The Protective Role of PAC1-Receptor Agonist Maxadilan in BCCAO-Induced Retinal Degeneration A. Vaczy 1 & D. Reglodi 1 & T. Somoskeoy 1 & K. Kovacs 3 & E. Lokos 1 & E. Szabo 1 & A. Tamas 1 & T. Atlasz 1,2,4 Received: 4 July 2016 /Accepted: 10 August 2016 # Springer Science+Business Media New York 2016 Abstract A number of studies have proven that pituitary ade- nylate cyclase activating polypeptide (PACAP) is protective in neurodegenerative diseases. Permanent bilateral common ca- rotid artery occlusion (BCCAO) causes severe degeneration in the rat retina. In our previous studies, protective effects were observed with PACAP1-38, PACAP1-27, and VIP but not with their related peptides, glucagon, or secretin in BCCAO. All three PACAP receptors (PAC1, VPAC1, VPAC2) appear in the retina. Molecular and immunohistochemical analysis demonstrated that the retinoprotective effects are most proba- bly mainly mediated by the PAC1 receptor. The aim of the present study was to investigate the retinoprotective effects of a selective PAC1-receptor agonist maxadilan in BCCAO- induced retinopathy. Wistar rats were used in the experiment. After performing BCCAO, the right eye was treated with in- travitreal maxadilan (0.1 or 1 μM), while the left eye was injected with vehicle. Sham-operated rats received the same treatment. Two weeks after the operation, retinas were proc- essed for standard morphometric and molecular analysis. Intravitreal injection of 0.1 or 1 μM maxadilan caused signif- icant protection in the thickness of most retinal layers and the number of cells in the GCL compared to the BCCAO- operated eyes. In addition, 1 μM maxadilan application was more effective than 0.1 μM maxadilan treatment in the ONL, INL, IPL, and the entire retina (OLM-ILM). Maxadilan treat- ment significantly decreased cytokine expression (CINC-1, IL-1α, and L-selectin) in ischemia. In summary, our histolog- ical and molecular analysis showed that maxadilan, a selective PAC1 receptor agonist, has a protective role in BCCAO- induced retinal degeneration, further supporting the role of PAC1 receptor conveying the retinoprotective effects of PACAP. Keywords Ischemia . Retinoprotection . Maxadilan . PAC1 receptor Introduction Pituitary adenylate cyclase activating polypeptide (PACAP) is a phylogenetically conserved neuropeptide distributed throughout the body in addition to the hypothalamus, the original source of isolation (Miyata et al. 1989; Vu et al. 2015; Krajcs et al. 2015; Tamas et al. 2016). The peptide belongs to the vasoactive intestinal peptide (VIP)/glucagon/ secretin peptide superfamily, showing the closest homology with VIP (Hashimoto 2002; Padua et al. 2016). PACAP exerts its actions through three distinct receptors: the PACAP receptor 1 (PAC1), as well as VPAC receptor 1 (VPAC1), and VPAC receptor 2 (VPAC2). The PAC1 recep- tor is specific to PACAP, while the VPAC receptors have similar affinity to PACAP and VIP (Ramos-Álvarez et al. 2015). This and the numerous splice variants of the PAC1 receptor are in the background of PACAP showing many different actions in various organs (Shioda and Nakamachi * T. Atlasz attam@gamma.ttk.pte.hu 1 Department of Anatomy, MTA-PTE PACAP Research Team, University of Pecs, Pecs, Hungary 2 Department of Sportbiology, University of Pecs, Ifjusag Street 6, Pecs H-7624, Hungary 3 Department of Biochemistry and Medical Chemistry, University of Pecs, Pecs, Hungary 4 Janos Szentagothai Research Center, University of Pecs, Pecs, Hungary J Mol Neurosci DOI 10.1007/s12031-016-0818-4