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

Mechanisms underlying the neuroprotective properties of the weak MAO-A inhi bitor moclobemide are not understood. Increasing evidence suggests that a m oderate increase in intracellular free protons may contribute to neuro-prot ective properties due to a protonmediated decrease in neuronal activity. Th erefore, we studied effects of 10-700 mu M moclobemide (i) on the intracell ular pH (pH(i)) of BCECF-AM loaded CA3 neurones as well as (ii) on spontane ous action potentials and epileptiform activity (induced by bicuculline-met hiodide, caffeine, or 4-aminopyridine) of CA3 neurones in the stratum pyram idale. Moclobemide-concentrations of greater than or equal to 300 mu M reve rsibly reduced the steady-state pH(i) by up to 0.25 pH-units within 5-20 mi n. Simultaneously, the frequency of spontaneous action potentials and epile ptiform discharges became depressed. Moclobemide also abolished 4-aminopyri dine-induced GABA-mediated hyperpolarisations suggesting that the inhibitor y 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 p H(i)-regulation we found that 700 mu M moclobemide impaired the recovery fr om intracellular acidification elicited by an ammonium prepulse which demon strates 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 substanti ally contribute to the neuroprotective properties of moclobemide. (C) 2000 Elsevier Science Ltd. All rights reserved.