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REVIEW article

Front. Pharmacol.

Sec. Neuropharmacology

Volume 16 - 2025 | doi: 10.3389/fphar.2025.1653056

From a Traditional Medicine Monomer to a Modern Neurotherapeutic Scaffold: A Review of SAR-Driven Tetramethylpyrazine Derivatives for Cerebrovascular and Cognitive Health

Provisionally accepted
Xiaodi  WangXiaodi Wang1Muhan  CaoMuhan Cao1Yi  XuYi Xu1*Xifei  YangXifei Yang2*Qinghua  HouQinghua Hou1*
  • 1Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China
  • 2Shenzhen Center for Disease Control and Prevention, Shenzhen, China

The final, formatted version of the article will be published soon.

Tetramethylpyrazine (TMP), a bioactive alkaloid isolated from the traditional Chinese medicine Ligusticum wallichii (Chuanxiong), has gained significant attention for its therapeutic potential in cerebrovascular diseases and cognitive impairment, mainly due to its antioxidant, anti-inflammatory, and anti-apoptotic properties. However, its clinical application is often limited by suboptimal pharmacokinetic characteristics and modest potency. This review highlights recent advancements in the structure-activity relationship (SAR) optimization of TMP, focusing on its derivatives' neuroprotective efficacy and vascular benefits. We specifically emphasize the clinical translational potential of several TMP derivatives, such as T-006, TMP-nitrone hybrids (e.g., TN-2), TMP-piperazine derivatives, and TMP-phenolic acid hybrids (e.g., T-VA). These compounds exhibit markedly improved drug-like properties, including enhanced lipid solubility, oral bioavailability, blood-brain barrier (BBB) permeability, and multi-target neuroprotective actions. Additionally, we critically examine the challenges these TMP derivatives face in clinical translation, such as metabolic instability, hepatotoxicity, and formulation challenges, while discussing current strategies to address these issues. The review concludes by emphasizing the significant promise of these next-generation TMP derivatives as therapeutic candidates for cerebrovascular and neurodegenerative disorders, and their need for further preclinical and clinical exploration to fully realize their therapeutic potential.

Keywords: Tetramethylpyrazine, Pharmacology, Pharmacodynamics, structure-activity relationships, Cerebrovascular function, Cognition

Received: 24 Jun 2025; Accepted: 31 Jul 2025.

Copyright: © 2025 Wang, Cao, Xu, Yang and Hou. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence:
Yi Xu, Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China
Xifei Yang, Shenzhen Center for Disease Control and Prevention, Shenzhen, China
Qinghua Hou, Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China

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