Experiment supports betaxolol neuroprotection

Topically applied drug reached the retina in an animal model and guarded against damage induced by hypoxia or glutamate.

Issue: December 1, 1999

OXFORD, England — Research has now shown that topical betaxolol (Betoptic, Alcon) reaches the retina in rabbit eyes in high enough concentrations to prevent hypoxia- or glutamate-induced damage.

Neville N. Osborne, PhD, DSc, of the Nuffield Laboratory of Ophthalmology, University of Oxford, had previously shown in animals that drugs like betaxolol that are used to lower intraocular pressure (IOP) can also protect against damage from hypoxia. Optic nerve hypoxia is being recognized as an important component of glaucoma.

Prof. Osborne wrote in the September issue of Experimental Eye Research that “Since betaxolol is used to reduce elevated IOP as occurs in glaucoma, and retinal ischemic damage is postulated to occur in glaucoma, the significance of the present studies is self evident.”

In Prof. Osborne’s earlier experiments on neuroprotection, betaxolol was injected directly into the vitreous humor or into blood vessels in order to achieve an appropriate concentration in the retina. In the latest study, betaxolol was applied topically in rabbit eyes and was later found in the retina in amounts sufficient to achieve beneficial effects.

Prof. Osborne told Ocular Surgery News that although the drug does not appear to accumulate in animal retinas after topical application, it is possible that repeated betaxolol administration in humans — as occurs in conventional IOP-lowering therapy for glaucoma — could have a cumulative beneficial effect and preserve visual fields.

Protection pathways

Betaxolol in retina

Levels of betaxolol in the retinas of treated and contralateral eyes following various treatment regimes. Drops were administered at 30 minute intervals; 1h, 4h=time of death after last drop of Betoptic. Results expressed as means ± SEM.

Prof. Osborne wrote in Experimental Eye Research that while timolol is slightly more effective than betaxolol in reducing IOP, a number of studies have shown that visual fields are better preserved in patients taking betaxolol. Other studies have shown that betaxolol prevents ganglion cell death by acting as a calcium channel blocker.

Topical betaxolol can also counteract the harmful effects of N-methyl-D-aspartate (NMDA), which was used in Prof. Osborne’s experiments to induce retinal damage in rabbit and rat eyes. Re search found that the presence of NMDA in creased the uptake of calcium into neurons by three times the normal rates, while betaxolol and NMDA antagonists reduced this influx of calcium significantly. It is known that when the calcium level within a neuron is elevated to unacceptable levels, cell death by apoptosis or necrosis can be initiated.

Prof. Osborne wrote that, “The present studies substantiate and extend our previous studies to show that topically applied betaxolol acts as a neuroprotective agent against retinal ischemia and NMDA-induced retinal toxicity.”

Betaxolol in retina

In the study, either four or eight drops of betaxolol were applied topically every 30 minutes in the eyes of rabbits. A radioassay was then performed to determine the amount of drug present in aqueous humor and retina.

As soon as 1 hour after the series of drops was applied, betaxolol was present in retinal tissue. Four hours after topical application, the retina still contained one-fourth the amount of drug found after 1 hour. At 1 hour, the betaxolol content in the aqueous humor was much greater than that found in the retina, but practically no betaxolol could be found in the aqueous humor after 4 hours

Most importantly, topical application of betaxolol to one eye resulted in betaxolol being found in both retinas. According to Prof. Osborne, this strongly suggests that topically applied betaxolol reaches the retina by retinal or systemic circulation.

In another phase of the experiment, pressure was raised in rabbit eyes and NMDA was injected in rat eyes to assess the possible neuroprotective effects of betaxolol versus no treatment.

“Repeated applications of betaxolol of different regimes to rats and rabbits counteracted the NMDA-induced toxicity to ganglion cells and the ischemic effects to the retina, respectively,” Prof. Osborne wrote. “The significance of these studies as related to the use of betaxolol in the treatment of glaucoma, where the death of the retinal ganglion cells needs to be counteracted, is self evident.”

For Your Information:

Neville N. Osborne, PhD, DSc, can be reached at the Nuffield Laboratory of Ophthalmology, University of Oxford, Walton Street, Oxford, OX2 6AW, England; (44) 1865-248996; fax: (44) 1865-794508. Prof. Osborne has no direct financial interest in any of the products mentioned in this article, nor is he a paid consultant for any companies mentioned.