Moclobemide reduces intracellular pH and neuronal activity of CA3 neurones in guinea-pig hippocampal slices - implication for its neuroprotective properties

Mechanisms underlying the neuroprotective properties of the weak MAO-A inhibitor moclobemide are not understood. Increasing evidence suggests that a moderate increase in intracellular free protons may contribute to neuro-protective properties due to a protonmediated decrease in neuronal activity. Therefore, we studied effects of 10-700 mu M moclobemide (i) on the intracellular pH (pH(i)) of BCECF-AM loaded CA3 neurones as well as (ii) on spontaneous action potentials and epileptiform activity (induced by bicuculline-methiodide, caffeine, or 4-aminopyridine) of CA3 neurones in the stratum pyramidale. Moclobemide-concentrations of greater than or equal to 300 mu M reversibly reduced the steady-state pH(i) by up to 0.25 pH-units within 5-20 min. Simultaneously, the frequency of spontaneous action potentials and epileptiform discharges became depressed. Moclobemide also abolished 4-aminopyridine-induced GABA-mediated hyperpolarisations suggesting that the inhibitory and acidifying effects of moclobemide do not result from an amplification of the GABA system. The stronger MAO-A inhibitors clorgyline or pargyline (both 10 mu M) mimicked the moclobemide-effects. Investigating effects on pH(i)-regulation we found that 700 mu M moclobemide impaired the recovery from intracellular acidification elicited by an ammonium prepulse which demonstrates an impairment of transmembrane acid extrusion. We suggest that the latter effect is responsible for the moderate decrease in the steady-state pH(i) which in turn reduced neuronal activity. This mechanism may substantially contribute to the neuroprotective properties of moclobemide. (C) 2000 Elsevier Science Ltd. All rights reserved.