Effects of Pituitary Adenylate Cyclase Activating Polypeptide and Its Fragments on Retinal Degeneration Induced by Neonatal Monosodium Glutamate Treatment

Abstract

Pituitary adenylate cyclase activating polypeptide (PACAP) is a member of the growing family of neurotrophic and neuroprotective factors playing important roles during neuronal development and protection against different types of injuries, such as Parkinson's disease, excitotoxicity, and ischemia. As shown with other neuronal tissues, we provide evidence that PACAP is protective in the retina against toxic injury induced by monosodium glutamate (MSG) in vivo. The need for characterization of its fragments and analogues has recently been emphasized. The aim of the present study was to compare the effects of the physiologically occurring fragments PACAP1-38 and 1-27 and the widely used antagonists (PACAP6-38 and 6-27) in retinal degeneration induced by MSG in neonatal pups. Histological analysis showed that MSG treatment caused the degeneration of the entire inner plexiform layer and the inner nuclear and ganglion cell layers seemed fused. The total thickness of the retina was significantly reduced. Similar and substantial protective effects could be observed after three treatments with PACAP1-38 and 1-27, while MSG toxicity was further aggravated by the PACAP antagonists PACAP6-38 and 6-27. Glutamate-induced toxicity is known to play a role in several retinal pathologies. Our results provide further evidence for the effectiveness of the endogenously present PACAP forms in counteracting retinotoxicity and call for further studies leading to the discovery of potent analogues that could be used in human ophthalmic diseases.

Protective Effects of PACAP in the Retina

“…In addition, we showed that the PACAP antagonist PACAP6-38 increased cytochrome-c release, caspase-3, JNK activity and decreased phosphoBad, phospho PKA, Bcl-xL, 14-3-3 protein activity [ 66 , 67 ]. These in vivo observations, similarly to the results of Atlasz et al [ 60 ], indicating that endogenously present PACAP has retinoprotective effects in glutamate-induced excitotoxicity.…”

“…Similar protection could be seen by PACAP1-27 treatment [ 60 ]. The application of the two widely used PACAP antagonists (PACAP6-38, PACAP6-27) led to a more pronounced degeneration, indicating that, endogenously present PACAP plays a key role against retinal toxicity [ 60 ]. A similar degree of retinoprotection was found using enriched environment, but combining these two neuroprotective strategies (PACAP and enriched environment) did not result in increased neuroprotection in excitotoxic retinal injury [ 63 ].…”

“…While 1 pmol PACAP1-38 was slightly effective, treatment with 100 pmol PACAP1-38 was able to signifi cantly attenuate the MSG-induced toxicity and the entire retina seemed to be normal. Similar protection could be seen by PACAP1-27 treatment [ 60 ]. The application of the two widely used PACAP antagonists (PACAP6-38, PACAP6-27) led to a more pronounced degeneration, indicating that, endogenously present PACAP plays a key role against retinal toxicity [ 60 ].…”

Ocular Delivery of PACAP1-27 Protects the Retina From Ischemic Damage in Rodents

“…15,16 We also found that PACAP counteracts the ischemia-induced cytokine changes and promotes antiapoptotic pathways. 17 Altogether, these results provide strong evidence that PACAP has potential therapeutic value in ischemic retinopathy.…”

Urocortin 2 treatment is protective in excitotoxic retinal degeneration

“…Ucn 2 treatments alone had no effect on normal control retinas (data and picture not shown). As we have previously described (2,4,6,7,32), retinal tissue from animals treated with MSG showed severe degeneration compared to normal retinas. The IPL was markedly shrunk and the INL and GCL were intermingled (Fig.…”