PACAP Is Protective in a Rat Model of Retinopathy of Prematurity

Abstract

The oxygen-induced retinopathy (OIR) is a well-established rodent model of retinopathy of prematurity (ROP), which is one of the most common causes of childhood visual impairment affecting preterm babies. Pituitary adenylate cyclase-activating polypeptide (PACAP) is known to have neuroprotective effects. Several studies have revealed the presence of PACAP and its receptors in the retina and reported its protective effects in ischemic and diabetic retinopathy. In this study, we investigated whether PACAP administration can influence the vascular changes in the rat OIR model. OIR was generated by placing the animals in daily alternating 10/50 oxygen concentrations from postnatal day (PD) 0 to PD14 then returned them to room air. Meanwhile, animals received PACAP or saline intraperitoneally or intravitreally from PD1 to PD8 or on PD11, PD14, and PD17, respectively. On PD19 ± 1, the retinas were isolated and the vessels were visualized by isolectin staining. The percentage of avascular to whole retinal areas and the number of branching points were measured. Change in cytokine expression was also determined. Intravitreal treatment with PACAP remarkably reduced the extent of avascular area compared to the non- and saline-treated OIR groups. Intraperitoneal PACAP injection did not influence the vascular extent. Retinal images of room-air controls did not show vascular alterations. No changes in the number of vessel branching were observed after treatments. Alterations in cytokine profile after local PACAP injection further supported the protective role of the peptide. This is the first study to examine the effects of PACAP in ROP. Although the exact mechanism is still not revealed, the present results show that PACAP treatment can ameliorate the vascular changes in the animal model of ROP.

Protective Effects of PACAP in the Retina

“…The excitotoxic damage of the retina is a main factor in retinal diseases, such as glaucoma and ischemia-induced retinopathy. We have previously shown in [ 103 ] a number of studies that PACAP is protective against excitotoxicity induced by systemic monosodium-glutamate lesion. We showed that, three times intravitreal MSG treatment on postnatal days 1, 5 and 9 caused severe neurodegeneration in the inner retinal layers in newborn rat pups [ 58 , 59 ].…”

“…Intravitreal PACAP1-38 treatment ameliorated the vascular extent of the retinopathic eyes without alterations in vessel morphology. Moreover, cytokine expression profi les indicate that PACAP may block the new vessel formation and have a positive infl uence on the remodeling of the tissue [ 103 ].…”

Passage through the Ocular Barriers and Beneficial Effects in Retinal Ischemia of Topical Application of PACAP1-38 in Rodents

“…In vitro, the peptide has been shown to protect whole retinal tissue cultures [20] and cell cultures from various cell types, including pigment epithelial cells [21,22] and retinal ganglion cells [23]. In vivo, PACAP is protective against NMDA-, glutamate- and kainate-induced retinal excitotoxicity [24,25,26], optic nerve transection [27], UV-induced retinal damage [28], diabetic retinopathy [29,30], retinopathy of prematurity [31] and ischemia-induced injury [32,33,34]. …”

Lack of Pituitary Adenylate Cyclase–Activating Polypeptide (PACAP) Disturbs Callus Formation

“…It decreases the activity of matrix degrading enzymes in chondrogenic cell cultures during mechanical overload (Szentleleky et al 2019). It also has a protective function in retinopathy of prematurity (Kvarik et al 2016) and ischemic conditions (Reglodi et al 2018b). All of these facts indicate that PACAP can have important functions in fractured bone remodeling and healing.…”