Moclobemide attenuates anoxia and glutamate-induced neuronal damage in vitro independently of interaction with glutamate receptor subtypes.

Abstract

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.

• Authors: Marc Verleye, Remy Steinschneider, François Xavier Bernard, Jean-Marie Gillardin
• Journal: Brain research (Brain Res) Vol. 1138 Pg. 30-8 (Mar 23 2007) ISSN: 0006-8993 [Print] Netherlands
• PMID: 17274964 (Publication Type: Journal Article)

Chemical References

• Monoamine Oxidase Inhibitors
• Neuroprotective Agents
• Receptors, Glutamate
• Glutamic Acid
• Veratridine
• Sodium
• Moclobemide
• Potassium
• Calcium

Topics

• Animals
• Astrocytes (drug effects, metabolism, pathology)
• Calcium (metabolism)
• Cell Survival (drug effects)
• Cells, Cultured
• Cerebral Cortex (drug effects, metabolism, pathology, physiopathology)
• Glutamic Acid (pharmacology)
• Hypoxia (pathology)
• Moclobemide (metabolism, pharmacology)
• Monoamine Oxidase Inhibitors (metabolism, pharmacology)
• Neurons (drug effects, metabolism, pathology)
• Neuroprotective Agents (metabolism, pharmacology)
• Potassium (pharmacology)
• Rats
• Rats, Wistar
• Receptors, Glutamate (metabolism)
• Sodium (pharmacokinetics)
• Veratridine (pharmacology)