Tetramethylpyrazine Preserves the Integrity of Blood-Brain Barrier Associated With Upregulation of MCPIP1 in a Murine Model of Focal Ischemic Stroke

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.

Altered Blood Brain Barrier Permeability and Oxidative Stress in Cntnap2 Knockout Rat Model

“…To gain a better understanding of BBB disruption and leakage, various tracers are currently used. One of the most popular tracers for assessing the permeability of the BBB is fluorescein isothiocyanate (FITC) labeled dextran [ 67 , 82 , 83 ]. Due to the fluorescein moiety that can be measured even in low concentrations, FITC-dextran serves as a sensitive and reliable marker to determine BBB permeability [ 67 ].…”

Tetramethylpyrazine-loaded electroconductive hydrogels promote tissue repair after spinal cord injury by protecting the blood–spinal cord barrier and neurons

“…The drug dose in the TMP group was 25 mg kg À1 (Harbin Sanlian Pharmaceutical Co., Ltd), as determined by the dose conversion factor for humans and rats and literature reports. 31 The rats in the sham, SCI, GMP, and GMPT groups were injected with an equal volume of saline. All SD rats were injected intraperitoneally once daily for 7 days with the above designed formulations as TMP or saline.…”

Regulatory mechanisms of tetramethylpyrazine on central nervous system diseases: A review

“…The monocyte chemotactic protein-induced protein 1 (MCPIP1) is a suppressor of inflammation ( Liang et al, 2010 ). Results from the cerebral I/R mice model induced by MCAO indicated that the TMP treatment effectively upregulates the expression of MCPIP1 and decreases the levels of inflammatory cytokines TNF-α, IL-1β, and IL-6 ( Jin et al, 2021 ). Nuclear factor E2 correlation factor 2 (Nrf2) can regulate the oxidative stress and inflammation response by promoting the expression of the downstream heme oxygenase-1 (HO-1) gene ( He et al, 2020 ).…”

“…Matrix metalloproteinases-9 (MMP-9) is an enzyme responsible for degrading the extracellular matrix and tight junctions ( Candelario-Jalil et al, 2011 ). TMP treatment was also shown to preserve the BBB integrity by decreasing the levels of MMP-9 ( Tan et al, 2015b ; Jin et al, 2021 ).…”