title: The beta-adrenoceptor antagonists metipranolol and timolol are retinal neuroprotectants: comparison with betaxolol.
abstract: beta-adrenoceptor antagonists are used clinically to reduce elevated intraocular pressure in glaucoma which is characterised by a loss of retinal ganglion cells. Previous studies have shown that the beta(1)-selective adrenoceptor antagonist, betaxolol, is additionally able to protect retinal neurones in vitro and ganglion cells in vivo from the detrimental effects of either ischemia-reperfusion or from excitotoxicity, after topical application. The neuroprotective effect of betaxolol is thought not to be elicited through an interaction with beta-adrenoceptors, but by its ability to reduce influx of sodium and calcium through voltage-sensitive calcium and sodium channels. In the present study it is shown that the non-selective beta-adrenoceptor antagonists, metipranolol and timolol behave like betaxolol. When topically applied they all attenuate the detrimental effect of ischemia-reperfusion. Protection of the retina was determined by evaluating changes in the electroretinogram and by assessing the loss of mRNA for Thy-1, which is expressed in retinal ganglion cells. In addition, studies conducted on neurones in mixed retinal cultures demonstrated that metipranolol, betaxolol and timolol were all able to partially counteract anoxia-induced cell loss and viability reduction. The influence of timolol was, however, not significant. Within the confines of these investigations, an order of neuroprotective efficacy was delineated for the three beta-adrenoceptor antagonists: betaxolol>metipranolol>timolol. The ability of the beta-adrenoceptor antagonists to attenuate ligand-induced stimulation of calcium and sodium entry into neuronal preparations showed a similar order of effectiveness. In conclusion, the ability to confer neuroprotection to retinal neurones is a common feature of three ophthalmic beta-adrenoceptor antagonists (betaxolol, metipranolol and timolol). A comparison of the effectiveness of the individual compounds in protecting retinal cells in vivo was not possible in these studies. However, in vitro studies show that the capacity of the individual beta-adrenoceptor antagonists to act as neuroprotectants appears to relate to their capacity to attenuate neuronal calcium and sodium influx.
authors.affiliation: Nuffield Laboratory of Ophthalmology, University of Oxford, Walton Street, Oxford OX2 6AW, UK. john.wood@eye.ox.ac.uk
authors.forename: J P M
authors.initials: JP
authors.lastname: Wood
authors.forename: K-G
authors.initials: KG
authors.lastname: Schmidt
authors.forename: J
authors.initials: J
authors.lastname: Melena
authors.forename: G
authors.initials: G
authors.lastname: Chidlow
authors.forename: H
authors.initials: H
authors.lastname: Allmeier
authors.forename: N N
authors.initials: NN
authors.lastname: Osborne
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000818:Animals; D015784:Betaxolol / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D015687:Cell Hypoxia / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004596:Electroretinography; D014290:Metipranolol / Q000494:pharmacology*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000503:physiopathology / Q000517:prevention & control; D012160:Retina / Q000187:drug effects* / Q000378:metabolism; D012171:Retinal Vessels / Q000503:physiopathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012964:Sodium / Q000378:metabolism; D018800:Thy-1 Antigens / Q000096:biosynthesis / Q000235:genetics; D013999:Timolol / Q000494:pharmacology*
chemical_list: D000319:Adrenergic beta-Antagonists; D018696:Neuroprotective Agents; D012333:RNA, Messenger; D018800:Thy-1 Antigens; D013999:Timolol; D012964:Sodium; D015784:Betaxolol; D002118:Calcium; D014290:Metipranolol