## 4 The Role of PACAP in the Cornea  
The expression of PACAP and its receptors has been shown in the cornea. Here, PACAP positive cells were found in rabbit and human corneal epithelium, particularly in the basal cells. Moreover, the expression of PACAP was detected in the corneal endothelial layer and weakly in the stroma [98; 99]. High expression levels of PAC1R were identified in the stromal and basal cells of the epithelium. Furthermore, the VPACRs were strongly expressed in all layers of the epithelium and in stromal cells of the rabbit cornea [99]. Previously, [PERSON] [95] et al. detected PACAP immunoreactivity in nerve terminals running in the stroma and sending off some branches into the epithelium. Corneal injury is frequently associated with damage of the epithelium and its innervating fibers. In an in vivo experimental model of laser-assisted in situ keratomileuses (LASIK) surgery, PACAP showed to accelerate recovery of corneal sensitivity after the creation of a corneal flap. In more detail, the administration of 10 uM PACAP27 increased up to 75% the corneal sensitivity eight weeks after the operation [100]. In accord, it has been demonstrated that PACAP induced the growth of neuronal processes in cultured trigeminal ganglion cells. These neurons secrete various biologically active molecules enhancing the proliferation and differentiation of corneal epithelial cells as well as collagen VII production, important to maintaining and repairing the corneal epithelium [101]. The protective effect of PACAP was confirmed by [PERSON] et al., 2015 [102], by showing that the peptide alone or in combination with the receptor protein of laminin, known as N-terminal agrin domain (NtA), significantly accelerated the process of repairing the mechanically injured corneal epithelial cells. It is well known that tear fluid contains different antibacterial proteins, growth factors, and secretory mucin important for corneal maintenance and its repairing [103, 101]. For this reason, tear fluid reduction, occurring in dry eye syndrome, is an inducing factor in corneal keratinization. PACAP played an important role in protecting the corneal surface by stimulating tear secretion [104]. As described above, in the lacimal gland, PACAP is an endogenous modulator of AQP5, involved in tear production [90]. In accord, PACAP null mice showed a reduction in the AQP5 expression, whereas the eye treatment with PACAP drops stimulated its transcription. Furthermore, PACAP null mice exhibited the dry eye syndrome phenotype with a corneal disorder associated with the reduction in tear volume [90]. Although PACAP has been shown to promote corneal repair, including epithelial and nerve regeneration, therapeutic use of the peptide presents some limitations. In fact, it has poor in vivo stability, with a half-life of fewer than ten minutes, due to its fast degradation by the proteolytic enzyme dipeptidyl peptidase IV [105]. A very recent study [106] compared the stability of PACAP1-27 and PACAP1-38 in four common media and a commercially available artificial tear solution either at room temperature or +4 \({}^{\circ}\)C. The results showed that PACAP1-38 has higher stability as compared to PACAP1-27, mainly at +4 \({}^{\circ}\)C in water solution. Moreover, both peptides can be stored in each medium for relatively long periods without significant degradation. These results suggested a therapeutic use of PACAP in eye drops. In a previous study, [PERSON] [107] et al. have synthesized a new PACAP agonist, known as PACAP27-derived mutant peptide (MPAPO), and tested its efficacy either in vitro or in vivo model of corneal damage [108]. The study was performed on C57 BL/6 mice by performing a whole corneal epithelium wound through the use of a trephine. The treatment with MPAPO significantly promoted corneal epithelial wound closure after 36 h from the administration.