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Dry eye syndrome is defined as a disorder of the tear film caused by either a decreased production in tears or a disruption to the stability of the complex tear film, which causes damage to the ocular surface. It has been developed the medicine for dry eye syndrome focusing anti-inflammation or mucin secretion, however, no treatment has been developed focusing on the effect of elevation of the lacrimal secretion. We recently identified that pituitary adenylate cyclase-activating polypeptide (PACAP)-null mice develop dry eye-like symptoms such as corneal keratinization and tear reduction. PACAP receptor (PAC1-R) immunoreactivity was observed in the acinar cells of the mouse lacrimal gland. PACAP eye drop significantly stimulated tear secretion level, and the effect was suppressed by pretreatment with PAC1-R antagonist or adenylate cyclase inhibitor. PACAP eye drop on the PACAP KO mouse significantly increased the tear secretion, and continuous eye drop suppressed progression of the corneal keratinization. PACAP eye drops increase aquaporin 5 (AQP5) levels in the membrane of acinar cells in lacrimal glands. AQP5 siRNA treatment significantly attenuates PACAP-induced tear secretion. Based on these results, PACAP might be clinically useful to treat dry eye disorder.

Ischemic delayed neuronal cell death (apoptosis) in the hippocampus is prevented by PACAP. PACAP inhibits the increasing activity of the MAP kinase family, especially on JNK/SAPK and p38, thereby protecting against apoptotic cell death. After the ischemia-reperfusion, both pyramidal cells and astrocytes increased their expression of PACAP receptors (PAC1-Rs). The pyramidal cells degenerated but reactive astrocytes increased their expression of PAC1-R. PACAP does not only inhibit apoptotic cell death directly, but also affects astrocytes through PAC1-Rs. Interleukin-6 (IL-6), produced in astrocytes, has several effects on the prevention of brain ischemia and trauma and stimulating neuronal growth. IL-6 secretion into the CSF was markedly stimulated after PACAP infusion, suggesting that PACAP stimulates IL-6 secretion from astrocytes. We studied the effects of PACAP on the wild type and IL-6 KO mice after brain ischemia. In wild-type animals, PACAP significantly inhibited cell death, but in IL-6 KO animals, no cytoprotective effect of PACAP was seen. These results suggest that PACAP inhibits apoptotic cell death partly through IL-6. It is considered that PACAP itself and IL-6, stimulated secretion by PACAP, both synergistically inhibit the JNK/SAPK and p38 signaling pathway, thereby protecting against neuronal cell death.