cgp-37849 and Cerebral-Infarction

The effect of the new competitive N-methyl-D-aspartate (NMDA) antagonist D-(E)-2-amino-4-methyl-5-phosphono-3-pentenoic acid (CAS 137424-81-8, CGP 40116) was examined in a cat model of focal cerebral ischemia. Effect of CGP 40116 was compared to that of another competitive NMDA antagonist, (+/-)-cis-4-phosphonomethyl-piperadine-2-carboxylic acid (CAS 110347-85-8, CGS 19755) under the same conditions. Drugs were administered intravenously 30 min before left middle cerebral artery (MCA) occlusion. After MCA occlusion for 8 h, infarction spreaded widely among caudate nucleus prepyriform cortex, amygdala and temporal lobe cortex in the ischemic hemisphere. CGP 40116 at the dose of 10 mg/kg and CGS 19755 at the dose of 30 mg/kg significantly decreased the infarcted area. CGP 40116 was effective in the frontal and central brain, although CGS 19755 showed neuroprotective effect in almost all sites. Thus, the compounds are potent neuroprotectants in focal ischemia.

Topics: 2-Amino-5-phosphonovalerate; Animals; Brain; Brain Ischemia; Cats; Cerebral Infarction; Excitatory Amino Acid Antagonists; Image Processing, Computer-Assisted; Male; Neuroprotective Agents; Pipecolic Acids; Receptors, N-Methyl-D-Aspartate

In the present study the in vitro and ex vivo distributions of [3H]dizocilpine binding sites in mouse brain after middle cerebral artery occlusion (MCA-O) were compared using receptor autoradiography. The distribution patterns of [3H]dizocilpine binding sites obtained in vitro and ex vivo in normal mouse brain were the same with the highest densities occurring in the hippocampus and cerebral cortex. MCA-O had little or no effect on the in vitro binding density for at least 24 hr post-ischaemia. However after 2-3 days binding densities in the region of infarct were significantly reduced compared to the contralateral cerebral cortex. Further reductions occurred after 5-7 days. By contrast ex vivo [3H]dizocilpine binding was reduced in the infarcted area by 78.7 +/- 4% within 2 hr of the ischaemic insult and at all subsequent times binding was reduced by more than 75%. Ex vivo binding after ischaemia was always less than 30% of in vitro binding and this decrease was apparent within 2 hr of the ischaemic insult whereas in vitro binding was maintained at control levels for at least 24 hr. The neuroprotective activity of the NMDA antagonists dizocilpine and CGP 37849 in this model at different times after MCA-O was assessed. The time scale for receptor access following MCA-O is discussed and it is suggested that although the population of NMDA receptors is maintained in the infarct region for some days access to them in vivo may be sufficiently impaired within 2 or 4 hr of ischaemic insult to reduce the neuroprotective activity of NMDA antagonists after this time.

Topics: 2-Amino-5-phosphonovalerate; Animals; Autoradiography; Binding Sites; Brain; Brain Ischemia; Cerebral Arteries; Cerebral Infarction; Dizocilpine Maleate; In Vitro Techniques; Male; Mice; Receptors, N-Methyl-D-Aspartate

Focal cerebral ischaemia was induced in rats by occlusion of the left middle cerebral artery. Two days later, infarct volume was determined by magnetic resonance imaging and the concentrations of the polyamines putrescine (PU), spermine and spermidine by HPLC. In control (occluded) animals, PU levels were elevated in infarcted and non-infarcted areas of the left hemisphere. Treatment with the ornithine decarboxylase (ODC) inhibitor alpha-difluoromethylornithine, prevented the ischaemia-induced increase in tissue PU without affecting infarct volume. Conversely, administration of the N-methyl-D-aspartate (NMDA) receptor antagonist CGP 40116 decreased cortical infarction without changing the tissue content of PU. We conclude that there is no direct link between NMDA receptor activation and brain PU, or PU and post-ischaemic tissue damage, and that inhibitors of ODC are not cerebroprotective in this animal model of stroke.

Topics: 2-Amino-5-phosphonovalerate; Animals; Brain; Brain Ischemia; Cerebral Infarction; Eflornithine; Magnetic Resonance Imaging; Male; Ornithine Decarboxylase Inhibitors; Polyamines; Putrescine; Rats; Rats, Inbred F344; Spermidine; Spermine