Received for publication April 6, 2004.
Revised July 30, 2004.
Accepted for publication August 2, 2004.

An investigation of the neuroprotective effects of tetracycline derivatives in experimental models of retinal cell death

Abstract

The purpose of this study was to determine the efficacy and putative mechanisms of action of tetracycline and minocycline in inhibiting retinal cell apoptosis following glutamate-induced excitotoxicity and trophic factor deprivation in a retinal cell line (E1A-NR.3) and in primary mixed retinal cell cultures. In addition, a differentiated PC12 cell line was used to determine if minocycline was neuroprotective following trophic withdrawal in a pure neuronal cell line devoid of glia. Results from this study demonstrated that minocycline, but not tetracycline, is protective in in vitro models of excitotoxicity-induced retinal cell apoptosis. Moreover, the protective effects provided by minocycline in retinal cells appeared independent of actions on N-methyl-D-aspartate receptors (NMDA-Rs) and glutamate-receptor-mediated Ca²⁺ influx: doses of the NMDA-R antagonist MK-801 and minocycline that alone provided no significant neuroprotection resulted in enhanced retinal cell survival when applied concurrently, suggestive of distinct signaling pathways, and minocycline was without effect on glutamate-induced induced Ca²⁺ influx, as assessed by calcium imaging. Minocycline was also neuroprotective following trophic factor withdrawal, producing a decrease in apoptosis and caspase-3 activation in both retinal cells and the PC12 neuronal-like cell line. These results support a role for minocycline as a retinal neuroprotectant and demonstrate that the anti-apoptotic actions of minocycline in retinal cells do not arise from block of NMDA-Rs or glutamate receptor-mediated Ca²⁺ influx, but do involve inhibition of caspase-3 activation. In addition, the survival promoting actions of minocycline may arise via actions on both neuronal and non-neuronal cell targets.

Key words: Glutamate, Ca imaging, Fluorescence techniques, Excitotoxicity, neurodegeneration

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