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M. Almasieh, Y. Zhou, M. E. Kelly, C. Casanova, A. Di Polo; Structural and Functional Neuroprotection in Glaucoma: Role of Galantamine-Mediated Activation of Muscarinic Acetylcholine Receptors. Invest. Ophthalmol. Vis. Sci. 2010;51(13):3178.
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© ARVO (1962-2015); The Authors (2016-present)
Galantamine is an acetylcholinesterase inhibitor and allosteric ligand of nicotinic ACh receptors (AChR) that is used clinically for the treatment of Alzheimer’s disease. We examined whether galantamine provides structural and functional neuroprotection of retinal ganglion cells (RGCs) after optic nerve damage, and addressed the molecular mechanisms underlying galantamine-mediated neuroprotection.
Optic nerve damage was induced by ocular hypertension (OHT), after injection of hypertonic saline into an episcleral vein (Morrison model), or by axotomy. Galantamine was administered daily by intraperitoneal injection. RGC neuroprotection was assessed by: i) quantification of retrogradely labeled RGCs, ii) axon counts obtained from optic nerve semi-thin sections, and iii) visual evoked potentials (VEP) measured from the superior colliculus. The role of AChR was established using selective antagonists for nicotinic AChR or muscarinic AChR.
Our data demonstrate that galantamine promotes structural and functional RGC protection following chronic (experimental glaucoma) or acute (axotomy) optic nerve injury. Quantitative analysis confirmed that galantamine led to a striking increase in RGC survival (~90%, n=11) at 3 weeks after OHT surgery compared to vehicle (55%, n=9). Although neuronal damage was more severe at 5 weeks after OHT surgery, galantamine protected ~70% of RGC soma (n=10) compared to only 37% with PBS (n=9) (ANOVA, p < 0.001). Importantly, functional deficits caused by high IOP were markedly improved by galantamine. Quantification of peak-to-peak VEP amplitudes showed that galantamine preserved 66% of the intact VEP response compared to only 30% in controls. Pharmacological block of either nAChR or mAChR indicated that galantamine-mediated neuroprotection occurred through activation of retinal muscarinic AChR types M1 and M4, while nicotinic AChR were not involved.
Our study supports the therapeutic potential of galantamine in glaucoma and reveals mAChR as a potential clinical target for this neurodegenerative disease.
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