Cepharanthine (also known as 千金藤素) is a natural bisbenzylisoquinoline alkaloid extracted from the plant Stephania cepharantha Hayata, used traditionally in Chinese medicine for over 70 years. It is being investigated as a potential disease-modifying treatment for Parkinson's disease (PD) due to its multi-target neuroprotective properties that address multiple pathogenic pathways simultaneously["@cepharanthine2015"][@cepharanthine2020].
Compound Information
| Property | Value | |----------|-------| | Chemical Name | (1R,2S,3R,4S,6R,7S,8R,13R,14R,15S,16S)-1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17-Octadecahydro-1,6-epoxy-4,15-dihydroxy-5,11-dimethyl-8-(1-methylethenyl)-7,13-epoxy-15H-cyclopenta[a]azulene-3-carboxylic acid | | Molecular Formula | C₃₇H₃₈N₂O₆ | | Molecular Weight | 606.7 g/mol | | Class | Bisbenzylisoquinoline alkaloid | | Source | Stephania cepharantha (Japanese: Kikyo, Chinese: Jin Qian Teng) | | Traditional Uses | Anti-inflammatory, anti-allergic, immune modulation |
Clinical Development Status
Current Phase
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Cepharanthine (千金藤素) — Investigational Therapy for Parkinson's Disease
Overview
Mermaid diagram (expand to render)
Cepharanthine (also known as 千金藤素) is a natural bisbenzylisoquinoline alkaloid extracted from the plant Stephania cepharantha Hayata, used traditionally in Chinese medicine for over 70 years. It is being investigated as a potential disease-modifying treatment for Parkinson's disease (PD) due to its multi-target neuroprotective properties that address multiple pathogenic pathways simultaneously["@cepharanthine2015"][@cepharanthine2020].
Compound Information
| Property | Value | |----------|-------| | Chemical Name | (1R,2S,3R,4S,6R,7S,8R,13R,14R,15S,16S)-1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17-Octadecahydro-1,6-epoxy-4,15-dihydroxy-5,11-dimethyl-8-(1-methylethenyl)-7,13-epoxy-15H-cyclopenta[a]azulene-3-carboxylic acid | | Molecular Formula | C₃₇H₃₈N₂O₆ | | Molecular Weight | 606.7 g/mol | | Class | Bisbenzylisoquinoline alkaloid | | Source | Stephania cepharantha (Japanese: Kikyo, Chinese: Jin Qian Teng) | | Traditional Uses | Anti-inflammatory, anti-allergic, immune modulation |
Clinical Development Status
Current Phase
Phase: Preclinical / Early clinical (IND-enabling studies)
Status: Active investigation, multiple research groups
Indication: Parkinson's disease (early to mid-stage)
Goal: Disease modification, not just symptomatic relief
Research Pipeline
Preclinical efficacy: Completed in cellular and animal models
Pharmacokinetics: Ongoing in preparation for human trials
Safety assessment: GLP toxicology studies in progress
Cepharanthine exerts neuroprotective effects through multiple interconnected pathways[@cepharanthine2020]. This multi-target approach is particularly attractive for PD, where multiple pathogenic mechanisms contribute to dopaminergic neuron loss.
Anti-inflammatory Effects
The neuroinflammatory response in PD involves activation of microglia in the substantia nigra pars compacta (SNpc), releasing pro-inflammatory cytokines that contribute to neuronal death.
NF-κB Inhibition:
NF-κB is a key transcription factor driving inflammatory gene expression
This blocks NF-κB nuclear translocation and DNA binding
Downstream effects include reduced iNOS, COX-2, and cytokine expression
Cytokine Reduction:
TNF-α: Reduced by up to 70% in microglial cultures
IL-1β: Decreased production and release
IL-6: Suppressed synthesis
MCP-1: Reduced monocyte recruitment
Microglial Modulation:
Shifts microglia from M1 (pro-inflammatory) to M2 (protective) phenotype
Enhances production of anti-inflammatory cytokines (IL-10, TGF-β)
Reduces NADPH oxidase-derived superoxide production
Antioxidant Activity
Oxidative stress is a hallmark of PD pathogenesis, with increased markers of lipid peroxidation, protein oxidation, and DNA damage in the SN of PD patients.
ROS Scavenging:
Direct neutralization of hydroxyl radicals (·OH) and superoxide (O₂⁻)
Preservation of endogenous antioxidant enzymes (SOD, catalase, GPx)
Metal chelation prevents Fenton reaction-mediated damage
Nrf2 translocates to the nucleus and binds antioxidant response elements (ARE)
Upregulates expression of:
Heme oxygenase-1 (HO-1)
NAD(P)H quinone dehydrogenase 1 (NQO1)
Glutamate-cysteine ligase (GCL)
Thioredoxin (Trx)
NADPH Oxidase Inhibition:
NOX2 is the major source of ROS in activated microglia
Cepharanthine prevents p47phox phosphorylation and assembly
Reduces superoxide production by up to 60%
Anti-apoptotic Effects
The intrinsic (mitochondrial) apoptotic pathway is activated in PD neurons due to oxidative damage, calcium dysregulation, and alpha-synuclein toxicity.
Caspase Inhibition:
Direct inhibition of caspase-3 and caspase-9
Prevention of cytochrome c release from mitochondria
Blocking of Apaf-1 apoptosome formation
Bcl-2 Upregulation:
Increases anti-apoptotic protein Bcl-2 expression
Decreases pro-apoptotic Bax translocation to mitochondria
Maintains mitochondrial membrane potential
Mitochondrial Protection:
Preserves complex I activity in the electron transport chain
Alpha-synuclein aggregation is the central pathogenic event in PD. Cepharanthine interferes with multiple steps in this process[@autophagy_cepharanthine].
Aggregation Inhibition:
Binds to the NAC (Non-Aβ Component) region of alpha-synuclein
Prevents nucleation and oligomer formation
Reduces formation of toxic soluble oligomers
Evidence from ThT fluorescence and AFM studies
Fibril Disassembly:
May promote clearance of existing aggregates
Disrupts established fibril structures
Reduces the seeding capacity of aggregates
Autophagy Enhancement:
Activates autophagy through mTOR-independent pathways
Enhances clearance of misfolded proteins via chaperone-mediated autophagy
Increases Beclin-1 expression and LC3 lipidation
Particularly important for neurons that cannot divide and must clear debris internally
Additional Mechanisms
Calcium Homeostasis:
Modulates L-type voltage-gated calcium channels
Reduces calcium influx that triggers excitotoxicity
Protects against calcium-induced mitochondrial dysfunction
Dopamine Protection:
Preserves dopaminergic neurons in the substantia nigra
Maintains tyrosine hydroxylase (TH) activity
Protects against 6-OHDA and MPTP toxicity
Blood-brain Barrier Penetration:
Evidence for CNS bioavailability from animal studies
P-glycoprotein substrate with moderate brain penetration