April 2009
Volume 50, Issue 13
Free
ARVO Annual Meeting Abstract  |   April 2009
An NGF Mimetic, MIM-D3, is a Mucin Secretagogue
Author Affiliations & Notes
  • K. Meerovitch
    Mimetogen Pharmaceuticals, Montreal, Quebec, Canada
  • P. Jain
    Mimetogen Pharmaceuticals, Montreal, Quebec, Canada
  • T. Lama
    Mimetogen Pharmaceuticals, Montreal, Quebec, Canada
  • Footnotes
    Commercial Relationships  K. Meerovitch, Mimetogen Pharmaceuticals Inc., E; P. Jain, Mimetogen Pharmaceuticals Inc., E; T. Lama, Mimetogen Pharmaceuticals Inc., E.
  • Footnotes
    Support  None.
Investigative Ophthalmology & Visual Science April 2009, Vol.50, 4261. doi:
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    • Get Citation

      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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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose: : 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.

Methods: : 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.

Results: : 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.

Conclusions: : 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.

Keywords: cornea: tears/tear film/dry eye • cornea: surface mucins • conjunctiva 
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