title: PACAP promotes neuron survival in early experimental diabetic retinopathy.
abstract: Metabolic changes induced by diabetes lead to a multifactorial progressive disease of the retina with an extremely complex pathogenesis. One of the mechanisms of retinal cell death in diabetes is via apoptosis. Our previous results show that pituitary adenylate cyclase activating polypeptide (PACAP) attenuates the morphological and neurochemical changes in a rat model of diabetic retinopathy. The aim of this study was to investigate the mechanisms of this protective effect. Retinas of streptozotocin-induced diabetic rats were analyzed using apoptosis detection combined with immunolabeling. Western blot was used to measure levels of pro- and anti-apoptotic pathways. Intraocular PACAP injection markedly attenuated diabetic retinal injury: increased levels of the anti-apoptotic p-Akt, p-ERK1, p-ERK2, PKC, Bcl-2, while decreased levels of the pro-apoptotic p-p38MAPK and activated caspases (8, 3, 12) were detected. The number of apoptotic cells increased in all nuclear layers of diabetic retinas, but significantly decreased after PACAP treatment. Our results clearly demonstrate that the protective effects of PACAP are mediated, at least partly, by attenuating apoptosis, including also that of the dopaminergic amacrine cells. Inhibition of apoptosis is one of the PACAP-induced pathways with therapeutic potential in early experimental diabetic retinopathy.
authors.affiliation: Department of Experimental Zoology and Neurobiology, University of Pecs, Pecs, Hungary. Electronic address: kriszta.szabadfi@gmail.com.
authors.forename: Krisztina
authors.initials: K
authors.lastname: Szabadfi
authors.affiliation: Department of Biochemistry and Medical Chemistry, University of Pecs, Pecs, Hungary.
authors.forename: Aliz
authors.initials: A
authors.lastname: Szabo
authors.affiliation: Department of Anatomy, PTE-MTA Lendulet PACAP Research Team, University of Pecs, Pecs, Hungary.
authors.forename: Peter
authors.initials: P
authors.lastname: Kiss
authors.affiliation: Department of Anatomy, PTE-MTA Lendulet PACAP Research Team, University of Pecs, Pecs, Hungary.
authors.forename: Dora
authors.initials: D
authors.lastname: Reglodi
authors.affiliation: Department of Medical Biology, University of Pecs, Pecs, Hungary.
authors.forename: Gyorgy
authors.initials: G
authors.lastname: Setalo
authors.affiliation: Department of Biochemistry and Medical Chemistry, University of Pecs, Pecs, Hungary.
authors.forename: Krisztina
authors.initials: K
authors.lastname: Kovacs
authors.affiliation: Department of Anatomy, PTE-MTA Lendulet PACAP Research Team, University of Pecs, Pecs, Hungary.
authors.forename: Andrea
authors.initials: A
authors.lastname: Tamas
authors.affiliation: Department of Medical Chemistry, University of Szeged, Szeged, Hungary.
authors.forename: Gabor
authors.initials: G
authors.lastname: Toth
authors.affiliation: Department of Experimental Zoology and Neurobiology, University of Pecs, Pecs, Hungary; Janos Szentagothai Research Center, Pecs, Hungary.
authors.forename: Robert
authors.initials: R
authors.lastname: Gabriel
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D003930:Diabetic Retinopathy / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D008297:Male; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D012160:Retina / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D013311:Streptozocin
chemical_list: D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D013311:Streptozocin
keywords: Anti-apoptotic factors; Caspases; Diabetic retinopathy; ER; ERKs; GAPDH; GCL; GSK3β; INL; IPL; MAPKs; ONL; OPL; PAC1-R; PACAP; PACAP type 1 receptor; PKA; PKC; TH; TUNEL; VIP; endoplasmatic reticulum; extracellular signal-regulated kinases; ganglion cell layer; glyceraldehyde 3-phosphate dehydrogenase; glycogen synthase kinase 3 beta; inner nuclear layer; inner plexiform layer; mitogen activated protein kinases; outer nuclear layer; outer plexiform layer; pituitary adenylate cyclase activating polypeptide; protein kinase A; protein kinase C; terminal transferase dUTP nick end labeling; tyrosine hydroxylase; vasoactive intestinal peptide