Potential Therapeutic Mechanism of Traditional Chinese Medicine Monomers on Neurological Recovery After Spinal Cord Injury

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Potential Therapeutic Mechanism of Traditional Chinese Medicine Monomers on Neurological Recovery After Spinal Cord Injury

Spinal cord injury (SCI) remains a devastating condition with profound physical, psychological, and societal consequences. As a traumatic disorder of the central nervous system, SCI leads to neuronal degeneration, glial scar formation, and permanent neurological deficits. Despite advances in understanding its pathophysiology, effective therapeutic strategies remain limited. Traditional Chinese medicine (TCM) has long been recognized for its holistic approach and multi-targeted interventions. Recent research has shifted focus toward isolating active TCM monomers—single chemical entities derived from herbal compounds—to elucidate their molecular mechanisms in SCI recovery. This article synthesizes current findings on TCM monomers, emphasizing their roles in modulating inflammation, apoptosis, autophagy, oxidative stress, and neural regeneration after SCI.

Anti-Inflammatory Effects of TCM Monomers

Inflammation is a hallmark of secondary injury following SCI. Activated microglia and astrocytes release pro-inflammatory cytokines, exacerbating neuronal damage and impeding recovery. TCM monomers demonstrate potent anti-inflammatory properties by targeting specific signaling pathways and cellular responses.

Triptolide, a diterpenoid triepoxide from Tripterygium wilfordii, suppresses microglial activation and reduces levels of tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1β) in SCI rats. This inhibition occurs via upregulation of microRNA-96 (miR-96), which downregulates pro-inflammatory mediators such as ionized calcium-binding adaptor molecule-1 (Iba-1), phosphorylated nuclear factor-kappa B (p-p65), and components of the IκB kinase (IKK) complex. Triptolide also attenuates astrocyte activation by decreasing intermediate filament proteins like glial fibrillary acidic protein (GFAP), thereby mitigating glial scar formation.

Ginsenoside Rg1, derived from Panax ginseng, enhances the migration of olfactory ensheathing cells (OECs) through the phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) pathway. These cells secrete neurotrophic factors and reduce inflammatory cytokines (TNF-α, IL-1, IL-6), creating a regenerative microenvironment. Similarly, curcumin from Curcuma longa modulates the toll-like receptor/transforming growth factor-beta-activated kinase 1 (TLR/TGF-β1/TAK1) and mitogen-activated protein kinase (MAPK) pathways, inhibiting nuclear factor-kappa B (NF-κB) translocation and reducing IL-6, IL-8, and Olig2 expression.

Other monomers, including sinomenine, paeoniflorin, ginkgolide, and baicalin, regulate distinct pathways. For instance, paeoniflorin inhibits the apoptosis signal-regulating kinase 1/p38/JNK (ASK1/p-p38/p-JNK) axis, while ginkgolide B targets the Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) pathway. These interventions collectively shift the cytokine balance, elevating anti-inflammatory factors like IL-4, IL-10, and TGF-β.

Inhibition of Neuronal Apoptosis

Post-SCI apoptosis is driven by imbalances between pro-apoptotic (Bax, caspases) and anti-apoptotic (Bcl-2) proteins. TCM monomers restore this equilibrium, promoting neuronal survival. Ginsenoside Rb1 downregulates caspase-3, caspase-9, and Bax while upregulating Bcl-2 in spinal cord ischemia-reperfusion models. This effect correlates with STAT3 activation, which enhances Bcl-2 transcription. Ginkgolide B similarly reduces Bax/Bcl-2 ratios and caspase activity, improving motor function in SCI rats.

Modulation of Autophagy

Autophagy, a cellular recycling process, is neuroprotective when appropriately regulated. Resveratrol, a polyphenol in Polygonum cuspidatum, activates autophagy via the adenosine monophosphate-activated protein kinase/mammalian target of rapamycin (AMPK/mTOR) pathway. Phosphorylated AMPK inhibits mTOR, upregulating autophagy markers like Beclin-1, LC3-II/I, and autophagy-related proteins. Curcumin exerts similar effects through the AKT/mTOR pathway, enhancing autophagic flux and reducing neuronal death.

Attenuation of Oxidative Stress

Oxidative stress exacerbates secondary injury by generating reactive oxygen species (ROS). TCM monomers activate antioxidant pathways to counteract this damage. Sinomenine, ginsenoside, and resveratrol upregulate nuclear factor erythroid 2-related factor 2 (Nrf2), a master regulator of antioxidant responses. Nrf2 induces heme oxygenase-1 (HO-1) and other enzymes, neutralizing ROS and restoring redox balance. In SCI models, these monomers reduce lipid peroxidation and enhance endogenous antioxidant defenses.

Promotion of Neural Regeneration

Neurotrophic factors like nerve growth factor (NGF) and fibroblast growth factor (FGF) are critical for axonal growth and synaptic plasticity. Matrine, an alkaloid from Sophora flavescens, directly activates extracellular heat shock protein 90 (HSP90), stimulating axonal regeneration and functional recovery. Although the precise mechanism remains unclear, matrine’s ability to enhance neurite outgrowth highlights its therapeutic potential.

The Wnt/β-Catenin/NF-κB Signaling Axis: A Novel Hypothesis

The authors propose an innovative mechanism centered on the Wnt/β-catenin/NF-κB pathway. In SCI, Wnt ligands bind to Frizzled receptors, stabilizing β-catenin by inhibiting glycogen synthase kinase-3 beta (GSK-3β). Accumulated β-catenin translocates to the nucleus, forming complexes with T-cell factor/lymphoid enhancer factor (TCF/LEF) to regulate gene expression. Concurrently, β-catenin interacts with NF-κB, modulating inflammatory responses. TCM monomers like triptolide and curcumin may disrupt this interaction, reducing NF-κB-driven inflammation and enhancing neuronal survival.

Challenges and Future Directions

Despite promising preclinical results, clinical translation remains challenging. Most studies are confined to animal models, with limited data on pharmacokinetics, bioavailability, or safety in humans. Furthermore, TCM monomers often exhibit multi-target effects, complicating mechanistic studies. Future research should prioritize the following:

  1. Elucidating the Wnt/β-catenin/NF-κB pathway in diverse neuronal subtypes.
  2. Standardizing extraction methods to ensure consistency and potency.
  3. Conducting clinical trials to validate efficacy and safety.
  4. Exploring synergistic combinations of monomers to enhance therapeutic outcomes.

Conclusion

TCM monomers represent a promising frontier in SCI treatment, offering multi-faceted neuroprotection through anti-inflammatory, anti-apoptotic, pro-autophagic, and antioxidant mechanisms. By targeting pathways like Wnt/β-catenin/NF-κB, these compounds address the complexity of secondary injury cascades. However, bridging the gap between preclinical success and clinical application requires rigorous investigation into their pharmacodynamics and long-term effects. As research progresses, TCM monomers may emerge as viable adjuncts or alternatives to conventional therapies, revolutionizing SCI management.

doi.org/10.1097/CM9.0000000000001476

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