The glio-toxic mechanism of alpha-aminoadipic acid on cultured astrocytes.

The mechanism of action of the glutamate analogue alpha-aminoadipic (AAA) acid was investigated in terms of its toxicity to cultured astrocytes. AAA was more toxic to type 1 astrocytes than type 2 astrocytes. Also the higher toxicity of the L-isomer as compared to the D-isomer was seen on type 1 astrocytes but not type 2. The toxicity of AAA can be reduced by co-culture of type 1 astrocytes with microglia. This inhibition may be due to glutamate release by microglia. No such effect is seen for type 2 astrocytes. The major uptake route for AAA by type 1 astrocytes is through the sodium dependent glutamate port. Both isomers of AAA are toxic to dividing astrocytes. The D-isomer appears to be toxic only for mitotic cells. The mechanism of this toxicity is protein synthesis dependent. It is suggested that AAA is toxic to mitotic astrocytes by interference with protein synthesis needed for cell division. D-AAA as opposed to L-AAA may prove a valuable tool for investigation of astrocyte proliferation in development and disease.