Neuroprotective Potential of Pituitary Adenylate Cyclase Activating Polypeptide in Retinal Degenerations of Metabolic Origin

Abstract

Pituitary adenylate cyclase-activating polypeptide (PACAP1-38) is a highly conserved member of the secretin/glucagon/VIP family. The repressive effect of PACAP1-38 on the apoptotic machinery has been an area of active research conferring a significant neuroprotective potential onto this peptide. A remarkable number of studies suggest its importance in the etiology of neurodegenerative disorders, particularly in relation to retinal metabolic disorders. In our review, we provide short descriptions of various pathological conditions (diabetic retinopathy, excitotoxic retinal injury and ischemic retinal lesion) in which the remedial effect of PACAP has been well demonstrated in various animal models. Of all the pathological conditions, diabetic retinopathy seems to be the most intriguing as it develops in 75% of patients with type 1 and 50% of patients with type 2 diabetes, with concomitant progression to legal blindness in about 5%. Several animal models have been developed in recent years to study retinal degenerations and out of these glaucoma and age-related retina degeneration models bear human recapitulations. PACAP neuroprotection is thought to operate through enhanced cAMP production upon binding to PAC1-R. However, the underlying signaling network that leads to neuroprotection is not fully understood. We observed that (i) PACAP is not equally efficient in the above conditions; (ii) in some cases more than one signaling pathways are activated; (iii) the coupling of PAC1-R and signaling is stage dependent; and (iv) PAC1-R is not the only receptor that must be considered to interpret the effects in our experiments. These observations point to a complex signaling mechanism, that involves alternative routes besides the classical cAMP/protein kinase A pathway to evoke the outstanding neuroprotective action. Consequently, the possible contribution of the other two main receptors (VPAC1-R and VPAC2-R) will also be discussed. Finally, the potential medical use of PACAP in some retinal and ocular disorders will also be reviewed. By taking advantage of, low-cost synthesis technologies today, PACAP may serve as an alternative to the expensive treatment modelities currently available in ocular or retinal conditions.

Pituitary Adenylate Cyclase-Activating Polypeptide: A Promising Neuroprotective Peptide in Stroke

“…Furthermore, the PLC and AC/cAMP signaling pathway could mediate downstream targets, such as ras-associated protein-1 (RAP1)[ 34 ], MAPKs [ 35 - 38 ], NF-kB [ 39 , 40 ], janus kinase (JAK) [ 41 , 42 ], cJun [ 43 , 44 ], and phosphatidylinositol 3-kinase (PI3K) [ 45 ]. In parallel with the PLC and AC/cAMP pathway, these downstream signaling pathways may also be directly activated by PAC1 in some cells [ 29 , 46 , 47 ] ( Fig. 1 ).…”

PACAP for Retinal Health: Model for Cellular Aging and Rescue

“…Neuropeptides have an essential role in retinal physiology, as they affect information processing through multiple retinal peptidergic pathways [ 4 , 5 , 6 ]. The neuropeptides somatostatin (SST) and pituitary adenylate cyclase-activating polypeptide (PACAP) have various effects in many retinal physiological and pathological conditions [ 5 , 7 , 8 , 9 ]. These two neuromodulators share similarities in their functional relevance and structural parameters.…”

“…Age-related retinal functional and structural changes in the retina are well described in the aging human population worldwide. Neuropeptides and/or their analogs could offer an opportunity for treatments in certain retinal pathological conditions [ 7 , 29 ]. Previous studies have described that endogenous PACAP deficiency accelerated age-related retinal degeneration [ 22 ].…”

“…Metabolomics analysis showed their protective effects in ischemia, where both PACAP and OCT ameliorated ischemia-induced oxidative stress, decreased cell death and downregulated VEGF overexpression [ 29 ]. With these facts in mind, these neuropeptides should be taken into account as therapeutic agents for decelerating age-related visual impairments [ 7 , 29 ]. Although our previous study described accelerated age-related retinal degeneration in PACAP-KO mice [ 22 ], and OCT treatment was demonstrated to stabilize visual acuity in age-related macular degeneration [ 30 ], the paucity of information on the relation between PACAP and retinal aging is striking.…”

Stability Test of PACAP in Eye Drops

“…It affects tear secretion (Nakamachi et al 2016), influences muscle responses of the iris (Yamaji et al 2005), increases blood flow in the eye (Dorner et al 1998) and regulates pigment epithelial cell functions (Fabian et al 2012(Fabian et al , 2019Maugeri et al 2019a). Most importantly, as a general protective peptide found not only in the central nervous system but several peripheral organs as well (Laszlo et al 2019;Liu et al 2019;Polanco and Pennuto 2018;Reglodi et al 2018d, e;Shioda et al 2019;Szegeczki et al 2019), PACAP has been shown to exert diverse retinoprotective effects in models of toxic, ischemic, inflammatory and traumatic retinal injuries (Atlasz et al 2016(Atlasz et al , 2019Cheng et al 2018;Endo et al 2011;Gabriel et al 2019;Kvarik et al 2016;Seki et al 2008;Szabadfi et al 2016;Vaczy et al 2016;Ye et al 2019a, b). Several retinal cell types can be protected by PACAP, including ganglion cells, bipolar neurons, amacrine and pigment epithelial cells (Atlasz et al 2008;Fabian et al 2019;Maugeri et al 2019a;Szabadfi et al 2012).…”