Protective Role of Endogenous PACAP in Inflammation-induced Retinal Degeneration

Abstract

Purpose. Pituitary adenylate cyclase activating polypeptide (PACAP) is a neuroprotective peptide that has been shown to exert protective effects in different models of neurodegenerative diseases, including retinal degenerations. Data obtained from PACAPdeficient (PACAP KO) mice provide evidence that endogenous PACAP has neuroprotective role in different pathologies. PACAP KO mice show enhanced sensitivity to different insults, such as oxidative stress, hypoxia and inflammation. The aim of the present study was to investigate the protective effects of endogenous PACAP in retinal inflammation. Methods. Endotoxin-caused eye inflammation was induced by intraperitoneal injection of lipopolysaccharide (LPS) in PACAP KO and wild type (Wt) mice. After LPS treatment, retinas were processed for histological examination. To detect the alterations of different proteins and cytokines, immunohistochemical, western blot and cytokine array were used. We also performed dark-adapted electroretinography (ERG) to detect the functional differences. Results. The thickness of nearly all layers was significantly less in LPS-injected PACAP KO mice compared to Wt animals. Increased expression of glial fibrillary acidic protein (GFAP) was induced in Müller glial cells after LPS treatment, which was more intense in PACAP KO mice. The levels of pAkt and pGSK were decreased in PACAP KO group during inflammation. LPS treatment significantly increased cytokines (sICAM-1, JE, TIMP-1) in both treated groups, but it was more expressed in PACAP KO animals. Furthermore, ERG responses were disturbed after LPS injection in PACAP KO mice. Conclusion. Our results showed that endogenous PACAP has a protective role in LPS-caused retinal inflammation.

Stability Test of PACAP in Eye Drops

“…Degradation of PACAP1-38 in Systane ® Ultra at RT and +4°C (e). Higher stability was found at +4°C, similar to the other examined media kainate-and glutamate-induced excitotoxicity (Atlasz et al 2009;Seki et al 2006), UV light-induced lesion (Atlasz et al 2011), lipopolysaccharide-induced inflammation (Vaczy et al 2018), oxygen-induced retinopathy of prematurity (Kvarik et al 2016), diabetic retinopathy (D'Amico et al 2017;Szabadfi et al 2016) and high intraocular pressureinduced retinopathy (Seki et al 2011).…”

Physical Activity Protects the Pathological Alterations of Alzheimer’s Disease Kidneys via the Activation of PACAP and BMP Signaling Pathways

“…PACAP has also been shown to modify amyloid aggregation (Reglodi et al, 2018c) and has important preventive functions in aging (Reglodi et al, 2018a;Szegeczki et al, 2019). The general protective role of the neuropeptide has been demonstrated in various disorders, such as retinopathy (Vaczy et al, 2018), diabetes (Banki et al, 2014), Parkinson's disease (Reglodi et al, 2006;Reglodi et al, 2017), and inflammatory processes (Sakamoto et al, 2015). It has been shown that PACAP diminishes the harmful effects of oxidative stress (Juhasz et al, 2014a), ischemic conditions (Reglodi et al, 2018d), and mechanical overload (Juhasz et al, 2015b).…”

Hearing impairment and associated morphological changes in pituitary adenylate cyclase activating polypeptide (PACAP)-deficient mice

“…This process involves the loss of inner and outer hair cells in the inner ear 51 . It is also known that aging processes are accelerated in PACAP KO mice affecting several organ systems 14,25,39–41 . An acceptable hypothesis could be that the changes we found in the auditory system of the PACAP KO mice are the result of the accelerated aging of the inner ear and auditory pathway.…”

“…retinoblasts and cells of the olfactory system, indicating that PACAP has important functions in different sensory organs 10,11 . It has well-known retinoprotective effects in different lesions of the retina, which were described morphologically, functionally and at the molecular level 12–14 . PACAP exerts protective functions in the olfactory system 15 .…”