Moclobemide attenuates anoxia and glutamate-induced neuronal damage in vitro independently of interaction with glutamate receptor subtypes.
Recent data suggested the existence of a bidirectional relation between depression and neurodegenerative diseases resulting from cerebral ischemia injury. Glutamate, a major excitatory neurotransmitter, has long been recognised to play a key role in the pathophysiology of anoxia or ischemia, due to its excessive accumulation in the extracellular space and the subsequent activation of its receptors. A characteristic response to glutamate is the increase in cytosolic Na(+) and Ca(2+) levels which is due mainly to influx from the extracellular space, with a consequent cell swelling and oxidative metabolism dysfunction. The present study examined the in vitro effects of the antidepressant and type-A monoamine oxidase inhibitor, moclobemide, in neuronal-astroglial cultures from rat cerebral cortex exposed to anoxia (for 5 and 7 h) or to glutamate (2 mM for 6 h), two in vitro models of brain ischemia. In addition, the affinity of moclobemide for the different glutamate receptor subtypes and an interaction with the cell influx of Na(+) and of Ca(2+) enhanced by veratridine and K(+) excess, respectively, were evaluated. Moclobemide (10-100 microM) included in the culture medium during anoxia or with glutamate significantly increased in a concentration-dependent manner the amount of surviving neurons compared to controls. Moclobemide displayed no binding affinity for the different glutamate receptor subtypes (IC(50)>100 microM) and did not block up to 300 microM the entry of Na(+) and of Ca(2+) activated by veratridine and K(+), respectively. These results suggest that the neuroprotective properties of moclobemide imply neither the glutamate neurotransmission nor the Na(+) and Ca(2+) channels.
Verleye
Marc
M
Biocodex, Département de Pharmacologie, Zac de Mercières-Chemin d'Armancourt, 60200 Compiègne, France. m.verleye@biocodex.fr
Steinschneider
Remy
R
Bernard
François Xavier
FX
Gillardin
Jean-Marie
JM
D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002118:Calcium / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D018698:Glutamic Acid / Q000494:pharmacology*; D000860:Hypoxia / Q000473:pathology*; D020912:Moclobemide / Q000378:metabolism / Q000494:pharmacology*; D008996:Monoamine Oxidase Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000378:metabolism / Q000494:pharmacology*; D011188:Potassium / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D017470:Receptors, Glutamate / Q000378:metabolism; D012964:Sodium / Q000493:pharmacokinetics; D014701:Veratridine / Q000494:pharmacology
D008996:Monoamine Oxidase Inhibitors; D018696:Neuroprotective Agents; D017470:Receptors, Glutamate; D018698:Glutamic Acid; D014701:Veratridine; D012964:Sodium; D020912:Moclobemide; D011188:Potassium; D002118:Calcium