Preliminary antifibrotic and vasoconstrictor effects of adrenaline in Schlemm's canal and suprachoroidal minimally invasive glaucoma surgery in primary open-angle glaucoma

Abstract

Purpose: To investigate the antifibrotic and vasoconstrictor effects of adrenaline in Schlemm's canal and suprachoroidal minimally invasive glaucoma surgery (MIGS).

Methods: Human trabecular meshwork (TM) cells were treated with different concentrations of adrenaline (0%, 0.0005%, 0.01%), and we measured the effects on contractility, cell viability and the expression of key cell cycle and fibrosis genes. Adrenaline 0.05% was also injected intracamerally in five primary open-angle glaucoma patients undergoing iStent inject or MINIject surgery combined with phacoemulsification. All patients were assessed for ocular and systemic adverse reactions, including the effects on intraoperative pupil size, preoperative and postoperative visual acuity, intraocular pressure, and anterior segment OCT results.

Results: Adrenaline significantly reduced the contractility of TM cells in a dose-dependent manner (87.8%, 80.6%, 7.9% matrix contraction with adrenaline 0%, 0.0005%, 0.01%, respectively). Adrenaline did not exhibit any significant cytotoxicity even at high concentrations (P > 0.05). Adrenaline 0.01% significantly downregulated the expression of key cell cycle genes in the G2 and M phases, and also decreased the expression of MRTFB and ACTA2 genes (P < 0.05). Intracameral injections of adrenaline 0.05% in the five MIGS patients did not result in any ocular or systemic adverse effects.

Conclusion: We recommend intracameral injections of adrenaline 0.05% as a cheap and safe drug to be used before MIGS insertion. Adrenaline decreases the risk of bleeding from the trabecular meshwork and also exhibits antifibrotic effects by arresting the cell cycle, thereby increasing the postoperative success rates in MIGS.

Key message: What is known Fibrosis is the main cause of surgical failure in minimally invasive glaucoma surgery (MIGS). Mitomycin-C and 5-fluorouracil are too toxic to be used inside the eye. What is new Adrenaline reduced the contractility of trabecular meshwork cells and inhibited the expression of key cell cycle genes and fibrosis genes, without significant cytotoxicity. Intracameral injection of adrenaline 0.05% did not result in any ocular or systemic adverse reactions in MIGS patients.

Keywords: Adrenaline; Fibrosis; Glaucoma; MIGS.

Fig. 1

a Photomicrographs of human TM cells in collagen gels treated with adrenaline (0%, 0.0005%, 0.01%) at day 4 and day 7. Red arrows pointing at TM cells in the gels. Scale bar = 200 µm. b Representative gel photos at day 4 and day 7. c Three-dimensional collagen contraction assay of human TM cells treated with adrenaline (0%, 0.0005%, 0.01%) from day 1 to day 7. The percentage contraction was calculated from the original area on day 0. Results represent mean ± SEM for 3 independent replicates. ns, not significant; ns not significant, *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001

Fig. 2

a Photomicrographs of human TM cells in 6-well plate after 1-day treatment with adrenaline (0%, 0.0001%, 0.0005%, 0.001%, 0.005%, 0.01%). Scale bar = 200 µm. b Cell viability of human TM cells after 1-day treatment with adrenaline (0%, 0.0001%, 0.0005%, 0.001%, 0.005%, 0.01%). Results represent mean ± SEM for 3 independent replicates. ns, not significant

Fig. 3

Gene expression in human TM cells after 1-day treatment with adrenaline (0%, 0.0005%, 0.01%). G1/S phase genes, including E2F7 and E2F8. S phase genes, including CLSPN and BRCA1. G2 phase genes, including AURKA, ASPM, CDCA3, CDCA8, CEP55, DBF4, KIF14, and MKI67. M phase genes, including PLK1, CCNB1, CDC20, and PRR11. MRTF-B, ACTA2, and COL1A2 genes. mRNA levels were normalised to GAPDH. Results represent mean ± SEM for 3 independent replicates. ns not significant, *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001

Fig. 4

Injection of intracameral adrenaline prior to MIGS implantation. Patients 1, 2 and 3 received MINIject implantation. Patients 4 and 5 received iStent inject implantation. a Intraoperative view of MIGS implantation using a gonio lens. b Gonioscopic view of the MIGS in clinic at 1 week postoperatively. c Anterior segment OCT of the angle after MIGS implantation using Anterion OCT at 1 week postoperatively. White arrows show positioning of the iStent inject or MINIject