 versus NS group; & P < 0.001 versus low-dose group.

Figure 5

Figure 5

Scutellarin treatment upregulated Mcl1 and suppressed Bax, caspase-3 p17 expression. Western immunoblot analysis of protein levels of (a) Mcl1, (b) Bax, and (c) cleavedcaspase-3 p17 in the rat cortex and striatum. Scutellarin significantly upregulated Mcl1 but dose-dependently decreased Bax and cleavedcaspase-3 p17 (c). *P < 0.001 versus sham group; ◆ P < 0.001 versus NS group; & P < 0.001 versus low-dose group.

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