Investigation of the therapeutic effect of adrenomedullin on experimental autoimmune uveitis

Abstract

Purpose : Adrenomedullin (AM) is a bioactive peptide isolated from human pheochromocytoma. AM is mainly secreted by vascular endothelial cells and has various physiological functions such as anti-inflammatory, anti-apoptotic, and anti-oxidative stress effects. We have reported that AM is also produced in the eye and that exogenous administration of AM ameliorates the pathogenesis of diabetic retinopathy and age-related macular degeneration (Am J Pathol. 2017, 2021). Experimental autoimmune uveitis (EAU) is an experimental model of human autoimmune uveitis and serves to investigate the mechanism of uveitis and evaluate therapeutics for ocular inflammatory diseases. In the present study, we investigated the therapeutic effect of AM-administration on EAU model in mice.

Methods : Female C57BL/6J mice aged 8 weeks were used. To induce EAU, N-terminal peptide fragment of human interphotoreceptor retinoid-binding protein (hIRBP(1-20)) emulsified with complete Freund’s adjuvant containing Mycobacterium tuberculosis H37Ra was subcutaneously injected at the base of tails. Subsequently, pertussis toxin was intraperitoneally injected. In the AM group, human recombinant AM was administered subcutaneously using osmotic pump at infusion rate of 29 μg/kg/day for 14 days. PBS was administered to the control group in the same manner. On day 14 after immunization, clinical scores were evaluated. According to the severity of inflammatory findings, clinical scores were classified into 4 categories (0-3) as previously reported, with some modifications. The clinical scores were evaluated by two ophthalmologists in a blinded manner, and the average of both eyes was used as the score for each mouse.

Results : No significant difference was found in the clinical score between AM-treated (2.00±0.42, n=8) and control groups (1.31±0.49, n=8).

Conclusions : In the present study, we could not confirm the therapeutic effect of AM- administration on the clinical score of EAU. Since anterior ocular lesions of EAU have a large variability among individuals, pathological examination including posterior ocular lesions would be necessary for more detailed evaluation. Furthermore, the therapeutic effects of higher concentrations of AM and intraocular AM-injection should be considered in the next study.

This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.