Alpha 2-adrenergic agonists reduce glutamate release and glutamate receptor-mediated calcium changes in hippocampal slices during hypoxia

Neuropharmacology. 1996 Jun;35(6):679-87. doi: 10.1016/0028-3908(96)84639-9.


The mechanisms by which alpha 2-adrenergic agonists reduce ischemic brain damage are not clear. In ischemia-vulnerable hippocampal neurons we tested whether alpha 2-agonists reduce glutamate efflux and glutamate receptor-mediated increase of cytosolic free calcium. Brain slices (300 microns thick) from rat hippocampal were located with fura-2 for measurements of cytosolic free calcium with a microscope fluorometer. Change of cytosolic calcium in CA1 neurons during application of N-methyl-D-aspartate (NMDA) was measured, as were calcium changes during simulated ischemia (hypoxia, NaCN, iodoacetate) of hypoxia plus high glutamate concentration (pO2 = 25 mmHg, 3 mM glutamate). In order slices, glutamate efflux evoked by anoxia (pO2 = 25 mmHg, 100 microM NaCN) was measured. The selective alpha 2-agonist mivazerol (1 microM) decreased NMDA receptor-mediated calcium changes in hippocampal CA1 neurons by 28% (p = 0.0079). With hypoxia and 3 mM glutamate, 1 microM mivazerol reduced early peak calcium changes in CA1 neurons by 57% (p = 0.0007). An alpha 2-antagonist (rauwolscine, 1 microM) blocked this. Mivazerol did not reduce the rate of calcium change during simulated ischemia. Clonidine (0.1 microM), a partial alpha 2-agonist, decrease glutamate/hypoxia-mediated calcium changes in CA1 (p = 0.01), but 1 microM clonidine, which stimulates alpha 1-receptors, did not. Mivazerol decreased hypoxia and KCl1-evoked glutamate release by 50% and 75% (p < 0.01), respectively. In addition, 1 microM mivazerol reduced lactate dehydrogenase leakage rate from brain slices during anoxia by 61% (p = 0.018). Thus, alpha 2-receptors influence glutamate release, calcium changes, and cell damage in ischemia-vulnerable hippocampal neurons. These effects may contribute to the cerebroprotective actions of alpha 2-agonists.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adrenergic alpha-Agonists / pharmacology*
  • Animals
  • Calcium / metabolism*
  • Clonidine / pharmacology
  • Dose-Response Relationship, Drug
  • Glutamic Acid / metabolism*
  • Hippocampus / drug effects*
  • Hypoxia / metabolism*
  • Imidazoles / pharmacology*
  • Rats
  • Rats, Sprague-Dawley


  • Adrenergic alpha-Agonists
  • Imidazoles
  • Glutamic Acid
  • Clonidine
  • Calcium
  • mivazerol