HYPOXIA, EXCITOTOXICITY, AND NEUROPROTECTION IN THE HIPPOCAMPAL SLICEPREPARATION

The excitotoxic hypothesis postulates a central role for the excitator y amino acids (EAAs) and their receptors in the neuronal damage that e nsues cerebral ischemia-hypoxia and numerous other brain disorders. A major premise of the excitotoxic hypothesis is that neuronal protectio n can be achieved via blockade of EAA receptors with specific antagoni sts. This paper describes the use of the rat hippocampal slice prepara tion in the evaluation of various EAAs and their analogues for their p otency as excitotoxins (agonists) and antagonists of the NMDA and the kainate/AMPA glutamate receptor subtypes. The hypersensitivity of hypo xic hippocampal slices to the presence of excitotoxins provided us wit h an inexpensive, sensitive tool to distinguish between structurally s imilar compounds. Moreover, these studies indicate that hypoxic neuron al damage cannot solely result from an excitotoxic mechanism; the invo lvement of voltage-dependent calcium channels in such damage is likely , as is evident from experiments performed in calcium-depleted medium and with the non-competitve NMDA antagonist MK-801. At sub-toxic doses , quinolinate, a tryptophan metabolite implicated in Huntington's dise ase, appears to be a strong potentiator of the toxicity of all excitot oxins tested.