Hypoxia, excitotoxicity, and neuroprotection in the hippocampal slice preparation.
The excitotoxic hypothesis postulates a central role for the excitatory amino acids (EAAs) and their receptors in the neuronal damage that ensues cerebral ischemia-hypoxia and numerous other brain disorders. A major premise of the excitotoxic hypothesis is that neuronal protection can be achieved via blockade of EAA receptors with specific antagonists. This paper describes the use of the rat hippocampal slice preparation in the evaluation of various EAAs and their analogues for their potency as excitotoxins (agonists) and antagonists of the NMDA and the kainate/AMPA glutamate receptor subtypes. The hypersensitivity of hypoxic hippocampal slices to the presence of excitotoxins provided us with an inexpensive, sensitive tool to distinguish between structurally similar compounds. Moreover, these studies indicate that hypoxic neuronal damage cannot solely result from an excitotoxic mechanism; the involvement of voltage-dependent calcium channels in such damage is likely, as is evident from experiments performed in calcium-depleted medium and with the non-competitive NMDA antagonist MK-801. At sub-toxic doses, quinolinate, a tryptophan metabolite implicated in Huntington's disease, appears to be a strong potentiator of the toxicity of all excitotoxins tested.
D000818:Animals; D004305:Dose-Response Relationship, Drug; D018846:Excitatory Amino Acids / Q000494:pharmacology; D018698:Glutamic Acid / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects*; D000860:Hypoxia; D066298:In Vitro Techniques; D007608:Kainic Acid / Q000494:pharmacology; D008297:Male; D016202:N-Methylaspartate / Q000494:pharmacology; D018696:Neuroprotective Agents; D009498:Neurotoxins / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017470:Receptors, Glutamate / Q000187:drug effects
D018846:Excitatory Amino Acids; D018696:Neuroprotective Agents; D009498:Neurotoxins; D017470:Receptors, Glutamate; D018698:Glutamic Acid; D016202:N-Methylaspartate; D007608:Kainic Acid