Protective effects of timolol against the neuronal damage induced by glutamate and ischemia in the rat retina

Goto, Wakana; Ota, Takumi; Morikawa, Nobuo; Otori, Yasumasa; Hara, Hideaki; Kawazu, Kouichi; Miyawaki, Nobuaki; Tano, Yasuo

doi:10.1016/s0006-8993(02)03372-3

Cited by 68 publications

(43 citation statements)

References 32 publications

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“…51 In vivo, oxygen induced rethinopathy in newborn rats was inhibited by timolol treatment. 52 Timolol also displays protective effects against the neuronal damage induced by glutamate in rat retina, 40 further confirming the antioxidant attitude of timolol because glutamate exerts its cytotoxicity through oxidative damage, as demonstrated in retinal ganglion cells. 53 The MTT test used under our experimental conditions specifically evaluates mitochondrial function.…”

Section: Discussionmentioning

confidence: 53%

“…It has been demonstrated that timolol displays a direct neuroprotective effect in experimental models of retinal injury and these protective effects are due in part to a mechanism independent of its action as an ocular hypotensive agent. 40 Some authors deny the neuroprotective effect of timolol; 41 nevertheless, recent studies support a potential neuroprotective effect of bblockers 40,42 although to a lesser extent than other molecules, 43 thus suggesting that the neuroprotective effect of timolol is possible, although in some way controversial.…”

Section: Discussionmentioning

confidence: 99%

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Antioxidant activity of timolol on endothelial cells and its relevance for glaucoma course

Izzotti

Saccà²,

Marco

et al. 2007

Eye

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Purpose A growing evidence in the scientific literature suggests that oxidative damage plays a pathogenic role in primary open-angle glaucoma. Therefore, it is of interest to test whether drugs effective against glaucoma display antioxidant activity. We test the hypothesis that the classic b-blocker therapy for glaucoma with timolol involves the activation of antioxidant protective mechanisms towards endothelial cells. Methods Oxidative stress was induced in cultured human endothelial cells by iron/ ascorbate with or without timolol pretreatment. Analysed parameters included cell viability (neutral red uptake and tetrazolium salt tests), lipid peroxidation (thiobarbituric reactive substances), and occurrence of molecular oxidative damage to DNA (8-hydroxy-2 0 -deoxyguanosine).Results Oxidative stress decreased 1.8-fold cell viability, increased 3.0-fold lipid peroxidation and 64-fold oxidative damage to DNA. In the presence of timolol, oxidative stress did not modify cell viability, whereas lipid peroxidation was increased 1.3-fold, and DNA oxidative damage 3.6-fold only.Conclusions The obtained results indicate that timolol exerts a direct antioxidant activity protecting human endothelial cells from oxidative stress. These cells employ mechanisms similar to those observed in the vascular endothelium. It is hypothesized that this antioxidant activity is involved in the therapeutic effect of this drug against glaucoma.

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Section: Discussionmentioning

confidence: 53%

Section: Discussionmentioning

confidence: 99%

Antioxidant activity of timolol on endothelial cells and its relevance for glaucoma course

Izzotti

Saccà²,

Marco

et al. 2007

Eye

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“…Several investigators have reported since initiation of the current study that timolol has neuroprotective effects in animal models. 37,38 Further, the possibility that neither nipradilol nor timolol had a clinically signifi cant IOP-independent effect could not be excluded.…”

Section: Discussionmentioning

confidence: 99%

Clinical efficacy of topical nipradilol and timolol on visual field performance in normal-tension glaucoma: a multicenter, randomized, double-masked comparative study

Araie

Shirato²,

Yamazaki

et al. 2008

Jpn J Ophthalmol

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“…The neuroprotective properties of ophthalmic β-antagonists, especially betaxolol, on NMDA / glutamate-dependent signals such as intracellular Ca 2+ increase (9, 10, 25) and cell death (11,26,27) have been demonstrated in previous studies using RGCs, but it has not been well discussed whether antiglaucoma drugs exert direct antagonistic effects on NMDA-receptor function. Therefore, we firstly investigated the direct effects of different types of antiglaucoma drugs on NMDA-and non-NMDA (AMPA)-receptor function using a Xenopus oocyte expression system.…”

Section: Discussionmentioning

confidence: 99%

Direct Inhibition of N-Methyl-D-Aspartate (NMDA)-Receptor Function by Antiglaucomatous β-Antagonists

et al. 2008

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Abstract. In the present study, we investigated the direct effects of antiglaucoma drugs (timolol, betaxolol, pilocarpine, and latanoprost) on N-methyl-D-aspartate (NMDA)-receptor function using a Xenopus oocytes expression system and electrophysiological techniques. In oocytes expressing wild-type NMDA (NR1a / NR2A) receptors, timolol and betaxolol significantly inhibited glutamate-evoked currents, whereas less inhibition was obtained with pilocarpine, and latanoprost had few effects. Moreover, the effect of timolol and betaxolol was noncompetitive with respect to glutamate. Mutations that changed Asn616 of the NR1a subunit, a critical residue for Mg 2+ blocking of NMDA receptors, to Arg (N616R) or Gln (N616Q) almost eliminated the inhibitory effects of timolol and betaxolol, as well as the blocking effect of Mg 2+. Experiments were also carried out to examine the protective effects of timolol and betaxolol against death of oocytes expressing NMDA receptors. During incubation of oocytes, especially in Mg 2+ -free medium, cell death was induced by addition of glutamate because of the continuous activation of the NMDA receptors expressed. Timolol and betaxolol significantly improved oocyte viability when they were added during the incubation period. These results suggest that timolol and betaxolol may have an additional role that they directly inhibit NMDA-receptor function, possibly via N616 of the NR1a subunit.

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Protective effects of timolol against the neuronal damage induced by glutamate and ischemia in the rat retina

Cited by 68 publications

References 32 publications

Antioxidant activity of timolol on endothelial cells and its relevance for glaucoma course

Antioxidant activity of timolol on endothelial cells and its relevance for glaucoma course

Clinical efficacy of topical nipradilol and timolol on visual field performance in normal-tension glaucoma: a multicenter, randomized, double-masked comparative study

Direct Inhibition of N-Methyl-D-Aspartate (NMDA)-Receptor Function by Antiglaucomatous β-Antagonists

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