Apigenin is a natural flavonoid found primarily in parsley, celery, chamomile, and citrus fruits—especially lemon peel. It has attracted considerable interest in recent years as a Anti-inflammatories, Neuroprotectant, Anxiety reliever and also in adjuvant oncological therapy. In the following, we summarize the clinical-preclinical study situation together, explain why natural apigenin from lemon extract is preferable to synthetic and why Piperine is indispensable as a bioenhancer.

1. Possible therapeutic use

1.1 Anti-inflammatory

• mechanism: Apigenin inhibits the activation of the transcription factor NF-κB and reduces the expression of proinflammatory cytokines (e.g., IL-1β, IL-6, TNF-α) in cell lines and animal models. In a mouse model of ulcerative colitis, apigenin significantly reduced colon length, reduced histological inflammatory damage, and normalized myeloperoxidase (MPO) activity.

1.2 Antitumoral effects

• In vitro: Apigenin induces apoptosis in various cancer cell lines (e.g. colon, breast and prostate carcinoma) via activation of Caspase-3/-9 and inhibition of PI3K/Akt as well as MAPK signaling pathways.
• In vivo: In murine xenograft models, apigenin reduced tumor volume by up to 60% without significant toxicity

1.3 Neuroprotection & cognitive effects

• Apigenin exhibits significant neuroprotective effects in numerous preclinical models, which can be explained by antioxidant, anti-inflammatory, and signal-modulating mechanisms. Recent studies provide impressive evidence of this:
• Apigenin acts as a free radical scavenger and increases the activity of endogenous antioxidants such as superoxide dismutase (SOD) and catalase (CAT), while reducing malondialdehyde (MDA)—a biomarker of lipid peroxidation. In an Alzheimer's disease model in rats, apigenin (50 mg/kg, orally) reduced MDA levels by 45% and significantly increased SOD and CAT activity by ~60% each compared to the control group (see Figure 1). https://alz-journals.onlinelibrary.wiley.com/doi/pdf/10.1002/alz.70223 ).
• Apigenin inhibits microglial activation and reduces the expression of proinflammatory cytokines as well as the activation of the NF-κB signaling pathway. In a mouse model of Parkinson's disease, apigenin (25 mg/kg) reduced microglial markers by 35% and IL-1β by 50% in the striatum (see Figure 1). https://pmc.ncbi.nlm.nih.gov/articles/PMC11084463/ ).
• By inhibiting caspase-3/-9 and increasing Bcl-2/Bax, apigenin prevents apoptosis of dopaminergic neurons. In an ischemic stroke model, apigenin (20 mg/kg) reduced the neuronal apoptosis rate by 40% and reduced infarct volume by 30% (see Figure 1). https://www.boragurer.com/wp-content/uploads/2024/01/A74.pdf ).
• Apigenin activates the cAMP/CREB/BDNF axis, which improves cognition and neuronal plasticity. Kim et al. found that apigenin (10 mg/kg, orally) increased BDNF expression in the hippocampus by 50% and significantly improved spatial learning in a memory test (see [Fig. https://www.sciencedirect.com/science/article/pii/S2667242124000897 ).
• In rat models, apigenin increases the activity of antioxidant enzymes (SOD, catalase) and protects against glutamate-induced neurotoxicity (cf. https://pmc.ncbi.nlm.nih.gov/articles/PMC6472148/

1.4 Sleep promotion

· Apigenin's sleep-promoting effects are primarily due to its binding to GABA_A receptors and the inhibition of excitatory signaling pathways – comparable, albeit significantly milder, to benzodiazepines. Several animal and human epidemiological studies support its sedative effect.

• In a large-scale observational study from 2020, a higher dietary intake of apigenin (mainly from citrus fruit peels) correlated significantly with better subjective sleep quality (Pittsburgh Sleep Quality Index) and shorter time to fall asleep (see [1]. https://www.researchgate.net/publication/378541330_Apigenin_a_natural_molecule_at_the_intersection_of_sleep_and_aging )
• In a mouse model, apigenin reduced both sleep latency and the number of waking periods, and the total sleep time also increased significantly (cf. https://pmc.ncbi.nlm.nih.gov/articles/PMC10929570/).

2. Natural apigenin from lemon extract vs. synthetic apigenin

1. Synergy effects
• Lemon extract contains apigenin as well as Hesperidin, Eriocitrin, Vitamin C and essential oils, which together Antioxidant capacity and Anti-inflammatory enhance (modulation of phase I/II enzymes); cf. https://www.sciencedirect.com/science/article/pii/S0002916522039144
2. Better metabolism
• Natural apigenin is often found as Apigenin-7-O-glucoside which is more soluble in aqueous environment and is metabolized more slowly. This results in more stable plasma levels compared to aglycones, synthetic apigenin (cf. https://onlinelibrary.wiley.com/doi/10.1155/2019/7010467 )
3. purity
• Our lemon extract is produced by CO₂ extraction (no solvent residues), while synthetic apigenin is often used in multi-step chemical syntheses solvent and Protection groups which have to be removed with great effort and can leave residues (cf. https://www.researchgate.net/publication/383212298_A_comprehensive_review_of_apigenin_a_dietary_flavonoid_biological_sources_nutraceutical_prospects_chemistry_and_pharmacological_insights_and_health_benefits )

3. Bioavailability & Piperine as an effective bioenhancer

Despite its promising efficacy profile, apigenin hydrophob and is administered orally rapidly glucuronidated and sulfated, so that the Plasma concentrations remain low (bioavailability ~30%) and the Tmax is reached after only 0.5–2.5 hours. Half-life in plasma is on average 2.5 h, which means rapid elimination and a frequent dosing necessary.

Source: https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2021.681477/full

Therefore, Apigenin should always be supplemented with piperine from black pepper extract as a bioenhancer:

• mechanism: Piperine inhibits UDP-glucuronosyltransferases and Cytochrome P450 isoenzymes (e.g. CYP3A4) as well as the P-glycoprotein transporter, whereby the Metabolism and elimination is slowed down by apigenin.
• Study certificate: Piperine increased the bioavailability of various phytochemicals by 30–200% (e.g., curcumin) and, in preliminary studies, increased the oral AUC of apigenin in animal models by approximately 100% (cf. https://pmc.ncbi.nlm.nih.gov/articles/PMC3634921/ )