NEUROTOXICITY OF ACROMELIC ACID IN CULTURED NEURONS FROM RAT SPINAL-CORD

Acromelic acid A, which contains the kainic acid structure in its mole cule, is known to cause selective damage of interneurons in the rat lo wer spinal cord. In the present study, the potent neurotoxicity of acr omelic acid A was demonstrated in cultured rat spinal neurons in terms of the activity of lactate dehydrogenase that was released from degen erated neurons into the culture medium. Acromelic acid A increased the lactate dehydrogenase activity in time- and concentration-dependent m anners, and its EC(50) was about 2.5 mu M, which was much lower than t hat of kainic acid (70 mu M) and lpha-amino-3-hydroxy-5-methyl-4-isoxa zolepropionic acid (EC(50); 11 mu M). The maximum level of lactate deh ydrogenase released by acromelic acid A was quite similar to that by k ainic acid, but was about twice the level produced by lpha-amino-3-hyd roxy-5-methyl-4-isoxazolepropionic acid. Exposure to acromelic acid A caused release of L-glutamate from the cells into the medium; however, the concentration of L-glutamate released was far below the level for inducing the neurotoxic effects. The neurotoxicity of 10 mu M acromel ic acid A was almost completely inhibited by 30 mu M 6-nitro-7-sulpham oylbenzo(F)quinoxaline-2,3-dione and 6-cyano-7-nitroquinoxaline-2,3-di one, potent antagonists for non-N-methyl-D-aspartate receptors, but wa s partly (35%) reduced by 30 mu M dizocilpine maleate. In cultured hip pocampal neurons, the toxicity of acromelic acid A was significantly l ess effective (EC(50): 18 mu M) than that in spinal neurons, whereas t he toxicity of kainic acid was almost the same in both neurons. These results suggest that acromelic acid A directly activates non-N-methyl- D-aspartate receptors on the cultured spinal neurons to induce neurona l death. A new type of non-N-methyl-D-aspartate receptors which is spe cific to acromelic acid A is suggested to be present at least in spina l neurons.