Functional and structural evaluation of lamotrigine treatment in rat models of acute and chronic ocular hypertension

Shai Sandalon, Birte Könnecke, Hani Levkovitch-Verbin, Mikael Simons, Katharina Hein, Muriel B. Sättler, Mathias Bähr, Ron Ofri*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

Abstract

Voltage gated sodium channels (Nav), are proposed mediators of neuronal damage in ischemic and excitotoxicity disease models. We evaluated the neuroprotective effects of lamotrigine, a Nav blocker, in the acute and chronic rat ocular hypertension models. Additionally, expression of the main Nav subtypes in the optic nerve (ON) was assessed to test whether their upregulation plays a role in the pathogenesis of ocular hypertension induced optic neuropathy. Unilateral intraocular pressure (IOP) elevation was induced for 60min (80mmHg) and 14-21 days (670-859mmHg*day) in the acute and chronic models, respectively. Lamotrigine was administered at dosages of 10mg/kg twice daily and 12.5mg/kg once daily in the acute (n=9) and chronic (n=11) trials, respectively. Treatment began 2 days prior to IOP elevation until sacrifice. Outer and inner retinal function was evaluated with dark- and light-adapted flash electroretinography and pattern electroretinography, respectively, 6 and 14 days post acute IOP elevation and 13, 28 and 48 days post chronic IOP elevation. Retinal ganglion cell and axon densities and inflammatory reaction were evaluated through Fluorogold, Bielschowsky's silver impregnation and ED1 labeling respectively. Immunohistochemistry for Nav1.1, 1.2 and 1.6 was performed in ONs of untreated rats 7 and 15 days post IOP elevation in the acute model and after 7, 28 and 50 days in the chronic model. In the acute model, no differences were found in the a-wave amplitudes between lamotrigine-treated and vehicle-treated rats. B-wave amplitudes decreased by 40-66% in both treatment groups 6 days post IOP elevation, with no significant difference between groups (p=0.38). However, a partial recovery of b-wave amplitudes was found in lamotrigine-treated rats between day 6 and day 14 post procedure (p<0.05). No differences were found in any other parameter tested in this model. Similarly, lamotrigine treatment did not result in any beneficial effect in structural parameters of the chronic model. Functional evaluation of this model was inconclusive due to super-normal values in the hypertensive eyes. Up-regulation of Nav1.1 and 1.2 expression was found in both models, beginning by day 7; an increase of the former continued in a time-dependent manner in the chronic model. Nav1.6 labeling was inconclusive. In conclusion we found lamotrigine treatment to be mostly ineffective in both acute and chronic ocular hypertension models.

Original languageAmerican English
Pages (from-to)47-56
Number of pages10
JournalExperimental Eye Research
Volume115
DOIs
StatePublished - Oct 2013

Bibliographical note

Funding Information:
This study was funded by Grant G2008-010 from The American Health Assistance Foundation (BrightFocus Foundation). Shai Sandalon was funded by the Joseph Alexander Foundation and Birte Könnecke was funded by the European Union (FP6 program LSHM-CT-2005-018637 , Neuropromise). We thank Britta Kaltwasser and Irina Graf for excellent technical assistance and Tali Bdolah-Abram for her invaluable assistance with statistical analysis of our results.

Keywords

  • Electroretinography
  • Glaucoma
  • Lamotrigine
  • Neuroprotection
  • Optic nerve
  • Retinal ganglion cell
  • Sodium channels

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