Levobetaxolol-induced Up-regulation of Retinal bFGF and CNTF mRNAs and Preservation of Retinal Function Against a Photic-induced Retinopathy

doi:10.1006/exer.2001.1145

Experimental Eye Research

Volume 74, Issue 4, April 2002, Pages 445-453

https://doi.org/10.1006/exer.2001.1145 Get rights and content

Abstract

Betaxolol (racemic), a β-adrenoceptor antagonist that is used to lower intraocular pressure in the treatment of glaucoma, has been shown to protect inner retina cells from various insults. To determine if such protection could be afforded to retinal photoreceptors and retinal pigment epithelial cells (RPE), levobetaxolol (S-betaxolol) was evaluated in a photic-induced retinopathy model. Rats were dosed (IP) with vehicle or levobetaxolol (10 and 20 mg kg⁻¹) 48, 24 and 0 hr prior to exposure for 6 hr to fluorescent blue light. The electroretinogram (ERG) and retinal morphology were assessed after a 3 week recovery period. Evaluation of the ERG demonstrated significant protection of retinal function in levobetaxolol (20 mg kg⁻¹)-dosed rats compared to vehicle-dosed rats. Similarly, the RPE and outer nuclear layer were significantly thicker in levobetaxolol (20 mg kg⁻¹)-dosed rats compared to vehicle-dosed rats. To elucidate potential mechanism(s) of the neuroprotective activity of levobetaxolol, bFGF and CNTF mRNA levels in normal rat retinas were evaluated 12 hr after a single i.p. injection. Northern blot analysis of levobetaxolol treated retinas demonstrated a 10-fold up-regulation of bFGF and a two-fold up-regulation of CNTF mRNA levels, trophic factors that have been shown to inhibit retinal degeneration in a number of species. These studies suggest that levobetaxolol can be used as a novel neuroprotective agent to ameliorate retinopathy.

References (51)

N. Agarwal
Diurnal expression of NGF-1A mRNA in retinal degeneration slow (rds) mutant mouse retina
FEBS Lett.
(1994)
N. Agarwal et al.
Immunocytochemical colocalization of clusterin in apoptotic photoreceptor cells in retinal degeneration slow rds mutant mouse retinas
Biochem. Biophys. Res. Commun.
(1996)
M.R. Al-Ubaidi et al.
Unscheduled DNA replication precedes apoptosis of photoreceptors expressing SV40 T-antigen
Exp. Eye Res.
(1997)
N.M. Bressler et al.
Age-related macular degeneration
Surv. Ophthalmol.
(1988)
R.K. Hester et al.
The direct vascular relaxing action of betaxolol, carteolol, and timolol in porcine long posterior ciliary artery
Surv. Ophthalmol.
(1994)
W.K. Noell
Possible mechanisms of photoreceptor damage by light in mammalian eyes
Vision Res.
(1980)
N.N. Osborne et al.
In vivo and in vitro experiments show that betaxolol is a retinal neuroprotective agent
Exp. Eye. Res.
(1997)
N.N. Osborne et al.
Neuroprotection in relation to retinal ischemia and relevance to glaucoma
Surv. Ophthalmol.
(1999)
J.P.M. Wood et al.
Topically applied betaxolol attenuates ischemia-induced effects to the rat retina and stimulates BDNF mRNA
Exp. Eye Res.
(2001)
A.S. Abler et al.
Photic injury triggers apoptosis in photoreceptor cells
Res. Commun. Mol. Pathol. Pharmacol.
(1996)

N. Agarwal et al.

Opsin synthesis and mRNA levels in dystrophic retinas devoid of outer segments in retinal degeneration slow (rds) mice

J. Neurosci.

(1990)

G. Chidlow et al.

Betaxolol, a β₁-adrenoceptor antagonist, reduces Na⁺ influx into cortical synaptosomes by direct interaction with Na⁺ channels: comparison with other β-adrenoceptor antagonists

Br. J. Pharmacol.

(2000)

J.M. Chirgwin et al.

Isolation of biologically active RNA from sources rich in ribonuclease

Biochemistry

(1979)

M. Cayouette et al.

Intraocular gene transfer of ciliary neurotrophic factor prevents death and increases responsiveness of rod photoreceptors in the retinal degeneration slow mouse

J. Neurosci.

(1998)

M. Cayouette et al.

Adenovirus-mediated gene transfer of ciliary neurotrophic factor can prevent photoreceptor degeneration in the retinal degeneration (rd) mouse

Hum. Gene Ther.

(1997)

E. Chen

Inhibition of cytochrome oxidase and blue-light damage in rat retina

Graefe's Arch. Clin. Exp. Ophthalmol.

(1993)

E. Chen et al.

Distribution of calcium and sulphur in the blue-light-exposed rat retina

Graefe's Arch. Clin. Exp. Ophthalmol.

(1995)

E. Chen et al.

Cytochrome oxidase activity in rat retina after exposure to 404 nm blue light

Curr. Eye Res.

(1992)

R. Collier et al.

Inhibition of photo-oxidative induced retinal damage by diphenylalkylamines

Invest. Ophthalmol. Vis. Sci.

(1995)

R.J. Collier et al.

Betaxolol and its isomers are neuroprotective in a photic retinopathy model

Invest. Ophthalmol. Vis. Sci.

(2000)

R.J. Collier et al.

Prevention of photic induced retinal injury by eliprodil

Invest. Ophthalmol. Vis. Sci.

(1999)

C.A. Curcio et al.

Photoreceptor loss in age-related macular degeneration

Invest. Ophthalmol. Vis. Sci.

(1996)

D.C. Dahlin et al.

Distribution of betaxolol to posterior ocular tissues of the cynomologous monkey following a 30-day BID topical ocular regimen of Betoptic-S

Invest. Ophthalmol. Vis. Sci.

(2000)

L. DeSantis et al.

Topical betaxolol attenuates ischemia-induced effects to the rat retina and stimulates BDNF mRNA

Invest. Ophthalmol. Vis. Sci.

(2000)

D.P. Edward et al.

Amelioration of light-induced retinal degeneration by a calcium overload blocker

Arch. Ophthalmol.

(1991)

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Perhaps the best studied neuroprotective protein is bFGF. Pre-conditioning rats with short term bright light exposure (Liu et al., 1998; Li et al., 2003), prior optic nerve injury (Bush and Williams, 1991), ischemic pre-conditioning (Casson et al., 2003) and drugs that prevent retinal ischemia (Agarwal et al., 2002), all reduce the extent of retinal light damage while increasing bFGF expression, or its re-localization (Kostyk et al., 1994). As shown by Stone et al. (1999) and Walsh et al. (2001), the highest regional levels of immunoreactive bFGF in the rat retina correlate with those areas incurring the least amount of light damage.
By its action on rhodopsin, light triggers the well-known visual transduction cascade, but can also induce cell damage and death through phototoxic mechanisms – a comprehensive understanding of which is still elusive despite more than 40 years of research. Herein, we integrate recent experimental findings to address several hypotheses of retinal light damage, premised in part on the close anatomical and metabolic relationships between the photoreceptors and the retinal pigment epithelium. We begin by reviewing the salient features of light damage, recently joined by evidence for retinal remodeling which has implications for the prognosis of recovery of function in retinal degenerations. We then consider select factors that influence the progression of the damage process and the extent of visual cell loss. Traditional, genetically modified, and emerging animal models are discussed, with particular emphasis on cone visual cells. Exogenous and endogenous retinal protective factors are explored, with implications for light damage mechanisms and some suggested avenues for future research. Synergies are known to exist between our long term light environment and photoreceptor cell death in retinal disease. Understanding the molecular mechanisms of light damage in a variety of animal models can provide valuable insights into the effects of light in clinical disorders and may form the basis of future therapies to prevent or delay visual cell loss.
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^f1: Address correspondence to: Robert J. Collier, Retinopathy—Degenerative Disease Unit, R3-24, Alcon Research, Ltd., 6201 South Freeway, Fort Worth, TX 76134-2099, U.S.A. E-mail: robert.collier @alconlabs.com

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Regular ArticleLevobetaxolol-induced Up-regulation of Retinal bFGF and CNTF mRNAs and Preservation of Retinal Function Against a Photic-induced Retinopathy

Abstract

FEBS Lett.

Biochem. Biophys. Res. Commun.

Exp. Eye Res.

Surv. Ophthalmol.

Surv. Ophthalmol.

Vision Res.

Exp. Eye. Res.

Surv. Ophthalmol.

Exp. Eye Res.

Photic injury triggers apoptosis in photoreceptor cells

Res. Commun. Mol. Pathol. Pharmacol.

Opsin synthesis and mRNA levels in dystrophic retinas devoid of outer segments in retinal degeneration slow (rds) mice

J. Neurosci.

Betaxolol, a β1-adrenoceptor antagonist, reduces Na+ influx into cortical synaptosomes by direct interaction with Na+ channels: comparison with other β-adrenoceptor antagonists

Br. J. Pharmacol.

Isolation of biologically active RNA from sources rich in ribonuclease

Biochemistry

Intraocular gene transfer of ciliary neurotrophic factor prevents death and increases responsiveness of rod photoreceptors in the retinal degeneration slow mouse

J. Neurosci.

Adenovirus-mediated gene transfer of ciliary neurotrophic factor can prevent photoreceptor degeneration in the retinal degeneration (rd) mouse

Hum. Gene Ther.

Inhibition of cytochrome oxidase and blue-light damage in rat retina

Graefe's Arch. Clin. Exp. Ophthalmol.

Distribution of calcium and sulphur in the blue-light-exposed rat retina

Graefe's Arch. Clin. Exp. Ophthalmol.

Cytochrome oxidase activity in rat retina after exposure to 404 nm blue light

Curr. Eye Res.

Inhibition of photo-oxidative induced retinal damage by diphenylalkylamines

Invest. Ophthalmol. Vis. Sci.

Betaxolol and its isomers are neuroprotective in a photic retinopathy model

Invest. Ophthalmol. Vis. Sci.

Prevention of photic induced retinal injury by eliprodil

Invest. Ophthalmol. Vis. Sci.

Photoreceptor loss in age-related macular degeneration

Invest. Ophthalmol. Vis. Sci.

Distribution of betaxolol to posterior ocular tissues of the cynomologous monkey following a 30-day BID topical ocular regimen of Betoptic-S

Invest. Ophthalmol. Vis. Sci.

Topical betaxolol attenuates ischemia-induced effects to the rat retina and stimulates BDNF mRNA

Invest. Ophthalmol. Vis. Sci.

Amelioration of light-induced retinal degeneration by a calcium overload blocker

Arch. Ophthalmol.

Regular Article
Levobetaxolol-induced Up-regulation of Retinal bFGF and CNTF mRNAs and Preservation of Retinal Function Against a Photic-induced Retinopathy

Betaxolol, a β₁-adrenoceptor antagonist, reduces Na⁺ influx into cortical synaptosomes by direct interaction with Na⁺ channels: comparison with other β-adrenoceptor antagonists