Abstract
Elevated intraocular pressure is the most prevalent and only treatable risk factor for glaucoma, a degenerative disease of the optic nerve. While treatment options to slow disease progression are available, all current therapeutic and surgical treatments have unwanted side effects or limited efficacy, resulting in the need to identify new options. Previous reports from our laboratory have established a novel ocular hypotensive effect of ATP-sensitive potassium channel (KATP) openers including diazoxide (DZ) and nicorandil (NCD). In the current study, we evaluated the role of Erk1/2 signaling pathway in KATP channel opener mediated reduction of intraocular pressure (IOP). Western blot analysis of DZ and NCD treated primary normal trabecular meshwork (NTM) cells, human TM (isolated from perfusion cultures of human anterior segments) and mouse eyes showed increased phosphorylation of Erk1/2 when compared to vehicle treated controls. DZ and NCD mediated pressure reduction (p<0.02) in human anterior segments (n = 7 for DZ, n = 4 for NCD) was abrogated by U0126 (DZ + U0126: -9.7 ± 11.5%, p = 0.11; NCD + U0126: -0.1 ± 11.5%, p = 1.0). In contrast, U0126 had no effect on latanoprostfree acid-induced pressure reduction (-52.5 ± 6.8%, n = 4, p = 0.001). In mice, DZ and NCD reduced IOP (DZ, 14.9 ± 3.8%, NCD, 16.9 ± 2.5%, n = 10, p<0.001), but the pressure reduction was inhibited by U0126 (DZ + U0126, 0.7 ± 3.0%; NCD + U0126, 0.9 ± 2.2%, n = 10, p>0.1). Histologic evaluation of transmission electron micrographs from DZ + U0126 and NCD + U0126 treated eyes revealed no observable morphological changes in the ultrastructure of the conventional outflow pathway. Taken together, the results indicate that the Erk1/2 pathway is necessary for IOP reduction by KATP channel openers DZ and NCD.
Highlights
Glaucoma is a neurodegenerative disease affecting over 60 million people worldwide.[1]
In human eyes perfused with DZ or vehicle for 6 or 14 hours, protein lysates isolated from trabecular meshwork (TM) cells showed a nominal increase in phosphorylated extracellular-signal regulated kinase 1/2 (Erk1/2) at 6 hours, but a 2.9 ± 0.2 fold change was observed in phosphorylated Erk1/2 by 14 hours (n = 2; Fig 1B)
To determine whether the Erk1/2 pathway was unique to KATP channel openers or was a more generalized pathway utilized in pressure reduction, we evaluated the effect of U0126 on anterior segments (n = 4) treated with DZ and the prostaglandin analog LFA
Summary
Glaucoma is a neurodegenerative disease affecting over 60 million people worldwide.[1]. Diazoxide and nicorandil lower IOP through activation of Erk1/2 signaling glaucoma drugs lower IOP by either increasing aqueous humor removal from the anterior segment (e.g. prostaglandin analogs or cholinergic agents) or lowering aqueous humor secretion from the ciliary body (e.g. β-adrenergic blockers and carbonic anhydrase inhibitors).[3, 4] all current glaucoma therapies have side effects and do not target the trabecular meshwork (TM) and Schlemm’s canal (SC), the primary tissues responsible for increased resistance to aqueous humor drainage through the conventional outflow pathway None of these drugs directly protects the retina and the optic nerve, which are the primary tissues affected during glaucoma. Development of new and improved glaucoma medications has been a priority for researchers worldwide.[5, 6]
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