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|Title:||GALANTAMINE: A NOVEL STRUCTURAL AND FUNCTIONAL NEUROPROTECTANT FOR INJURED RETINAL GANGLION CELLS AND OPTIC NERVE IN GLAUCOMA. |
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|Authors/Affiliations:||1 Mohammadali Almasieh*; 1 Yu Zhou; 1 Christian Casanova; 1 Adriana Di Polo; |
1 Universite de Montreal, QC, Canada
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|Content:||Introduction: Glaucoma, the second cause of blindness worldwide, is characterized by progressive optic nerve degeneration, irreversible visual field loss and retinal ganglion cells (RGCs) death. Since the major risk factor for development of glaucoma is elevated intraocular pressure (IOP), the current standard therapy for glaucoma is limited to lower the IOP by medication and/or surgery. However, a significant proportion of patients continue to experience vision loss in spite of responding well to pressure lowering drugs. Thus, it is clear that current therapeutic strategies for glaucoma are insufficient and new approaches to slow disease progression are urgently needed. Galantamine, a modest acetylcholinesterase inhibitor and an allosteric potentiator of nicotinic receptors is an approved drug for the treatment of Alzheimer’s disease by the FDA. Here we investigated the neuroprotective effect of galantamine in an experimental glaucoma model.|
Methods: Unilateral ocular hypertension (OHT) was induced by injection of a hypertonic saline solution (1.85 M NaCl) into an episcleral vein of Brown Norway rats. Treatment began on the first day of IOP increase by daily dose (3.5 mg/kg) of galantamine. Structural neuroprotection studied carried on by quantification of RGC soma and axons. DiI-labeled neurons were counted in 12 standard retinal areas; RGC axons were counted in optic nerve semi-thin cross sections. Functional neuroprotection was evaluated by recording visually evoked potentials following flash stimulus from superior colliculus (SC).
Results: In animals with pressure increase (ΔIOP) between 5-10 mmHg, galantamine preserved 90% of RGCs at 5 weeks after OHT (n=10) compared with 65% of RGCs that survived in saline treated (n=7). Galantamine was also more effective than donepezil (n=8), another AChE inhibitor, or memantine (n=8), an NMDA receptor blocker. Following 70% structural preservation of axons in optic nerve; functionally, galantamine dramatically improved electrical activities recorded in SC as the main target of RGC axons in the brain. Our results also demonstrate that administration of galantamine did not reduce IOP, to further confirm, we examined galantamine effect following optic nerve transection (as IOP independent optic nerve damage); in this model, intraocular injections of galantamine dramatically increased the survival of RGCs.
Conclusions: Galantamine promotes robust protection and significantly preserves functional properties of RGCs in experimental glaucoma model. Galantamine is effective when administered systemically or intravitreally and its neuroprotective effect is not caused by reduction of IOP.
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