title: Lamotrigine monotherapy does not provide protection against the loss of optic nerve axons in a rat model of ocular hypertension.
abstract: Sodium channel blocking agents such as lamotrigine are potent agents for neuroprotection in several animal models of neurodegenerative and neuroinflammatory disease. We therefore explored whether lamotrigine therapy was neuroprotective in a rat model of ocular hypertension characterized by axonal injury and selective loss of retinal ganglion cells. Twenty-seven male Wistar rats were injected subcutaneously twice daily with either lamotrigine (14 mg/kg/day) or vehicle. Two weeks after the first injection, experimental ocular hypertension was induced in one eye by 532 nm trabecular laser treatment. Intraocular pressure (IOP) was monitored by rebound tonometry and four weeks after the elevation of IOP the loss of optic nerve axons was quantified relative to eyes without either IOP elevation or lamotrigine exposure. In other animals with ocular hypertension, the optic nerves were examined by immunohistochemistry for the expression of the inducible form of nitric oxide synthase (iNOS) at 7 and 28 days. Four weeks after initiation of IOP elevation, no significant difference in axonal loss was observed between rats treated with lamotrigine (30.8% ± 10.5%) or vehicle (17.8% ± 5.7%) (P = 0.19, T-test). There was no significant difference in mean IOP, peak IOP and integral IOP exposure. Furthermore, optic nerve axon counts per unit integral IOP exposure were similar in both groups (P = 0.44). The optic nerves were not positive for the expression of iNOS. In conclusion, this study provides no evidence that lamotrigine is neuroprotective for RGC axons after four weeks of experimental ocular hypertension in the rat, in a model where axonal degeneration occurs in the absence of iNOS expression.
authors.affiliation: Centre for Brain Repair, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Nephtali
authors.initials: N
authors.lastname: Marina
authors.forename: Marija
authors.initials: M
authors.lastname: Sajic
authors.forename: Natalie D
authors.initials: ND
authors.lastname: Bull
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Hyatt
authors.forename: David
authors.initials: D
authors.lastname: Berry
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Smith
authors.forename: Keith R
authors.initials: KR
authors.lastname: Martin
mesh_terms: D000818:Animals; D001369:Axons / Q000187:drug effects* / Q000473:pathology; D002121:Calcium Channel Blockers / Q000627:therapeutic use*; D002452:Cell Count; D002851:Chromatography, High Pressure Liquid; D004195:Disease Models, Animal; D007124:Immunoenzyme Techniques; D007279:Injections, Subcutaneous; D007429:Intraocular Pressure / Q000502:physiology; D000077213:Lamotrigine; D008297:Male; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D009798:Ocular Hypertension / Q000175:diagnosis / Q000201:enzymology / Q000517:prevention & control*; D009901:Optic Nerve Diseases / Q000175:diagnosis / Q000201:enzymology / Q000517:prevention & control*; D051381:Rats; D017208:Rats, Wistar; D012165:Retinal Ganglion Cells / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D014065:Tonometry, Ocular; D014129:Trabecular Meshwork / Q000601:surgery; D014227:Triazines / Q000627:therapeutic use*
chemical_list: D002121:Calcium Channel Blockers; D018696:Neuroprotective Agents; D014227:Triazines; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D000077213:Lamotrigine