Anti-Aging Neurotransmitter-inhibiting Peptides

Active ingredients in skincare products typically include peptides, growth factors, antioxidants, anti-inflammatory botanicals, and polysaccharides. Due to their drug-like effects, these products are given the composite name "cosmeceuticals". As natural molecules, peptide substances exhibit unparalleled physiological effects on many skin-related conditions. Initially, interest in peptides in the cosmetics field stemmed from their beneficial effects on wound healing, gradually uncovering their efficacy in combating skin aging.

Skin Aging

Although the skin has many layers, it can generally be divided into three main parts:

• External (Epidermis): Contains skin cells, pigments, and proteins.
• Middle layer (Dermis): Includes skin cells, blood vessels, nerves, hair follicles, and oil glands. The dermis nourishes the epidermis.
• Inner layer below the dermis (Subcutaneous Layer): Contains sweat glands, some hair follicles, blood vessels, and fat.

Each layer also includes connective tissue and collagen fibers to provide support, as well as elastic protein fibers to provide flexibility and strength.

Like all organs, the skin ages as cellular functions and physiological integrity gradually decline. Skin aging is a complex biological process influenced by internal (constitutive) and external (environmental) factors, leading to cumulative changes in skin structure, function, and appearance. Natural pigments seem to offer some protection against sun-induced skin damage. Among endogenous factors, neuroendocrine plays a key role.

With age, the outer layer of skin (epidermis) becomes thinner, even if the number of cell layers remains unchanged. The number of pigment cells (melanocytes) decreases, and the remaining melanocytes increase in volume. Aging skin appears thinner, paler, and more translucent. Pigment spots, including age spots, may appear in sun-exposed areas of the skin. Changes in connective tissue reduce the strength and elasticity of the skin, known as elastosis, which is more apparent in sun-exposed areas. Blood vessels in the dermis become more fragile, leading to bruising, subcutaneous bleeding (commonly called senile purpura), and cherry angiomas (benign red moles). With age, sebum production from sebaceous glands decreases, making it harder for the skin to retain moisture, leading to dryness and itching. The subcutaneous fat layer thins, increasing the risk of skin injury and reducing the ability to maintain body temperature.

Fig 1. Mechanism of neurotransmission. (Gasmi, 2023)

Anti-Skin Aging Peptide Cosmeceuticals

The role of peptides in cosmeceuticals is becoming increasingly prominent, with many anti-aging formulations featuring peptides. Based on the mechanisms of action during skincare, peptides can be roughly categorized into three types:

• Signal Peptides: Regulate the process of skin protein renewal, with many signal peptides enhancing collagen production. They are named for their ability to emit or mimic signals for extracellular matrix (ECM) protein synthesis, inducing collagen formation.
• Carrier Peptides: While not directly involved in skincare and repair, carrier peptides can transport essential Cu²⁺ ions to cells. Copper is crucial for various physiological processes, including enzyme reactions, wound healing, and blood vessel formation. In cosmetics, copper is an important cofactor in the formation of lysyl oxidase, which mediates the formation of collagen or elastic fibers.
• Neurotransmitter-inhibiting Peptides: A category of peptides used in skincare formulations to address signs of aging, particularly wrinkles. These peptides target the neurotransmitter acetylcholine, which plays a role in muscle contraction and is implicated in the formation of wrinkles.

Neurotransmitters

Neurotransmitters are chemical messengers essential for bodily functions. They transmit chemical signals from one neuron (nerve cell) to the next target cell (nerve cell, muscle cell, or gland). Communication between two neurons occurs in the synaptic cleft (the small gap between nerve cell synapses). Neurotransmitters are released into the synaptic cleft from presynaptic vesicles when presynaptic neuronal activity is stimulated, a process dependent on Ca²⁺. The released neurotransmitters, via chemical signals, briefly transform electrical signals propagated along the axon into chemical signals, triggering specific reactions in the receiving neuron. They interact with neurotransmitter receptors on target cells.

Neurotransmitters can affect neurons in three ways: excitatory, inhibitory, or modulatory. Excitatory neurotransmitters promote the generation of electrical signals in the receiving neuron, while inhibitory neurotransmitters prevent it. It's important to note that neurotransmitter inhibitors are not inhibitory neurotransmitters.

From a chemical structure perspective, neurotransmitters can be classified into four types:

• Amino Acid Neurotransmitters: e.g., glutamate, γ-aminobutyric acid (GABA), glycine.
• Monoamine Neurotransmitters: e.g., serotonin, histamine, dopamine, epinephrine (adrenaline), norepinephrine (noradrenaline).
• Acetylcholine Neurotransmitter
• Peptide Neurotransmitters: Over 100 types of peptide neurotransmitters, also known as neuropeptides, including substance P, enkephalins, pituitary peptides, hypothalamic peptides.
• Mechanism of Action of Neurotransmitters in Skin Aging

In skincare, inhibiting or eliminating the formation of wrinkles is crucial. One reason for the formation of wrinkles is excessive pressure stimulation on facial muscles. From a physiological perspective, the release of the neurotransmitter acetylcholine (ACh) can cause muscle contraction. This process begins at the presynaptic terminal, where protein-protein interactions lead to the influx of vesicles containing acetylcholine to the neuronal membrane. Once there, they fuse with the membrane and release acetylcholine into the cholinergic synapse. Releasing acetylcholine requires calcium ions and a specific transport protein chain called the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex. The SNARE complex assists in the fusion of acetylcholine vesicles with the neuronal membrane and the subsequent release of acetylcholine. ACh passes through this synapse to the other side, where it can stimulate the response of the next cell (e.g., muscle cell).

The other side of the synapse is the target cell membrane, which requires acetylcholine receptors to capture the released acetylcholine. There are two types of receptors—nicotinic and muscarinic. Most muscle cells (except for heart and some smooth muscles) have nicotinic receptors. Acetylcholine, when binding to its receptors on muscle cells, induces muscle contraction by releasing Ca²⁺ ions and may lead to the formation of wrinkles.

Neurotransmitter-inhibiting Peptides

The release of acetylcholine is a complex process. In simple terms, a vesicle-associated membrane protein called SNAP-25 (Synaptosomal-Associated Protein, 25kDa) plays a crucial mediating role. SNAP-25 is a component of the SNARE complex responsible for the fusion of acetylcholine vesicles with the neuronal membrane and the subsequent release of acetylcholine. Some synthetic peptides used in anti-aging cosmetics mimic the sequence of the N-terminal region of SNAP-25 (AA12-AA17) and compete with SNAP-25, disrupting protein-protein binding involved in acetylcholine release. This inhibition leads to a reduction in muscle contraction that causes the formation of wrinkles. These peptides, specifically inhibiting neurotransmitter release (such as acetylcholine), relaxing muscles, and softening wrinkles, are called neurotransmitter-inhibiting peptides.

• Botulinum Toxin

Botulinum toxin is a neurotoxic protein produced by Clostridium botulinum and related species. It can cleave SNAP-25 protein. As mentioned earlier, SNAP-25 protein mediates the fusion of vesicles containing acetylcholine with the neuronal membrane. Activated botulinum toxin cleaves SNAP-25, a key protein in the SNAP-25 protein complex responsible for vesicle fusion. Cleaved SNAP-25 cannot mediate the fusion of vesicles with the host cell membrane, meaning vesicles containing acetylcholine cannot bind to the intracellular cell membrane. This prevents the release of acetylcholine from the presynaptic terminal of the nerve-muscle junction, terminating the transmission of nerve signals and causing flaccid paralysis. Therefore, botulinum toxin, commercially used for medical and cosmetic purposes, is considered relatively safe and effective for reducing facial wrinkles, especially in the upper third of the face.

Three botulinum toxin approved by the FDA are as follows: Onabotulinum toxin A (Botox®/Vistabel®); Abobotulinum toxin A (Dysport®/Azzalure®); Incobotulinum toxin A (Xeomin®/Bocouture®).

In addition to botulinum toxin, common peptide neurotransmitter inhibitory cosmeceutical products are summarized in the table below:

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