Argireline: an alternative to botulinum toxin for expression wrinkles?

Under its INCI name Acetyl Hexapeptide-8, argireline is a peptide whose efficacy against expression lines has prompted comparisons with botulinum toxin.

As a reminder, expression lines, or dynamic wrinkles, are caused by repetitive muscle movements. These are the first signs to appear over time. They commonly occur around the eye contours – the well-known crow’s feet – between the eyebrows, on the forehead or around the lips, areas frequently used. To eliminate dynamic wrinkles, injectable neurotoxins, such as the botox, are undeniably powerful solutions. By paralysing the muscles, they prevent movement and effectively “freeze” the skin. However, injections are not pleasant and can cause adverse effects (pain, itching, swelling, skin rashes…), hence the interest in topical alternatives, such as argireline.

From a mechanistic viewpoint, botox acts directly at the neuromuscular junction, where nerve terminals control facial muscle contraction. Once injected, the botulinum toxin binds to the motor nerve endings and is then internalised into the cell. It targets the SNAP-25 protein, a component of the SNARE complex. Under normal circumstances, this complex allows vesicles packed with acetylcholine to fuse with the neuronal membrane and release the neurotransmitter into the synaptic cleft. By cleaving SNAP-25, the toxin halts this process: vesicles can no longer fuse, and acetylcholine is not released. Without this chemical signal, the muscle receives no command to contract.

The argireline, however, acts upstream of this cascade. This biomimetic SNAP-25 peptide interferes with SNARE complex assembly at the surface of neurones, yet without penetrating the nerve fibre or cleaving proteins as botulinum toxin does. By partially occupying certain interactions within the complex, it limits the neurone’s capacity to efficiently organise the fusion of acetylcholine-containing vesicles. Neurotransmitter release is thus reduced, which mitigates facial muscle contractions without inducing complete paralysis.

Argireline has a gentler, less invasive mechanism of action than botox, but likewise induces relaxation of the muscles responsible for expression lines.

Numerous studies have demonstrated the efficacy of argireline in reducing expression lines, but none has directly compared it with botulinum toxin injections.

An initial study examined the ability of argireline to penetrate the skin, an essential prerequisite for it to exert an effect on expression lines. The researchers conducted a permeation test in vitro using stratum corneum samples. After two hours of contact, approximately 30% of the amount originally placed in the donor chamber had crossed the skin barrier to reach the receptor compartment, confirming its capacity to diffuse through the stratum corneum and thus to act in vivo.

Building on this observation, the protocol continued with a clinical evaluation. An emulsion containing 10% of argireline was applied twice daily for 30 days to one of the periorbital areas in ten volunteers, with the other side receiving only the base formulation as a control. Silicone impressions were taken on days 0, 15 and 30, then analysed by confocal microscopy. The results show a marked reduction in wrinkle depth and roughness on the hexapeptide-treated side. While the emulsion alone led to approximately a 10% reduction in wrinkle depth, likely due to the added hydration, the argireline-enriched formula achieved around a 30% decrease, confirming the peptide’s effectiveness in attenuating wrinkles.

Another study in vivo looked at the effects of argireline on wrinkles and skin hydration. The researchers evaluated two types of formulations – an emulsion designed for dry skin and a gel suited to oily skin – applied daily for 30 days. Within the first 24 hours, a measurable increase in the hydration level of the stratum corneum was observed, followed by progressive improvement throughout the study. At the same time, instrumental measurements revealed a net reduction in wrinkle depth.

Finally, it is interesting to outline the work of WANG and his team on the efficacy of argireline against peri-orbital wrinkles. The study involved 60 volunteers, randomised to receive either a formulation containing 10% peptide or a placebo, in a 3:1 ratio. The products were applied twice daily for four weeks, after which improvements were evaluated using both subjective and objective assessment tools.

For subjective analysis, the results show a perceived efficacy of 48.9% in the argireline-treated group, whereas no improvement was noted in the placebo group. The objective assessment confirmed these observations: silicone replicas revealed a significant reduction in wrinkle depth in the argireline group, while no notable change was detected in the placebo group. The photographs of the two participants below also show a visible reduction in wrinkles.

In light of the available data, argireline stands out as an interesting alternative to botulinum toxin for attenuating expression wrinkles.

Furthermore, the argireline has a significantly better safety profile than botox injections. However, there remains a grey area: the precise duration of effects is not specified in the studies, as clinical assessments are not continued after discontinuation of argireline use, which limits direct comparison with botox. However, the botulinum toxin itself provides only transient efficacy, typically lasting between six and eight months. In practice, argireline therefore appears as a gentler, non-invasive and highly promising option for smoothing expression wrinkles on a daily basis.

• FERRER-MONTIEL A. & al. A synthetic hexapeptide (argireline) with antiwrinkle activity. International Journal of Cosmetic Science (2002).

• GALLARDO V. & al. Evaluation of the anti-wrinkle efficacy of cosmetic formulations with an anti-aging peptide (Argireline®). ARS Pharmaceutica (2010).

• WANG Y. & al. The anti-wrinkle efficacy of argireline, a synthetic hexapeptide, in Chinese subjects. American Journal of Clinical Dermatology (2013).

• JIRANUSORNKUL S. & al. Molecular modeling elucidates the cellular mechanism of synaptotagmin-SNARE inhibition: A novel plausible route to anti-wrinkle activity of botox-like cosmetic active molecules. Molecular and Cellular Biochemistry (2018).

• YI T.-H. Sustainable dynamic wrinkle efficacy: Non-invasive peptides as the future of botox alternatives. Cosmetics (2024).