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Experimental investigation of neuroprotective drugs in models of retinal cell death.

Date

2004

Authors

Baptiste, Darryl Cassius.

Journal Title

Journal ISSN

Volume Title

Publisher

Dalhousie University

Abstract

Description

Glaucomatous optic neuropathy (GON) results in retinal ganglion cell (RGC) death and vision loss. The underlying mechanism(s) for RGC death in GON may include glutamate-induced excitotoxicity, trophic factor deprivation (TFD), inflammatory reactions or axonal injury. Drugs that intervene at various points in the apoptotic pathways leading to neuronal death may provide neuroprotection. Recent studies have demonstrated that the intraocular pressure-reducing drugs betaxolol, a beta1-adrenergic receptor (AR) antagonist, and brimonidine, an alpha2-AR agonist, as well as the tetracycline derivative, minocycline, are neuroprotective in models of the degenerating retina and central nervous system. The main objectives of this thesis research were to determine the efficacy and mechanism(s) of action of the AR drugs and tetracycline derivatives in inhibiting retinal neuron death in experimental models.
Betaxolol, brimonidine, and minocycline were all neuroprotective in retinal cell culture, with increased viability occurring at concentrations ranging from 0.02--200 muM. In comparison to other beta-AR antagonists, betaxolol was the only drug with neuroprotective capabilities, suggesting that the neuroprotective actions by betaxolol occur independent of interactions with beta-ARs. In contrast, the increased neuronal survival mediated by brimonidine could be blocked by the alpha2-AR antagonist, yohimbine, suggesting that the neuroprotective actions of brimonidine occur via an alpha2-AR pathway. Minocycline, but not tetracycline, increased neuron survival following excitotoxicity or TFD. The anti-apoptotic actions of minocycline in retinal cell cultures appeared independent of interactions with N-methyl-D-aspartate receptors and were associated with a reduction in caspase-3 mRNA and protein activation. Minocycline was also able to inhibit TFD-induced apoptosis in pure differentiated pheochromocytoma cell cultures, implying that the neuroprotective actions mediated by minocycline may arise, in part, via direct actions on neurons.
The neuroprotective actions of the tetracycline drugs on RGC survival and MG activation were also assessed in a rat model of ON axotomy. Treatment of axotomized animals with minocycline, but not tetracycline, significantly increased the viability of RGCs. Minocycline also decreased MG activation suggesting that minocycline can provide neuroprotection for RGCs following ON injury, and that this property is not shared by all tetracycline drugs.
Thesis (Ph.D.)--Dalhousie University (Canada), 2004.

Keywords

Health Sciences, Ophthalmology., Health Sciences, Pharmacology.

Citation