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

Brain Res. 2007 Mar 23:1138:30-8. doi: 10.1016/j.brainres.2006.12.089. Epub 2007 Jan 9.

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.

MeSH terms

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

Substances

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