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An Investigation of the Neuroprotective Effects of Tetracycline Derivatives in Experimental Models of Retinal Cell Death

Retina and Optic Nerve Research Laboratory, Departments of Pharmacology (D.C.B., C.A.B.J., M.E.M.K.), Anatomy & Neurobiology (A.T.E.H., W.H.B.), and Ophthalmology & Visual Sciences (W.H.B., M.E.M.K.), Dalhousie University, Halifax, Nova Scotia, Canada; and Departments of Ophthalmology and Physiology and Biophysics, University at Buffalo, Buffalo, New York (G.M.S.)

The purpose of this study was to determine the efficacy and putative mechanisms of action of tetracycline and minocycline in inhibiting retinal cell apoptosis after 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 PC-12 cell line was used to determine whether minocycline was neuroprotective after 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 seemed independent of actions on N-methyl-D-aspartate receptors (NMDARs) and glutamate receptor-mediated Ca²⁺ influx. Doses of the NMDAR antagonist MK-801 (dizocilpine) 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 Ca²⁺ influx, as assessed by calcium imaging. Minocycline was also neuroprotective after trophic factor withdrawal, producing a decrease in apoptosis and caspase-3 activation in both retinal cells and the PC-12 neuronal-like cell line. These results support a role for minocycline as a retinal neuroprotectant and demonstrate that the antiapoptotic actions of minocycline in retinal cells do not arise from the blockage of NMDARs 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.

Address correspondence to: Dr. Melanie Kelly, Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada, B3H 4H7. E-mail: melanie.kelly{at}dal.ca

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