We evaluated several doses of cis-4-(phosphonomethyl)-2-piperidine-carboxylic acid (CGS-19755), a potent competitive N-methyl-D-aspartate (NMDA) receptor antagonist, systemically administered either before or after 20 to 30 minutes of global ischemia in rats. We measured outcome by mortality, histological damage by light microscopy, and learning ability on an eight-arm maze, and determined the drug's mechanism of action by an immunohistochemical assay of calcium-calmodulin binding. High-dose treatment begun prior to ischemia resulted in reduced cellular damage in severely ischemic hippocampal tissue, but also caused high mortality due to respiratory depression. Treatment begun 30 minutes after ischemia resulted in little histological protection but significantly improved learning ability when tested 1 month after ischemia, and did not increase mortality. Furthermore, CGS-19755, 10 mg/kg intraperitoneally, begun either before or after ischemia substantially reduced calcium influx into ischemic neurons as evidenced by reduced calcium-calmodulin binding. We conclude that CGS-19755 prevents calcium entry into ischemic neurons and may be effective therapy for very acute cerebral ischemia.

Summ ary: Since ionic Ca 2 + binds with intracellular cal modulin (CaM) before activating proteases, kinases, and phospholipases, demonstration of persistent Ca 2 + -CaM binding in neurons destined to show ischemic cellular in jury would support the concept that elevated intracellular Ca2+ plays a causative role in ischemic neuronal damage. In order to characterize Ca 2 + -CaM binding, we used a sheep anti-CaM antibody (CaM-Ab) which recognizes CaM that is not bound to Ca 2 + or brain target proteins. Therefore, immunohistochemical staining of brain sec tions by labeled CaM-Ab represented only unbound CaM. Six normal rats were compared to 15 animals ren dered ischemic for 30 min by a modification of the four vessel occlusion model. Animals were killed immediately after ischemia, and after 2 and 24 h of reperfusion. Brain sections through hippocampus were incubated in CaM Ab, and a diaminobenzadiene labeled anti-sheep second ary antibody was added to stain the CaM-Abo Staining in the endal limb of dentate, dorsal CAl, lateral CA3, and parietal cortex was graded on a 4-point scale. All normal This study describes intraneuronal calcium calmodulin binding in a commonly used in vivo model of global cerebral ischemia. The project was undertaken for two reasons. It is now commonly accepted that calcium entry into neurons and re lease of stored intracellular calcium are pivotal events leading to irreversible cellular damage dur ing the reperfusion phase following an ischemic in sult. In the last several years many laboratories have demonstrated increased calcium in brain and in neurons after cerebral ischemia using a variety of

Presynaptic release of glutamate into the extracellular compartment and activation of receptor-operated calcium channels may contribute to ischemic neuronal damage. We evaluated the effect of baclofen, a selective inhibitor of presynaptic glutamate release, on mortality, working memory, and light microscopic hippocampal and cortical damage in the four-vessel occlusion model of cerebral ischemia using 64 male Wistar rats. Baclofen (10 mg/kg i.p.) given 1 hour before and 30-60 minutes after 20 minutes of global ischemia did not lessen mortality, prevent ischemic cellular damage, or significantly improve working memory compared with no treatment. We conclude that preischemic and postischemic administration of baclofen does not protect neurons from ischemic injury.

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A variety of eyelid movement abnormalities have been attributed to lesions of the central nervous system. Apraxia of lid movements, and especially of lid opening, has received the least attention. We present 2 cases of lid opening apraxia and propose that this abnormality may be due to right hemisphere dysfunction.