Abstract
Tetramethylpyrazine (TMP), a prominent ingredient of Chinese herb Ligusticum chuanxiong Hort, is known to suppress neuroinflammation and protect blood-brain barrier (BBB) integrity. We investigated whether monocyte chemotactic protein-induced protein 1 (MCPIP1, also known as Regnase-1), a newly identified zinc-finger protein, plays a role in TMP-mediated anti-inflammation and neuroprotection. Male C57BL/6 mice were subjected to focal cerebral ischemia induced by middle cerebral artery occlusion (MCAO) for 2 h, followed by reperfusion for 24 h. TMP (25 mg/kg or 50 mg/kg) or vehicle was administered intraperitoneally 12 h before and post MCAO. The TMP significantly upregulated MCPIP1 in the ischemic brain tissues and effectively inhibited extravasation of fluorescein isothiocyanate (FITC)-dextran, resulting in attenuation of brain edema. These effects of the TMP were associated with a significant reduction in levels of inflammatory cytokines tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, and MMP-9 in the ischemic brain tissues. The TMP upregulated the expression of MCPIP1 in primary cultures of neurons and protected against oxygen–glucose deprivation-induced neuron death, while this neuroprotective effect of TMP was abolished by knockdown of MCPIP1 using MCPIP1-specific siRNA. These results suggest that preservation of BBB integrity by TMP is associated with its anti-inflammatory activity. The effect of TMP is mediated, at least in part, via upregulation of MCPIP1 in the ischemic brain.
Highlights
Traditional Chinese herb Ligusticum chuanxiong Hort is widely used for the treatment of stroke and cardiovascular diseases due to its proven clinical benefits. (Ran et al, 2011)
To determine whether monocyte chemotactic proteininduced protein 1 (MCPIP1) contributes to anti-inflammatory effects of TMP in a murine model of ischemic stroke, we examined the mRNA levels of MCPIP1 in the mice brains upon TMP treatment
Data presented here indicate that TMP significantly attenuated blood-brain barrier (BBB) permeability and brain edema accompanied by the upregulation of MCPIP1 and downregulation of pro-inflammatory cytokines, tumor necrosis factor (TNF)-α, IL-1β, IL-6, Monocyte chemoattractant protein (MCP)-1 as well as matrix metalloproteinases (MMPs)-9 in the ischemic brain tissues in vivo
Summary
Traditional Chinese herb Ligusticum chuanxiong Hort is widely used for the treatment of stroke and cardiovascular diseases due to its proven clinical benefits. (Ran et al, 2011). TMP was reported to reduce the infarct volume, neurological score and brain edema in animal models of ischemic cerebral injury, (Xiao et al, 2010; Kao et al, 2013), Anti-Inflammatory Action of TMP which has been further confirmed by multiple in vitro studies. TMP has been shown to improve inflammation-mediated permeability blood-brain barrier (BBB), a key event that leads to brain edema and the progression of neurological dysfunction, in animal models of traumatic brain injury (Wang et al, 2017) and focal cerebral ischemia and reperfusion (Tan et al, 2015). An increase of pro-inflammatory cytokines, such as tumor necrosis factor (TNF)-α, interleukin (IL)-6, MCP-1 and IL-1β, has been reported to promote the permeability of the BBB. Matrix metalloproteinases (MMPs), such as MMP-9 induced by the pro-inflammatory cytokines (i.e., TNF-α, IL-1β), can degrade the extracellular matrix and tight junction proteins, resulting in the disruption of the BBB (Yang and Rosenberg, 2011)
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