Abstract
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.
Highlights
The neuropeptide pituitary adenylate cyclase activating polypeptide (PACAP) exists in two active forms, PACAP1-38 and PACAP1-27, both of which are well-established neuro- and general cytoprotective peptides, with 38 and 27 amino acid residues, respectively (Reglodi et al 2017, 2018a, b; Shioda and Nakamachi 2015)
The results show that at +4 °C, all four solutions have significantly higher stability than the solutions at room temperature (RT), and the rate of degradation is higher in the SOCB and thimerosal solution than in the other two vehicles (0.9% saline and water)
PACAP1-27 was almost completely degraded in benzalkonium chloride solution at RT, while 65% remained intact at the colder temperature
Summary
The neuropeptide pituitary adenylate cyclase activating polypeptide (PACAP) exists in two active forms, PACAP1-38 and PACAP1-27, both of which are well-established neuro- and general cytoprotective peptides, with 38 and 27 amino acid residues, respectively (Reglodi et al 2017, 2018a, b; Shioda and Nakamachi 2015). PACAP and its receptors are found in ocular tissues, including the lacrimal gland, conjunctiva, inner eye muscles and different layers of the eye It has been found in all three layers of the eyecup: the fibrous, vascular and nervous layers (Atlasz et al 2016; Seki et al 2000a, b). As a general protective peptide found 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, 2019; Cheng 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)
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