dizocilpine-maleate and Cerebral-Arterial-Diseases

Topics: Animals; Arterial Occlusive Diseases; Calcium; Cell Survival; Cerebral Arterial Diseases; Cerebrovascular Disorders; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Glutamates; Glutamic Acid; Humans; Intracranial Embolism and Thrombosis; Neurons; Pipecolic Acids; Receptors, N-Methyl-D-Aspartate; Tissue Plasminogen Activator; Tomography, Emission-Computed

Topics: Animals; Catecholamines; Central Nervous System; Cerebral Arterial Diseases; Disease Models, Animal; Dizocilpine Maleate; Glutamates; Humans; Middle Cerebral Artery; Models, Neurological; Neuroprotective Agents; Rats; Receptors, N-Methyl-D-Aspartate; Stroke

Delayed neuronal damage in the ischemic region of the rat brain following middle cerebral artery (MCA) occlusion in stroke-prone spontaneously hypertensive rats was studied. The distribution of neuronal damage was determined by 45Ca autoradiography. Accumulation of 45Ca was observed in the corpus callosum and ipsilateral cerebral cortex immediately following MCA occlusion. After 3 days of occlusion, 45Ca had accumulated in the ipsilateral pyramidal tract, the ventral posterior nucleus of the thalamus, and the lateral portion of the striatum. Significant accumulation of 45Ca was observed in the same areas after 7 and 14 days of occlusion. Next the effect of MK-801 on accumulation of 45Ca after MCA occlusion was examined using the same technique. MK-801 (0.5-10 mg/kg i.v.) or saline was administered 15 min before MCA occlusion, and volumes of accumulation of 45Ca were calculated 1 week after ischemic insults. MK-801 significantly reduced 45Ca uptake in the cortex, striatum, and thalamus. Furthermore, there was a strong statistical correlation between the volume of accumulation of 45Ca in the cortex and that in the thalamus (r = 0.8974; p < 0.001; n = 25). We speculate that delayed neuronal damage in the corpus callosum, ipsilateral pyramidal tract, and thalamus may be caused by secondary neuronal degeneration. However, neuronal damage in the striatum, a segment not supplied by the MCA, may be related to excessive release of glutamate.

Topics: Animals; Arterial Occlusive Diseases; Autoradiography; Blood Pressure; Brain; Calcium; Cerebral Arterial Diseases; Dizocilpine Maleate; Male; Neurons; Rats; Rats, Inbred SHR; Time Factors

Cortical spreading depression (CSD) is a transient depression of neuronal activity that spreads across the cortical surface. In the present studies, we have investigated CSD activity in the penumbral zone following permanent middle cerebral artery (MCA) occlusion in the rat (n = 16/group), using double-barreled Ca(2+)-sensitive microelectrodes. Measurements of CSD activity were made for 3 h in each animal. During this time, a varying number of spontaneous CSDs were seen in the control group (total was 30, with a range of 0-7/rat). These CSDs were of varying duration: "small" (approximately 1 min) and "big" (5-45 min) CSDs. During a CSD, the extracellular [Ca2+] decreased to 0.11 +/- 0.07 mM (mean +/- SD). After 3 h, the extracellular [Ca2+] in the cortex (penumbral zone) was either normal (10/16 rats) or lowered to 0.5 mM (2/16 rats) or to 0.1 mM (4/16 rats). In the caudate nucleus (ischaemic core area), all rats had an extracellular [Ca2+] of approximately 0.1 mM when measured after the 3 h recording period. Neuropathological evaluation of the brains of the animals, which had been allowed to survive for 24 h after MCA occlusion, revealed ischaemic damage in the dorsolateral cortex and caudate nucleus. Administration of the noncompetitive NMDA antagonist, MK-801 (3 mg/kg i.p.), 30 min after MCA occlusion resulted in 24 and 29% reductions in the volume of hemispheric and cortical damage, respectively, which was highly significant (p less than 0.0001); no protection was seen against caudate damage.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Brain Ischemia; Calcium; Cerebral Arterial Diseases; Cerebral Cortex; Dizocilpine Maleate; Male; Rats; Rats, Inbred Strains; Synaptic Transmission; Tissue Survival

Following permanent occlusion of the left middle cerebral artery (MCA) in rats, electrophysiological and hemodynamic characteristics of the periinfarct border zone were investigated in sham-operated (n = 6), untreated (n = 6), and MK-801-treated (3.0 mg/kg; n = 6) animals. For this purpose, direct current potential (DC), EEG, and blood flow (laser-Doppler flowmetry) were recorded from the cortex in the periphery of the MCA territory. In sham-operated rats, a single negative cortical DC deflection was observed after electrocoagulation of the cortex, whereas in untreated MCA-occluded animals, three to eight transient DC deflections were monitored during the initial 3 h of ischemia. The duration of these cortical DC shifts gradually increased from 1.2 +/- 0.3 to 3.7 +/- 2.7 min (mean +/- SD; p less than 0.05) during this time. In animals treated intraperitoneally with MK-801 (3.0 mg/kg) immediately after MCA occlusion, the number of cortical DC shifts significantly declined to one to three deflections (p less than 0.005). The EEG of the treated animals revealed low-amplitude burst-suppression activity. In the untreated and treated experimental group, the reduction of cortical blood flow amounted to 69 +/- 25 and 49 +/- 13% of control, respectively. Despite the more pronounced cortical oligemia, MK-801 treatment resulted in a significant decrease of the volume of the ischemically injured tissue from 108 +/- 38.5 (untreated group) to 58 +/- 11.5 (p less than 0.05) mm3. Our results suggest that repetitive cortical DC deflections in the periinfarct border zone contribute to the expansion of ischemic brain infarcts.

Topics: Action Potentials; Animals; Arterial Occlusive Diseases; Brain Ischemia; Cerebral Arterial Diseases; Cerebral Cortex; Cerebrovascular Circulation; Dizocilpine Maleate; Electroencephalography; Male; Rats

1. An acute model of focal ischaemia, which involves permanent occlusion of the middle cerebral artery of the rat with 4 h survival, was used to find the minimum effective plasma concentration of dizocilpine (MK-801) and to determine its dose-effect relationship. 2. MK-801 was administered at the time of occlusion and was given as an i.v. bolus followed by an infusion for 4 h to maintain a steady state plasma concentration of the drug throughout the study. MK-801 was given at 3 dose levels; 0.04 mg kg-1 i.v. bolus + 0.6 micrograms kg-1 min-1 infusion; 0.12 mg kg-1 i.v. bolus + 1.8 micrograms kg-1 min-1 infusion; 0.4 mg kg-1 i.v. bolus + 6 micrograms kg-1 min-1 infusion, which gave mean plasma levels over the 4 h of 8.0 ng ml-1, 18.9 ng ml-1 and 113.2 ng ml-1 respectively. 3. MK-801 at 8.0 ng ml-1 gave 10% reduction in the volume of ischaemic brain damage in the cerebral cortex which just reached significance. The middle dose of MK-801 (18.9 ng ml-1) gave a highly significant reduction in the volume of ischaemic brain damage in the cerebral cortex and hemisphere, volumes of ischaemic tissue being reduced by 60% and 50% compared to saline-treated animals, respectively. The highest plasma concentration of MK-801 (113.2 ng ml-1) resulted in a 35% reduction in the volume of hemispheric damage and a 40% reduction in the volume of cortical damage, which were significant.4. The reduction in the amount of protection afforded by the highest dose of MK-801 may be due to the hypotensive effect of this dose. There was no protection against the volume of damage in the caudate nucleus for any of the doses of MK-801 tested.5. Therefore the minimum effective plasma concentration of MK-801 was 8.0 ngml1, although the greatest protection was seen with a plasma level of 18.9 ng ml- 1. This correlates well with the concentration of MK-801 required to block N-methyl-D-aspartate (NMDA) receptors and prevent NMDA receptor mediated neurotoxicity in vitro.

Topics: Animals; Brain Ischemia; Cerebral Arterial Diseases; Dizocilpine Maleate; Dose-Response Relationship, Drug; Male; Rats; Rats, Inbred Strains