Gliotoxicity in brain reaggregate cultures caused by oxidants and excitatory amino acids can be prevented by alpha-tocopherol and MK-801.
Glutamine synthetase (GS) is a key enzyme involved in glutamate compartmentalisation which may be pivotal in the course of both central free-radical mediated and excitotoxic events. The ability of the oxidants FeCl2 and H2O2 and the excitatory amino acid, N-methyl-D-aspartate (NMDA) to induce changes in astrocytic GS and glial fibrillary acidic protein (GFAP), were assessed in whole rat brain reaggregate cultures. Both FeCl2 and H2O2 reduced GS activity whereas NMDA produced a large increase in enzyme activity. GFAP was not altered significantly by either oxidant although NMDA increased the level of this protein. These effects on such astroglial markers could be reversed in vitro following exposure to a-tocopherol (FeCl2 and H2O2) and MK-801. This study therefore demonstrates that inactivation of GS can be caused by free radical insult whereas stimulation of brain GS and reactive gliosis is produced by excitatory amino acids acting at neuronal NMDA receptors. The study of these gliotoxic events in 3-dimensional reaggregate cultures suggests that this model may be used to detect neuroprotective effects of novel pharmacological agents.
Fox
R M
RM
Cellular Toxicology Unit, University of Hertfordshire, Herts, U.K.
Jones
J E
JE
Atterwill
C K
CK
D000818:Animals; D001921:Brain / Q000187:drug effects*; D002478:Cells, Cultured; D016291:Dizocilpine Maleate / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity*; D009457:Neuroglia / Q000187:drug effects*; D016877:Oxidants / Q000633:toxicity*; D051381:Rats; D014810:Vitamin E / Q000494:pharmacology*
D018690:Excitatory Amino Acid Agonists; D016877:Oxidants; D014810:Vitamin E; D016291:Dizocilpine Maleate