Inciting excitotoxic cytocide among central neurons.

Here I have reviewed evidence from electron microscopic studies showing that each of several sustained limbic seizure syndromes is associated with a type of acute brain damage which is ultrastructurally indistinguishable from the brain damage induced by Glu and other excitotoxins. In addition, I have presented evidence that persistent stimulation of specific axonal tracts that use Glu as transmitter results in Glu-like excitotoxic degeneration of postsynaptic neurons innervated by such tracts. Phencyclidine and ketamine, which powerfully block the neurotoxicity of the Glu analog NMA, protect against seizure-related brain damage. This may be explained by either an anticonvulsant or antiexcitotoxic mechanism, or both. Recent evidence suggests that an excitotoxic mechanism (excessive activation of Glu/Asp receptors) may underlie both seizure-mediated and anoxic brain damage. The acute fulminating type of neuronal degeneration induced by Glu is a Na+ and Cl- but not Ca2+ dependent phenomenon. According to a recent study, however, Glu may induce neuronal necrosis not only by an acute Ca2+ independent process but by a more slowly evolving Ca2+ dependent process. If, as these data suggest, an excitotoxic mechanism underlies brain damage associated with anoxia and epilepsy, a better understanding of excitotoxic mechanisms may lead eventually to prophylactic approaches for preventing such forms of brain damage.

Tremor: role of striatal cholinergic neurons and the effect of intrastriatal kainic acid.

Rats injected intrastriatally with kainic acid (KA) showed increased tremor responses to arecoline and tremorine, but not to harmaline. Since KA significantly reduced both pre- and postsynaptic measurements of cholinergic function in the striatum, the results indicate that integrity of the striatal cholinergic system is not essential to tremor response. Further investigations of cholinergic function in the brains of rats injected with KA did not reveal evidence of cholinergic supersensitivity; thus, the altered responses to cholinergic agents may reflect KA-associated destruction of some pathway normally opposing the behavioral output of cholinergic stimulation. If, as recently proposed, intrastriatal injection of KA produces an animal model of Huntington's disease (HD), then these results may also be relevant to experimental therapeutics of this disorder.