Abstract
Diminazene is an anti-infective medication from the diarylamidine group. In this work we have shown for the first time that it inhibits AMPA type ionotropic glutamate receptors. Experiments were conducted on isolated Wistar rat neurons. Calcium-permeable AMPA receptors were studied on giant striatum cholinergic interneurons, while calcium-impermeable AMPA receptors – on hippocampal CA1 pyramidal neurons. Cells were isolated from slices by vibrodissociation. Currents were recorded by whole-cell patch-clamp method. Diminazene inhibited kainate-induced currents in both types of neurons in a concentration-dependent manner. IC50 values for calcium-permeable and calcium-impermeable AMPA receptors were 60±11 and 160±30 µM, respectively. It is interesting that the degree of inhibition by fixed diminazene concentration was increased with the increase of agonist concentration. The voltage-dependence curve for the inhibition of calcium-permeable AMPA receptors by fixed diminazene concentration was biphasic: minimal inhibition was observed at positive holding potentials, maximal – at -40 - -60 mV, while further hyperpolarization resulted in the smooth decrease of block. All these features strongly suggest that channel block with the ability to permeate into the cytoplasm is the main molecular mechanism of AMPA receptor inhibition by diminazene.
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