Sensory innervation is a combination of free nerve endings and endings associated with corpuscular structures. Free nerve endings communicate stimuli from external environment to the brain. These nerve endings are located in dermis and epidermis reaching the uppermost viable layer of skin. Cutaneous innervation is closely associated with major skin functions such as immune function, inflammation, thermoregulation, wound-healing, influences keratinocyte proliferation and epidermal thickness and contributes to skin homeostasis. Skin aging is caused by chronological aging and photoaging and both are associated with changes in neuronal functions and structures. Wound-healing, repair process, sense of touch, perception of thermal stimuli as well as intra-epidermal nerve fibre density on face decrease with aging. For centuries, honey has been utilized for wound healing purposes. In recent times, this specific topic has become a field of interest, the information regarding honey's mechanisms of action on wound healing and as a therapeutic agent for skin disorders has accumulated at a rapid pace. However, each honey is very specific especially due to the surrounding flora and bee strains associated. Our previous studies have showed that all honeys were not equivalent and consequently, they did not induce the same biological activities. So, in order to counteract skin aging associated with the alteration of sensory innervation system, we studied the biological activities of a forest honey from Ikaria Island on a new human sensory neurons 2D model. Human sensory neurons were derived from human induced pluripotent cells obtained from human fibroblasts and they were co-cultured with human keratinocytes. After treatment by forest honey from Ikaria Island for 10 days; the numbers of neurons, the growth of neurites and the expression of TrkA (NGF receptor) and mu-opioid receptors (MOR), which are four key parameters for sensory neurons homeostasis, were studied by immunocytofluorescence. We have observed that treatment by forest honey from Ikaria Island did not induce neurone proliferation but significantly stimulated by 30% the growth of neurites and the increase of TrkA and MOR expressions by +38% and +45% respectively. These results indicate that forest honey from Ikaria Island stimulates the development of neuronal network, protects its functionalities and suggest a beta-endorphin-like activity of this natural compound making this forest honey from Ikaria a good candidate for maintaining the homeostasis of human cutaneous sensory neuron system.

Stimulation and Protection of Cutaneous Sensory Neuron System induced by Forest Honey from Ikaria Island