Argireline, an alternative to botulinum toxin for treating expression wrinkles?

Known by its INCI name Acetyl Hexapeptide-8, argireline is a peptide whose efficacy on expression wrinkles has led to comparisons with botulinum toxin.

As a reminder, expression lines, also known as dynamic wrinkles, are caused by repeated muscle movements. These are the first signs to appear over time. They commonly occur around the eyes – the so-called crow’s feet – between the eyebrows, on the forehead, or around the lips, areas often in motion. When it comes to eliminating dynamic wrinkles, injectable neurotoxins, such as botox, are highly effective solutions. By paralyzing the muscles, they prevent movement and "freeze" the skin. However, injections are not pleasant and can cause side effects (pain, itching, swelling, skin rashes...), hence the interest in topical alternatives, such as argireline.

From a mechanistic point of view, botox acts directly at the neuromuscular junction, where nerve terminals command the contraction of facial muscles. Once injected, botulinum toxin binds to motor nerve terminals and is then internalized into the cell. It then targets the protein SNAP-25, which is part of the SNARE complex. This complex normally enables acetylcholine-filled vesicles to fuse with the neuronal membrane in order to release the neurotransmitter into the synaptic cleft. By cleaving SNAP-25, botulinum toxin interrupts this process: the vesicles can no longer fuse, and acetylcholine is no longer released. Without this chemical signal, the muscle no longer receives the command to contract.

The argireline, however, acts upstream in this cascade. This SNAP-25–mimetic peptide interferes with SNARE complex formation at the neuronal surface without entering the nerve fiber or cleaving proteins as botulinum toxin does. By partially occupying certain interactions of the complex, it limits the neuron’s ability to efficiently organize the fusion of acetylcholine-containing vesicles. Neurotransmitter release is thus reduced, which attenuates facial muscle contractions without causing complete paralysis.

Argireline exerts a gentler, less invasive effect than botox, yet it also induces relaxation of the muscles responsible for expression lines.

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

An initial study first investigated argireline’s ability to penetrate the skin, an essential prerequisite for exerting 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 initially applied 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 proceeded with a clinical evaluation. An emulsion containing 10% of argireline was applied twice daily for 30 days to one periorbital area of ten volunteers, while the other side received only the formula base and served as a control. Silicone replicas were taken on days 0, 15, and 30, then analyzed by confocal microscopy. The results show a marked reduction in wrinkle depth and roughness on the side treated with the hexapeptide. While the emulsion alone led to about a 10% decrease in furrow depth, likely due to its hydrating effect, the argireline-enriched formula achieved around a 30% reduction, confirming the peptide’s efficacy in attenuating wrinkles.

Another study in vivo explored the effects of argireline on wrinkles and skin hydration. The researchers evaluated two types of formulations – an emulsion for dry skin and a gel for oily skin – applied daily for 30 days. Within the first 24 hours, a measurable increase in stratum corneum hydration was observed, followed by progressive improvement throughout the study. Concurrently, instrumental assessments revealed a significant reduction in wrinkle depth.

Finally, it is interesting to present the work of WANG and his team on the efficacy of argireline against periorbital wrinkles. These studies were conducted on 60 volunteers, randomly assigned in a 3:1 ratio to receive either a formulation containing 10% peptide or a placebo. The products were applied twice daily for four weeks, and improvements were then assessed using both subjective and objective evaluation tools.

In the subjective analysis, results show a perceived efficacy of 48.9% in the argireline-treated group, while 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, whereas no notable change was detected in participants using the placebo. The photos of the two participants below also demonstrate a visible attenuation of wrinkles.

In view of the available data, argireline emerges as a promising alternative to botulinum toxin for reducing expression wrinkles.

Moreover, the argireline has a significantly better safety profile than botox injections. However, one area of uncertainty remains: the exact duration of its effects is not specified in the studies, where clinical evaluations are not continued after discontinuing argireline use, which limits direct comparison with botox. However, the botulinum toxin itself only offers transient efficacy, generally lasting between 6 and 8 months. In practice, argireline therefore appears as a gentler, noninvasive, and highly promising option for smoothing expression lines 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).