Ligustillide
Also known as: Z-ligustilide, Ligustilide, LIG, 3-butylidene-4,5-dihydrophthalide
Overview
Z-ligustilide is a bioactive phthalide derivative primarily found in the rhizomes of Ligusticum chuanxiong (Chuanxiong) and Angelica sinensis (Danggui), herbs commonly used in traditional Chinese medicine. It is being investigated for its potential neuroprotective, anti-inflammatory, antioxidant, and antidepressant-like effects. Preclinical studies suggest it may have applications in cognitive health, mood disorders, and vascular health. Z-ligustilide is volatile and unstable in its free form, often requiring liposomal or encapsulated formulations to enhance stability and bioavailability. Research is primarily preclinical, with limited human clinical trials available. The quality of evidence is moderate for preclinical studies but low for human evidence due to the lack of large, well-controlled trials. Further research is needed to confirm its efficacy and safety in humans.
Benefits
Z-ligustilide has demonstrated several potential benefits primarily in preclinical studies. In rats subjected to chronic unpredictable mild stress, Z-ligustilide (20 and 40 mg/kg, i.p.) significantly reduced immobility time in the forced swim test and increased sucrose preference, comparable to the antidepressant sertraline. In a mouse model of Alzheimer’s disease, liposome-packaged ligustilide reduced oxidative stress, β-amyloid deposition, and improved cognitive function, with effects mediated via the PKA/AKAP1 signaling pathway. Additionally, it exhibits anti-inflammatory and antioxidant properties in multiple preclinical models. Systematic reviews suggest possible therapeutic effects in atherosclerosis, but human evidence is lacking. These benefits are primarily observed in animal models, and human data are currently absent, necessitating further research to validate these findings in humans.
How it works
Z-ligustilide's mechanism of action involves several biological pathways. In neuroprotection, it upregulates PKA/AKAP1 signaling, reduces oxidative stress, and mitigates mitochondrial dysfunction. For mood regulation, it modulates progesterone and allopregnanolone levels. These effects are reversed by progesterone receptor and 5α-reductase inhibitors. Z-ligustilide interacts with the central nervous system, exhibiting neuroprotective, antidepressant-like, and cognitive-enhancing effects. It also shows potential anti-atherosclerotic effects in the cardiovascular system. Molecular targets include the PKA/AKAP1 signaling pathway and progesterone and allopregnanolone pathways. Its absorption and bioavailability are low in free form but improved by liposomal encapsulation.
Side effects
The overall safety assessment of Z-ligustilide is based primarily on preclinical evidence, where it is generally well-tolerated in animal models, with no major toxicity reported at effective doses. However, human evidence is insufficient to fully characterize its safety profile. Common, uncommon, and rare side effects have not been reported in available studies. Based on animal data, there is a potential interaction with progesterone receptor modulators and 5α-reductase inhibitors. Due to the lack of human data, contraindications have not been established. There is no data available regarding its use during pregnancy, lactation, or in pediatric populations. Further research is needed to comprehensively assess the safety of Z-ligustilide in humans.
Dosage
Due to limited human data, specific dosage guidelines for Z-ligustilide are not well-established. Animal studies have used a minimum effective dose of 20 mg/kg (intraperitoneal) and optimal dosage ranges of 20–40 mg/kg (intraperitoneal). A human equivalent dose has not been established, and extrapolation is speculative. The maximum safe dose in humans is also not established. Timing considerations are not well-defined, although both acute and chronic administration have been effective in animals. Liposomal or encapsulated forms may improve stability and bioavailability. No required cofactors have been identified. Human dosing and safety are not established, and liposomal formulations may be preferable for stability.
FAQs
What is the appropriate human dosage for Z-ligustilide?
Human dosing and safety are not established. Animal studies have shown efficacy at 20-40 mg/kg (i.p.), but human equivalent doses are unknown. Consult a healthcare professional before use.
Are there any known side effects of Z-ligustilide?
No major safety concerns have been reported in animal studies. However, human safety is unknown due to limited data. Monitor for any adverse reactions and discontinue use if they occur.
How should Z-ligustilide be administered for best results?
Optimal timing is not defined; both acute and chronic use have been effective in animals. Liposomal formulations may improve stability and bioavailability. Follow product-specific instructions.
What are the expected benefits of taking Z-ligustilide?
Preclinical evidence supports neuroprotective and antidepressant-like effects. However, human relevance is unclear. It is not a proven treatment for any human condition; evidence is primarily preclinical.
Research Sources
- https://pmc.ncbi.nlm.nih.gov/articles/PMC8112151/ – This study investigated the antidepressant-like effects of Z-ligustilide in rats subjected to chronic unpredictable mild stress (CUMS). The findings showed that Z-ligustilide significantly reduced immobility time in the forced swim test and increased sucrose preference, comparable to the antidepressant sertraline, suggesting potential antidepressant properties.
- https://pubmed.ncbi.nlm.nih.gov/32135035/ – This review summarizes the pharmacokinetics and pharmacology of Z-ligustilide, highlighting its broad pharmacological properties, including neuroprotective, anti-inflammatory, and antioxidant effects. However, it notes the limited human clinical data available, emphasizing the need for further research to validate these findings in humans.
- https://www.mdpi.com/2218-273X/14/12/1623 – This study explored the effects of ligustilide-loaded liposomes in a mouse model of Alzheimer’s disease. The results indicated that liposome-packaged ligustilide reduced oxidative stress and β-amyloid deposition, leading to improved cognitive function via the PKA/AKAP1 signaling pathway, suggesting a potential therapeutic approach for Alzheimer's disease.
- https://inplasy.com/inplasy-2025-4-0083/ – This is a registration record for a systematic review/meta-analysis. Without the full study, it's difficult to provide a detailed summary, but it indicates ongoing research interest in the therapeutic potential of Z-ligustilide.
- https://onlinelibrary.wiley.com/doi/abs/10.1111/cns.14460 – This study investigates the neuroprotective effects of ligustilide. The abstract indicates that ligustilide protects against neuronal damage and improves cognitive outcomes in preclinical models, suggesting its potential as a therapeutic agent for neurodegenerative diseases.
