Tetramethylpyrazine: An Active Ingredient of Chinese Herbal Medicine With Therapeutic Potential in Acute Kidney Injury and Renal Fibrosis

Abstract

As an increasing public health concern worldwide, acute kidney injury (AKI) is characterized by rapid deterioration of kidney function. Although continuous renal replacement therapy (CRRT) could be used to treat severe AKI, effective drug treatment methods for AKI are largely lacking. Tetramethylpyrazine (TMP) is an active ingredient of Chinese herb Ligusticum wallichii (Chuan Xiong) with antioxidant and anti-inflammatory functions. In recent years, more and more clinical and experimental studies suggest that TMP might effectively prevent AKI. The present article reviews the potential mechanisms of TMP against AKI. Through search and review, a total of 23 studies were finally included. Our results indicate that the undergoing mechanisms of TMP preventing AKI are mainly related to reducing oxidative stress injury, inhibiting inflammation, preventing apoptosis of intrinsic renal cells, and regulating autophagy. Meanwhile, given that AKI and chronic kidney disease (CKD) are very tightly linked by each other, and AKI is also an important inducement of CKD, we thus summarized the potential of TMP impeding the progression of CKD through anti-renal fibrosis.

Keywords: Chinese medicine; acute kidney injury; mechanism; renal fibrosis; tetramethylpyrazine.

FIGURE 1

Illustration of Ligusticum wallichii plant (A), decoction pieces (B) and chemical structure of TMP (C).

FIGURE 2

Categories of the causes of AKI.

FIGURE 3

Summary of the literature search process.

FIGURE 4

The mechanism of TMP intervention in AKI. The figure summarizes the molecular pathways of TMP treatment of AKI involved in this review. Receptors such as TNR, TLR, and CCR2 are stimulated by nephrotoxic drugs, LPS, I/R, and inflammatory factors. In addition, hypoxia and I/R can also directly affect the mitochondrial quality control process and membrane potential, leading to the generation of ROS. The activation of the above receptors and the production of intracellular ROS can activate downstream pathways, further triggering inflammation, apoptosis, and autophagy, and ultimately leading to kidney damage. TMP can target Nfr2 and HIF-1 to activate the expression of antioxidant factors and enhance cell tolerance to oxidative stress. TMP can also inhibit TLR4 and TNFR or, by activating PPAR-γ, further inhibit the NF-κB pathway and reduce inflammation. In addition to the targeted inhibition of caspase-8/3/6/7 through the TNFR pathway, TMP can also affect mitochondrial-related apoptosis by inhibiting the ERK/JNK pathway. There is still controversy regarding the regulation of autophagy by TMP. It is generally believed that TMP activates the autophagy process and eliminates damaged mitochondria by targeting mitochondrial quality control, ultimately reducing cell damage.