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K. Meerovitch, P. Jain, T. Lama; An NGF Mimetic, MIM-D3, is a Mucin Secretagogue. Invest. Ophthalmol. Vis. Sci. 2009;50(13):4261.
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MIM-D3 is a small molecule NGF peptidomimetic, which has agonistic activity on TrkA Receptors. The purpose of this study was to evaluate MIM-D3 as a potential mucin secretagogue in vitro on rat conjunctival goblet cell (CGC) cultures and in vivo on normal rats.
CGCs were cultured from pieces of male rat conjunctivas and used to evaluate secretagogue activity. MIM-D3 was added at increasing concentrations to cultured cells. NGF was a positive control. CGC secretion of mucin glycoconjugates was measured by an enzyme-linked lectin assay (ELLA) using the lectin UEA-1. Western blotting using antibodies specific to the phosphorylated form of ERK1/2 was used to determine MAPK activation. NGF and PMA were positive controls. Proliferation of CGCs treated with increasing concentrations of MIM-D3 was evaluated by Alamar Blue. Fetal bovine serum was used as a positive control. The solubility and stability of MIM-D3 in saline were studied for topical ocular administration. Normal male rats (n=9 per group) were treated with 6 topical instillations of increasing MIM-D3 concentrations every hour. The saline vehicle and NGF were used as controls. Tear fluid washings were collected from the conjunctival sac with capillary pipettes prior to dosing and 1-hour after the last instillation. The concentration of mucin glycoprotein was determined in the tear fluid by ELLA.
MIM-D3 induced in vitro CGC glycoprotein secretion in a concentration-dependent manner. Treatment of CGCs with MIM-D3 for 5 minutes caused increased MAPK phosphorylation. However, there was no increase in CGC proliferation. Acute treatment of normal rats with MIM-D3 induced a statistically significant two-fold increase in mucin concentration in the tear fluid washings in a dose dependent manner.
MIM-D3 is a soluble, stable compound with favorable drug-like properties, acting as an NGF mimetic. In CGCs, MIM-D3 causes activation of MAPK and stimulation of mucin secretion, in the absence of cell proliferation. Because, MIM-D3 acts as a mucin secretagogue in vivo in normal rats, it is predicted that it would be beneficial as a therapeutic for dry eye.
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