# Involvement of Vasoactive Intestinal Peptide Family Members in Diabetic Keratopathy
## 3 Expression of Neuropeptides in the Cornea
### Activity-Dependent Neuroprotective Protein (ADNP)  
In 1999, [PERSON] et al. [104] identified the human _ADNP_ gene, localized on the q13.13 band of chromosome 20, and contains 5 exons and 4 introns with alternative splicing of an untranslated second exon. This gene interacts with nuclear chromatin, regulating more than 400 genes involved in brain formation and plasticity, organ development, autophagy, and axonal transport [149; 150; 151]. _ADNP_ de novo mutations are responsible for ADNP syndrome, also known as Helsmoortel-Van der Aa syndrome (HVDAS) [105; 152]. This syndrome, belonging to autism spectrum disorders (ASDs), is characterized by intellectual development delay, motor abnormalities, facial dysmorphisms, hypotonia, and also ocular problems, such as convergent strabismus, astigmatism, hyperopia, unilateral iris coloboma, bilateral optic nerve coloboma, and retinal dysfunctions [153; 154; 155]. The neuroprotective functions of ADNP are attributed to the octapeptide NAP sequence (NAPVSIPQ = Asn-Ala-Pro-Val-Ser-Ile-Pro-Gln), which exert several beneficial effects in different neurodegenerative disorders at femtomolar concentration [156; 104; 157]. NAP induces neuroplasticity, since through the SIP motif, interacts with the end-binding proteins 1 and 3 (EB1 and EB3), promoting the microtubule intervention [158; 159]. It is well known that EB3 exerts a key role in dendritic spine formation, and the effect of NAP is EB3-dependent. Moreover, NAP strongly increases EB proteins-Tau interaction protecting microtubule [160].  
ADNP is expressed in different tissues and organs of the body with the highest expression in the human brain, gastrointestinal system, respiratory, and reproductive system (Figure 4) [161]. The expression of ADNP was also detected in the eye, particularly in the retina and cornea [51; 162; 163].  
In the retina, the administration of NAP was shown to exert protective effects against different types of insults, including neurotrophic factor deprivation, retinal ischemia, optic nerve crush, and laser-induced retinal damage [164; 165; 166]. Moreover, targeted NT4-NAP fusion gene transfection of rat retinal Muller cells (RMC), protected from hypoxic-ischemic injury not only RMCs, but also retinal neurons, by promoting their viability and neurite growth [167]. The role of NAP in diabetic retinopathy (DR) was also largely demonstrated [107]. In particular, the treatment with the ADNP active fragment protected the integrity of the outer blood-retinal barrier (BRB), modulating the expression of hypoxic inducible factors (HIFs), and counteracting human retinal pigment epithelium app  
Figure 4: Tissue distribution of ADNP. Boxplot of transcripts per million (TPM) showing the bulk tissue gene expression for PACAP. The Genotype-tissue Expression (GTEx) on 10 January 2024.  
tosis induced by hyperglycemic/hypoxic insult [168; 169; 170]. Furthermore, NAP treatment modulated the inflammatory event characterizing the early phase of DR, downregulating interleukin (IL)-1\(\beta\) and its related receptors and upregulating IL-1 Ra expression [168].