Anti-excitotoxic Activity of Trimetazidine in the Retina

Abstract

Abstract: : Purpose: The aim of this study was to investigate the neuroprotective activity of trimetazidine in animal retina stressed by ischemia or kainate, an excitotoxic analogue of glutamate, and to specify the mechanism of action of the drug. Methods: Flash electroretinograms (ERGs) were recorded in guinea pigs after a 75 min episode of ischemia, induced by an acute increase in the intraocular pressure, or after an intravitreal injection of kainate. The animals were treated with trimetazidine per os. The effect of the drug on the accumulation of glutamate induced by ischemia was studied by incubating whole rat retinas in vitro with sodium azide. Extracellular aminoacid content was measured by HPLC/fluorimetry. Then the compound activity on the glial uptake of glutamate was studied in a rat Müller cell line (rMC-1) in culture submitted to chemical ischemia. Results: Ischemia or kainate injection dramatically alter the ERG recorded 24 h after the stress, in particular the b-wave was totally suppressed after ischemia and strongly decreased by kainate. Treatment with trimetazidine afforded a significant protection of the ERG against the ischemic as well as the excitotoxic insult as an antioxidant (dimethylthiourea) and a nitric oxide synthase inhibitor (nitroarginine) did. Trimetazidine was able to inhibit the glutamate extracellular accumulation which represents the first step of the excitotoxic phenomenon . Chemical ischemia inhibited the active 3H-glutamate transport, an effect which was reversed by trimetazidine at micromolar concentrations. Conclusions: These results demonstrate that trimetazidine which is recognized as an efficient drug against ischemic injuries is also capable to protect the retina against excitotoxicity. This effect appears to be related to the known antioxidant activity of the drug. Moreover, trimetazidine can interfere with the excitotoxic processes by reducing ischemia-induced accumulation of glutamate due in particular to glial transporter inhibition.

Keywords: ischemia • neuroprotection • retina