RESUMO
In the Western world, over 350,000 deaths and $30 billion in medical costs are attributed annually to stroke. Head and spinal cord trauma cause an estimated 250,000 deaths annually and result in medical costs of $15 billion. Although stroke and head/spinal cord trauma are leading causes of disability and death in humans, no adequate neuroprotective treatment is available. Glutamate antagonists derived from the quinoxa-linedione scaffold are as drug candidates for neuroprotection in stroke and trauma. Quinoxalinedione derivatives such as 2,3-dihydroxy-6- nitro-7-sulfamoylbenzo(f)quinoxaline and 6-(1H-imidazol-1-yl)-7-nitro-2,3-(1H,4H)-quinoxalinedione failed clinical trials because of insolu-bility and resulting nephrotoxicity. Introduction of a phosphonate group into the quinoxalinedione skeleton improves solubility and leaves potency for the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptor unchanged. Phosphonate quinoxalinedione derivatives ZK202000 and ZK200775 protected rodent brain against sequelae of permanent occlusion of the middle cerebral artery and head trauma. No major deleterious effects on motor coordination, cardiovascular, or respiratory systems were detected in doses required for neuroprotection. No psychotomimetic and no neurotoxic side effects, typical for N-methyl-D-aspartate antagonists, were observed following treatment with phosphonate quinoxalinediones.
RESUMO
The effects of quisqualic acid lesions of the nucleus basalis magnocellularis on short-term memory capacities of the rat have been investigated using the delayed matching and non-matching to position tasks. The lesions do not disrupt performance of either task by pretrained animals, but do disrupt the ability to acquire the non-matching contingency, and to reverse to the non-matching task when trained on the matching task. The unidirectional nature of the reversal deficit has been replicated. The generalized disruption of performance of either task by the muscarinic antagonist scopolamine was comparable in lesioned and control rats. The lesions were associated with extensive loss of acetylcholinesterase staining in the basal forebrain and in the neocortex, and 55% depletions of choline acetyltransferase activity in the neocortex but not in the hippocampus. These observations demonstrate that the cholinergic projection from nucleus basalis to the neocortex is not critical for normal short-term memory, but that lesions involving this system do disrupt specific types of conditional discrimination learning.
