Pituitary Adenylate Cyclase Activating Polypeptide, A Potential Therapeutic Agent for Diabetic Retinopathy in Rats: Focus on the Vertical Information Processing Pathway

Szabadfi, Krisztina; Reglődi, Dóra; Szabó, Andrea; Szalontai, Bálint; Valasek, Andrea; Sétáló, G.; Kiss, P.; Tamás, Andrea; Wilhelm, Márta; Gábriel, Róbert

doi:10.1007/s12640-015-9593-1

Cited by 28 publications

(21 citation statements)

References 76 publications

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“…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).…”

Section: Discussionsupporting

confidence: 75%

“…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).…”

Section: Introductionmentioning

confidence: 99%

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Stability Test of PACAP in Eye Drops

et al. 2020

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PACAP is a neuropeptide with widespread distribution and diverse biological functions. It has strong cytoprotective effects mediated mainly through specific PAC1 receptors. Experimental data show protective effects of PACAP in the retina and cornea in several pathological conditions. Although intravitreal injections are a common practice in some ocular diseases, delivery of therapeutic agents in the form of eye drops would be more convenient and would lead to fewer side effects. We have previously shown that PACAP, in the form of eye drops, is able to pass through the ocular barriers and can exert retinoprotective effects. As eye drops represent a promising form of administration of PACAP in ocular diseases, it is important to investigate the stability of PACAP in solutions used in eye drops. In this study, the stability of PACAP1-27 and PACAP1-38 in eye drops was measured in four common media and a commercially available artificial tear solution at both room temperature and +4°C. Mass spectrometry results show that the highest stability was gained with PACAP1-38 in water and 0.9% saline solution at +4°C, representing 80-90% drug persistence after 2 weeks. PACAP1-38 in the artificial tear showed very fast degradation at room temperature, but was stable at +4°C. In summary, PACAP1-38 has higher stability than PACAP1-27, with highest stability at +4°C in water solution, but both peptides in each medium can be stored for relatively longer periods without significant degradation. These data can provide reference for future therapeutic use of PACAP in eye drops.

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Section: Discussionsupporting

confidence: 75%

Section: Introductionmentioning

confidence: 99%

Stability Test of PACAP in Eye Drops

et al. 2020

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“…Pituitary adenylate cyclase activating peptide has been reported to exert neuroprotective functions in a variety of retinal injuries 21 and in the retina of streptozotocin-treated rats. 23,49,50 Regarding possible direct effects on VEGF, most experimental evidence reports an inducing, and not inhibitory, effect of PACAP on VEGF. Indeed, PACAP treatment results in increased VEGF in rat retinal hypoperfusion, 51 in lung cancer cells, 52 and in pituitary folliculostellate cells.…”

Section: Discussionmentioning

confidence: 99%

VEGF as a Survival Factor in Ex Vivo Models of Early Diabetic Retinopathy

Amato

Biagioni

Cammalleri

et al. 2016

Invest. Ophthalmol. Vis. Sci.

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These data show that protecting retinal neurons from diabetic stress also reduces VEGF expression and release, while inhibiting VEGF leads to exacerbation of apoptosis. These observations suggest that the retina in early DR releases VEGF as a prosurvival factor. Neuroprotective agents may decrease the need of VEGF production by the retina, therefore limiting the risk, in the long term, of pathologic angiogenesis.

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“…The selective degeneration of related structures such as bipolar and ganglion cells could be ameliorated by PACAP treatment. In summary, intravitreal administration of PACAP may have therapeutic potential in streptozotocininduced DR through maintaining synapse integrity in the vertical pathway [ 94 ].…”

Section: Diabetic Retinopathy In the Retinamentioning

confidence: 95%

Protective Effects of PACAP in the Retina

Atlasz

Vaczy

Werling

et al. 2016

Current Topics in Neurotoxicity

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Pituitary adenylate cyclase activating polypeptide (PACAP) is a widespread neuropeptide that is well known for its general cytoprotective effects in different neuronal injuries, such as traumatic brain and spinal cord injury, models of neurodegenerative diseases, and cerebral ischemia. PACAP and its receptors also occur in the retina. In this review, we summarize the retinoprotective effects of PACAP. In vitro, PACAP is protective against glutamate, thapsigargin, anisomycin, oxidative stress, UV light, high glucose, infl ammation, and anoxia. Both the neural retina and the pigment epithelial cells can be protected by PACAP in various experimental paradigms. In vivo, the protective effects of intravitreal PACAP treatment have been shown in the following models in rats and mice: excitotoxic injury induced by glutamate, N -methyl-D -aspartate (NMDA) or kainate, ischemic injury induced by carotid artery ligation and high intraocular pressure, degeneration caused by UV-A light, optic nerve transection, and streptozotocin-induced diabetic retinopathy as well as retinopathy of prematurity. Molecular biological methods have revealed that PACAP activates anti-apoptotic, while inhibits pro-apoptotic signaling pathways, and it also stimulates an anti-infl ammatory environment in the retina. Altogether, PACAP is suggested to be a potential therapeutic retinoprotective agent in various retinal diseases.

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Pituitary Adenylate Cyclase Activating Polypeptide, A Potential Therapeutic Agent for Diabetic Retinopathy in Rats: Focus on the Vertical Information Processing Pathway

Cited by 28 publications

References 76 publications

Stability Test of PACAP in Eye Drops

Stability Test of PACAP in Eye Drops

VEGF as a Survival Factor in Ex Vivo Models of Early Diabetic Retinopathy

Protective Effects of PACAP in the Retina

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