Integrating traditional Chinese medicine and modern technology: A new approach to understanding Changmaxifeng granules for tic disorders

Abstract

Tic disorders (TDs) are neuropsychiatric conditions characterized by involuntary motor and vocal tics, predominantly affecting children and adolescents. Conventional treatments, primarily psychotropic agents, are often associated with significant side effects and limited long-term efficacy. Changmaxifeng granules (CG), a traditional Chinese medicine formulation, have demonstrated promising clinical results in managing TDs; however, their pharmacodynamic basis and mechanisms of action remain poorly understood. This editorial highlights a study by Xie et al that integrates serum pharmacochemistry, network pharmacology, and molecular docking to systematically elucidate the multi-component, multi-target therapeutic profile of CG. The study identified 187 chemical constituents in vitro and 75 blood-absorbed components (49 prototypes and 26 metabolites) in vivo, with paeoniflorin, gastrodin, tenuifolin, and gallic acid emerging as key bioactive compounds. Network analysis identified critical targets - including tumor necrosis factor, interleukin-6, Fos proto-oncogene, vascular endothelial growth factor A, and estrogen receptor 1 - and highlighted the involvement of inflammatory and neuroactive pathways in TD pathology. Molecular docking confirmed strong binding affinities between core compounds and these targets, supporting CG’s potential as a safer and effective alternative therapy. While these computational findings are compelling, they require validation in physiological systems. These findings bridge traditional medicine and modern pharmacology, providing a good foundation for future clinical validation and new drug development. Future research should prioritize in vivo functional studies, quantitative pharmacokinetic profiling, and larger-scale clinical trials utilizing precision medicine frameworks that integrate artificial intelligence-driven syndrome stratification, metabolomic biomarkers, and real-time monitoring to fully realize CG’s potential for personalized herbotherapy in TD management.

Key Words: Tic disorders; Changmaxifeng granules; Network pharmacology; Molecular docking; Precision medicine

Core Tip: This article highlights a study that integrates modern analytical and computational methods to systematically uncover the multi-component, multi-target mechanism of Changmaxifeng granules for tic disorders. It identifies 75 blood-absorbed components and their key targets (e.g., tumor necrosis factor, interleukin-6, Fos proto-oncogene), highlighting Changmaxifeng granules’s potential in modulating neuroinflammation and synaptic signaling, and provides a framework for future personalized herbotherapy.

INTRODUCTION

Tic disorders (TDs) represent a complex spectrum of neurodevelopmental conditions marked by involuntary, repetitive movements and vocalizations. Affecting approximately 2% of children globally, TDs impose substantial burdens on quality of life, academic performance, and social integration[1]. Current first-line treatments, including dopamine receptor antagonists and alpha-2 adrenergic agonists, are often limited by adverse effects such as sedation, weight gain, and metabolic disturbances[2,3]. Consequently, there is growing interest in complementary and alternative therapies, particularly traditional Chinese medicine (TCM), which emphasizes holistic, multi-target approaches with potentially fewer side effects[4-7]. Unlike single-herb preparations, complex TCM formulations like Changmaxifeng granules (CG) offer synergistic therapeutic effects through multi-component, multi-target mechanisms[8].

Among TCM approaches, CG-derived from a clinically validated prescription comprising Paeoniae Radix Alba, Gastrodiae Rhizoma, Polygalae Radix, Acori Tatarinowii Rhizoma, and Margaritifera Concha-have shown encouraging results in alleviating TD symptoms[6,7]. Compared with other neuropsychiatric TCM formulas such as Shaoma Zhijing granules (used for Tourette syndrome) or Danhong Injection (for cerebrovascular disorders), CG comprise a unique combination of herbs specifically targeting both neurological and inflammatory aspects of TD[6,7].

However, the lack of clarity regarding the active components and mechanisms of action of GC has hindered their widespread adoption and regulatory approval. In this issue, Xie et al[8] present a comprehensive study that adeptly integrates advanced analytical techniques with systems pharmacology to decode CG’s material basis and mechanistic underpinnings. Their work exemplifies how modern technology can validate and refine traditional remedies, offering a blueprint for future TCM research.

BRIDGING TRADITION AND INNOVATION: THE CG STUDY

Xie et al[8] employed ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry to characterize CG’s chemical profile, identifying 187 compounds, including terpenoids, flavonoids, phenolic acids, and saccharides. Subsequent serum pharmacochemical analysis revealed 75 blood-borne components (49 prototypes and 26 metabolites), underscoring the importance of both parent compounds and biologically transformed metabolites in CG’s efficacy[8].

Leveraging network pharmacology, the authors mapped these components to known TD targets, identifying 225 overlapping genes. Among these, tumor necrosis factor, interleukin-6, Fos proto-oncogene, vascular endothelial growth factor A, and estrogen receptor 1 emerged as hub targets, enriched in pathways related to neuroinflammation, synaptic signaling, and immune response - key domains in TD pathophysiology[9,10]. Molecular docking simulations further confirmed robust interactions between core active compounds (e.g., paeoniflorin, tenuifolin) and these targets, with binding energies more negative than -5 kcal/mol, indicative of high affinity and functional relevance[8].

IMPLICATIONS FOR TD PATHOPHYSIOLOGY AND TREATMENT

The convergence of CG’s active components on inflammatory and neuro-modulatory pathways aligns with emerging evidence that neuroimmune dysregulation plays a pivotal role in TD[11,12]. Microglial activation, cytokine release (e.g., interleukin-6, tumor necrosis factor α), and disrupted synaptic signaling are increasingly implicated in TD pathogenesis[13,14]. CG’s multi-target engagement - simultaneously modulating inflammation, oxidative stress, and neuronal excitability, could explain their superior clinical profile vs single-target synthetic drugs[15-19].

This multi-target approach is shared by other TCM formulations for neuropsychiatric disorders, such as the use of Chaihu Longgu Muli Tang for anxiety and depression, though CG appears uniquely focused on tic-specific pathways[8,20-23].

However, a balanced perspective is necessary when interpreting these findings. The heavy reliance on computational predictions and in vitro data means that the proposed mechanisms, although compelling, remain hypothetical until confirmed in physiological systems. This presents challenges for precise mechanistic delineation and standardization, underscoring the need for rigorous in vivo validation[24-26]. Some bioactive compounds of CG and their potential therapeutic targets are presented in Table 1.

Table 1 Some bioactive compounds of Changmaxifeng granules and their potential therapeutic targets.

Compound	Source herb	Key targets	Main pharmacological activities	Ref.
Paeoniflorin	Paeoniae Radix Alba	TNF, IL-6, NLRP3	Anti-inflammatory, neuroprotective, inhibits microglial activation	[9,16,17]
Gastrodin	Gastrodiae Rhizoma	FOS, VEGFA, BDNF	Antioxidant, neuroregulation, improves synaptic plasticity	[7,14]
Tenuifolin	Polygalae Radix	ESR1, FOS, ACHE	Anti-neuroinflammatory, cognitive enhancement, cholinesterase inhibition	[8,15,22]
Gallic acid	Multiple herbs1	TNF, IL-6, COX-2	Antioxidant, anti-inflammatory, apoptosis regulation	[8,14,23]
Ferulic acid2	Metabolite of onjisaponin F	NF-κB, TNF-α, IL-1β	Anti-inflammatory, neuroprotective, blood-brain barrier protection	[8,15,24]
Albiflorin	Paeoniae Radix Alba	5-HT, GABA	Anxiolytic, antidepressant, neuro-modulatory	[25,26]
Tatarinan A/B	Acori Tatarinowii Rhizoma	DA, Glu receptors	Dopaminergic and glutamatergic modulation, improves synaptic transmission	[6,21]

¹Gallic acid is widely distributed in multiple herbal components.

²Ferulic acid is a key metabolite identified through in vivo biotransformation of onjisaponin F.

TNF: Tumor necrosis factor; IL: Interleukin; NLRP3: NOD-, LRR- and pyrin domain-containing protein 3; FOS: Fos proto-oncogene; VEGFA: Vascular endothelial growth factor A; BDNF: Brain-derived neurotrophic factor; ESR1: Estrogen receptor 1; ACHE: Acetylcholinesterase; COX-2: Cyclooxygenase-2; NF-κB: Nuclear factor kappa B; 5-HT: 5-hydroxytryptamine (serotonin); GABA: Gamma-aminobutyric acid; DA: Dopamine; Glu: Glutamate.

Moreover, the identification of phase-I and phase-II metabolites highlights the dynamic interplay between drug metabolism and bioactivity. For instance, the hydrolysis of onjisaponin F to ferulic acid, a compound with established anti-inflammatory and neuroprotective properties, exemplifies the ability of in vivo biotransformation to generate or enhance therapeutic effects[15,16]. This metabolic activation pathway shares similarities with other neuroactive TCM formulas, such as Danhong Injection, which also requires in vivo biotransformation for full therapeutic efficacy[14], suggesting a common pharmacokinetic strategy among complex herbal formulations.

LIMITATIONS AND FUTURE DIRECTIONS

Although the study by Xie et al[8] is methodologically robust, it primarily relies on computational and in vitro analyses. The reliance on predictive algorithms and in vitro data means that the proposed mechanisms, although compelling, remain hypothetical until confirmed in physiological systems. The proposed mechanisms require validation in relevant in vivo models, such as TD animal models or microglial cell assays, to confirm their physiological relevance. Additionally, quantitative analysis of key compounds in biological matrices and detailed pharmacokinetic studies will be critical for dose optimization and safety assessment.

Future research should also explore CG’s effects on comorbid conditions often associated with TDs, such as anxiety, attention deficit hyperactivity disorder, and obsessive-compulsive disorder[17,18]. Given the role of neuroinflammation in these disorders, CG’s broad anti-inflammatory profile might offer complementary benefits. Finally, large-scale, randomized controlled trials are needed to establish CG’s efficacy and safety in diverse patient populations. The integration of artificial intelligence (AI) could enable more personalized treatment approaches[19]. For example, machine learning algorithms could analyze patient symptom clusters, cytokine profiles, and metabolomic data to identify subgroups most likely to respond to specific CG components. This AI-driven stratification could match patients with optimal herbal combinations based on their clinical phenotypes, creating a true “precision herbotherapy” approach. Real-time monitoring technologies could further optimize therapeutic outcomes through dynamic adjustment of treatment regimens[20].

CONCLUSION

The study by Xie et al[8] marks a significant stride toward demystifying TCM formulations through state-of-the-art scientific methods. By delineating CG’s pharmacodynamic basis and mechanistic network, it provides a compelling case for CG’s use in TD management and sets a precedent for the integration of traditional medicine and modern pharmacology. This work offers a valuable, evidence-based framework for understanding CG’s potential mechanism, though further functional validation is needed. As we advance, collaborative efforts among pharmacologists, clinicians, and TCM experts will be essential to translate these findings into tangible therapeutic benefits for patients globally. Future research should prioritize in vivo functional studies, quantitative pharmacokinetic profiling, and larger-scale clinical trials utilizing precision medicine frameworks that integrate AI-driven syndrome stratification, metabolomic biomarkers, and real-time monitoring to fully realize CG’s potential for personalized herbotherapy in TD management. Such a framework could harmonize ancient wisdom with contemporary science to deliver personalized, effective, and safe care.