December 2002
Volume 43, Issue 13
Free
ARVO Annual Meeting Abstract  |   December 2002
The ß-Adrenoceptor Antagonists Metipranolol and Timolol Attenuate Rat Retinal Neurone Damage in Vitro and In Vivo
Author Affiliations & Notes
  • JP M Wood
    Nuffield Lab of Ophthalmology University of Oxford Oxford United Kingdom
  • KG Schmidt
    Nuffield Lab of Ophthalmology University of Oxford Oxford United Kingdom
  • J Melena
    Nuffield Lab of Ophthalmology University of Oxford Oxford United Kingdom
  • NN Osborne
    Nuffield Lab of Ophthalmology University of Oxford Oxford United Kingdom
  • Footnotes
    Commercial Relationships   J.P.M. Wood, None; K.G. Schmidt, None; J. Melena, None; N.N. Osborne, None.
Investigative Ophthalmology & Visual Science December 2002, Vol.43, 3620. doi:
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      JP M Wood, KG Schmidt, J Melena, NN Osborne; The ß-Adrenoceptor Antagonists Metipranolol and Timolol Attenuate Rat Retinal Neurone Damage in Vitro and In Vivo . Invest. Ophthalmol. Vis. Sci. 2002;43(13):3620.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Abstract: : Purpose: To determine whether the ß-blockers, metipranolol and timolol, can prevent retinal neuronal injury in culture or in vivo as reported previously for the ß1-antagonist, betaxolol. Furthermore, to assess possible mechanisms of action for these compounds. Methods: 15µl of either 0.3% metipranolol hydrochloride (Betamann; Dr. Mann Pharma, Berlin, Germany), 0.5% timolol maleate (Martindale Pharmaceuticals, Romford, UK) or saline were applied topically twice daily to two groups of rats. Electroretinograms (ERGs) were recorded before treatment. After three days, retinal ischemia was induced to one eye by raising the IOP to 120mmHg for 45 minutes. ERGs were recorded again 5 days later and the animals killed after a further 3 days. Retinas were analysed for death of ganglion cells by RT-PCR. Mixed 7 day rat retinal cultures (from 3 day old pups) on borosilicate glass coverslips were subjected to oxygen deprivation for 24 hours and the influence of metipranolol or timolol (both 100µM) was determined on the numbers of GABA-labelling neurones after the insult by immunocytochemistry. Rat retinas or rat brain synaptosomes were exposed to radioactive calcium or sodium and NMDA (100µM) or veratridine (100µM) respectively and the effect of metipranolol or timolol on the stimulated influx of these radioactive cations was assessed. Results: Ischemia/reperfusion caused a reduction in the ERG b-wave amplitude (21% of pre-ischemic value) which was significantly attenuated by topically applied metipranolol or timolol (38.3% and 38.2% of pre-ischemic values, respectively). Both metipranolol and timolol also partially counteracted the loss of retinal Thy-1 mRNA compared with GA-3-PDH mRNA (from 28.4% in saline-treated animals to 5.5% after metipranolol and 16.1% after timolol). Metipranolol and timolol reduced the loss of GABA-IR neurones in anoxia-treated retinal cultures (53% and 45% of the control numbers compared with 24% in vehicle treated cultures). Both compounds were also able to significantly attenuate the stimulated influx of radioactive calcium into retinas or sodium into brain synaptosomes. Conclusion: Metipranolol and timolol can partially blunt the detrimental effects of ischemia to the retina, in vivo, or of anoxia to cultured retinal cells. Since they also reduce both sodium and calcium entry into neurones, it is suggested that they may protect neurones by partial blockade of channels, as has been previously reported for betaxolol.

Keywords: 554 retina • 489 neuroprotection • 448 ischemia 
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