dizocilpine-maleate and Arterial-Occlusive-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

To explore the action mechanism of Tongxinluo Capsule (TXL) in protecting brain from ischemic damage.. SD rats were divided into five groups randomly, the sham operation group, the model group, the MK-801 group, the large and low dosage TXL groups (TXLL and TXLS). After the middle cerebral arterial obstructive (MCAO) model was established, peritoneal injection of MK-801 0.5 mg/kg per day was given to the MK-801 group, and 1.0 g/(kg x d) and 0.5 g/(kg x d) of TXL powder was administered in twice via gastrogavage to the two TXL groups respectively. The nerve cell apoptosis rate, protein and mRNA expressions of Caspase-3, p53 and heat shock protein (HSP70) were observed using flow cytometry, Western blot and RT-PCR technique.. Both TXL and MK-801 could obviously lower the apoptosis rate in model rat (P < 0.05, P < 0.01), TXLL showed the optimal effect. Caspase-3, p53 protein and mRNA expression in the model group were obviously higher than those in the sham operated group. As compared with the model group, the expressions of Caspase-3 and p53 were lower and those of HSP70 and mRNA were higher in the two TXL and MK-801 groups (P < 0.05 or P < 0.01).. TXL displays it brain protective effect through reducing nerve cell apoptosis rate in MCAO model rats, the mechanism may be related to its actions in inhibiting apoptosis related factors Caspase-3 and p53, and promoting stress protecting factor HSP70.

Topics: Animals; Apoptosis; Arterial Occlusive Diseases; Blotting, Western; Brain Ischemia; Capsules; Caspase 3; Cerebral Arteries; Disease Models, Animal; Dizocilpine Maleate; Drugs, Chinese Herbal; Male; Neurons; Neuroprotective Agents; Random Allocation; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Tumor Suppressor Protein p53

1. The purpose of the present study was to investigate the effect of bilateral common carotid artery occlusion (BCCAO) on cardiovascular responses and nitric oxide (NO) formation in the nucleus tractus solitarius (NTS). 2. Twenty-three adult cats were anaesthetized intraperitoneally with urethane (400 mg/kg) and alpha-chloralose (40 mg/kg). The femoral artery was cannulated to allow monitoring of systemic arterial pressure (SAP) and heart rate (HR). The femoral vein was cannulated for intravenous drug administration. 3. Extracellular NO levels in the NTS were measured by in vivo voltammetry using an NO microsensor combined with a microcomputer-controlled apparatus. 4. Microinjection of l-arginine (30 nmol) into the NTS produced hypotension and NO release. This effect of l-arginine was not changed by 2 min of BCCAO. 5. Bilateral common carotid artery occlusion produced increases in SAP and NO levels. These effects were more apparent in vagotomized than in intact animals. 6. The onset latency of BCCAO-induced changes in SAP levels (8.4 +/- 2.5 s) was longer than that for changes in NO (4.7 +/- 1.7 s). 7. Bilateral common carotid artery occlusion induced hypertension and NO release in the NTS of intact and vagotomized animals. These cardiovascular and NO responses to BCCAO were significantly attenuated by NG-nitro-l-arginine methyl ester (10 mg/kg, i.v.) and MK-801 (2.5 mg/kg, i.v.). These data suggest that NO synthase and activation of N-methyl-d-aspartate receptors are involved in the cardiovascular and NO responses to BCCAO.

Topics: Animals; Arterial Occlusive Diseases; Blood Pressure; Carotid Artery Diseases; Carotid Artery, Common; Cats; Dizocilpine Maleate; Female; Hypertension; Male; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Receptors, N-Methyl-D-Aspartate; Solitary Nucleus; Time Factors

Levetiracetam (LEV) is a new antiepileptic drug with a promising preclinical profile involving both anticonvulsant and antiepileptogenic effects in kindling models. The latter stimulated the present study to compare its neuroprotective properties with the potent and selective, non-competitive NMDA antagonist, MK-801, in the rat middle cerebral artery occlusion model. Twenty-four hours after a transient occlusion of 90 minutes the animals were sacrificed and infarct volume and lesion distribution were determined from stained coronal sections. LEV was administered by intraperitoneal (i.p.) bolus injections of 5.5, 11, 22 and 44 mg x kg(-1), 30 minutes before occlusion followed by a continuous 24 hour i.p. infusion of 1.25, 2.6, 5.1 and 10.2 mg x kg(-1) per hour, respectively. LEV administration did not alter body temperature but reduced the infarct volume by 33% (P< 0.05) at the highest dose tested. An i.p. bolus injection of 0.04, 0.12 and 0.4 mg x kg(-1) of MK-801 followed by continuous i.p. infusion of 0.036, 0.108 and 0.36 mg x kg(-1) per hour, reduced the infarct volume by 49, 51 and 74% (P< 0.05), respectively. However, only the highest dose of MK-801 induced a significant reduction in the infarct volume (P< 0.05) and this was associated with hypothermia. These results suggest that LEV possesses neuroprotective properties which may be relevant for its antiepileptogenic action.

Topics: Animals; Anticonvulsants; Arterial Occlusive Diseases; Body Temperature; Brain; Brain Ischemia; Cerebrovascular Circulation; Disease Models, Animal; Dizocilpine Maleate; Levetiracetam; Male; Middle Cerebral Artery; N-Methylaspartate; Neuroprotective Agents; Piracetam; Rats; Rats, Wistar

The contribution of glutamatergic and dopaminergic mechanisms to bladder hyperactivity after left middle cerebral artery occlusion was evaluated by determining the effects of intravenous cumulative doses of an N-methyl-D-aspartate (NMDA) glutamatergic antagonist (MK-801) and D1-selective (Sch-23390), D2-selective (sulpiride), or nonselective (haloperidol) dopaminergic antagonists on bladder activity in sham-operated (SO) and cerebral-infarcted (CI) rats. MK-801 (1 and 10 mg/kg) or sulpiride (3-30 mg/kg) significantly increased bladder capacity (BC) in CI but decreased or had no effect, respectively, on BC in SO. Sch-23390 (0.1-3 mg/kg) decreased BC in both SO and CI. In both CI and SO, low doses of haloperidol (0.1-1 mg/kg) increased BC, but a higher dose (3 mg/kg) reversed this effect. Administration of haloperidol (0.3 mg/kg) or sulpiride (10 mg/kg) in combination with MK-801 (0.01-10 mg/kg) markedly increased BC in CI but produced small decreases or increases in BC depending on the dose of MK-801 in SO. These results indicate that the bladder hyperactivity induced by cerebral infarction is mediated in part by NMDA glutamatergic and D2 dopaminergic excitatory mechanisms.

Topics: Animals; Arterial Occlusive Diseases; Benzazepines; Cerebral Infarction; Cerebrovascular Disorders; Dizocilpine Maleate; Dopamine; Dopamine Antagonists; Drug Interactions; Excitatory Amino Acid Antagonists; Female; Glutamic Acid; Haloperidol; Rats; Rats, Sprague-Dawley; Sulpiride; Urinary Bladder; Urinary Bladder, Neurogenic

Two patterns of transforming growth factor-beta1 (TGF-beta1) expression were identified in brains of normotensive rats following permanent occlusion of the middle cerebral artery (MCAO). First, a relative increase of TGF-beta1 mRNA by 37% was found at 12 h after MCAO in the ipsilateral cingulate cortex as compared to the homotopic contralateral region. The cingulate cortex is located distant from the ischemic territory. Treatment with the glutamate receptor antagonists MK-801 and NBQX did not reduce this expression (34% and 26% increase, respectively). Therefore, peri-infarct depolarization waves were probably not responsible for induction. Secondly, an increase of TGF-beta1 mRNA by 116% was found at 7 days after MCAO within infarcted tissue. This expression was not reduced by the glutamate receptor antagonists MK-801 (increase 140%) and NBQX (increase 137%), either. TGF-beta1 mRNA expression in the cingulate cortex at 12 h after MCAO is possibly mediated by neurons and astroglia and may support cell survival. Expression in the infarcted tissue at 7 days after MCAO is most likely related to the invasion of monocytes and may be involved in the downregulation of inflammatory events, in neoangiogenesis, and in formation of a glial scar around the infarct.

Topics: Animals; Arterial Occlusive Diseases; Brain; Cerebral Arteries; Chronic Disease; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Male; Quinoxalines; Rats; Rats, Inbred F344; RNA, Messenger; Transforming Growth Factor beta

The effect of middle cerebral artery (MCA) occlusion on the activity-regulated cytoskeleton-associated protein (Arc) mRNA expression has been investigated using in situ hybridization. It was induced in the extensive regions of cerebral cortex, medial striatum, and distant areas such as the ipsilateral lateral septal nucleus, bilateral hippocampal formation and contralateral amygdala following MCA occlusion. In the hippocampal formation, it was induced in the granule cell layer and the stratum pyramidale at 1 h and in the molecular layer and in the stratum oriens and stratum radiatum bilaterally at 4 h. MK-801 pretreatment strongly attenuated the induction of Arc mRNA. The present results suggest that Arc may play an important role in the neuronal plasticity through NMDA activation following focal cerebral ischemia.

Topics: Animals; Arterial Occlusive Diseases; Autoradiography; Cytoskeletal Proteins; Dendrites; Dizocilpine Maleate; DNA Probes; Excitatory Amino Acid Antagonists; Genes, Immediate-Early; In Situ Hybridization; Ischemic Attack, Transient; Male; Middle Cerebral Artery; Nerve Tissue Proteins; Rats; Rats, Sprague-Dawley; RNA, Messenger

The response of microglia and astrocytes, as detected immunohistochemically by the monoclonal antibody OX-42 and anti-glial fibrillary acidic protein (GFAP) respectively, was studied in the rat lumbar spinal cord following focal cerebral ischaemia produced by permanent occlusion of the middle cerebral artery (MCA) above the rhinal fissure. At 1 and 2 days after right-sided MCA occlusion, OX-42 immunoreactivity of microglia in both the contralateral dorsal and ventral horns of the lumbar spinal cord was moderately increased compared with cells of the ipsilateral side. The microglial reaction was progressive, with some cells transformed into amoeboid form considered to be macrophages at day 3. By 5 days, many of the reactive microglia, notably in the ventral horn, appeared to encircle the soma of motoneurons. At 7 days, the microglial reaction had subsided while astrocytes in the same area were hypertrophied to replace the perineuronal microglia. The microglial response in both the cerebral cortex and lumbar spinal cord was effectively reduced by the N-methyl-D-aspartate (NMDA) receptor antagonist, MK-801. Present results suggest that following MCA occlusion, the vigorous response of microglia, and subsequently astrocytes, in the spinal cord in extra-focal areas far removed from the primary site of ischaemia may be mediated by glutamate released from the ischaemic corticospinal neurons through NMDA receptors on the postsynaptic spinal cord neurons.

Topics: Animals; Arterial Occlusive Diseases; Astrocytes; Cerebral Arteries; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Immunohistochemistry; Ischemic Attack, Transient; Lumbosacral Region; Male; Microglia; Rats; Rats, Wistar; Spinal Cord

The neuroprotective activity of the novel, selective glycine antagonist GV150526 was assessed in the middle artery occlusion (MCAo) model of focal ischemia. Postischemia administration of GV150526 (3 mg/kg i.v.) up to 6 h post-MCAo resulted in a significant reduction of the infarct volume measured histologically 24 h later. The neuronal protection by GV150526 was accompanied by functionally significant protection determined by somatosensory evoked potential (SEP) responses recorded from the primary somatosensory cortex of rats under urethane anesthesia. Experimental occlusion of the MCA 7 days prior to electrophysiological testing induced a clear reduction in the SEP amplitude. GV150526 (3mg/kg, i.v.) was able to protect SEP responses recorded from the hindpaw cortical field in two groups of animals treated either 1 (n = 9) or 6 h (n = 10) post-MCAo. SEP responses recorded from the forepaw cortical field, an area closer to the core of the ischemic damage, were significantly protected only in the group treated 1 h post-MCAo. Histological evaluation of the rat brain regions showed a correlated decrease in the ischemic area of GV150526-treated groups. The volumes of the ischemic brains of both GV150526 groups were statistically different from the MCAo group (P < 0.05). These findings demonstrate that GV150526 is able to prevent the ischemic damage assessed histologically and affect the functional correlates of the ischemia evaluated by the electrophysiological SEP measurements.

Topics: Animals; Arterial Occlusive Diseases; Brain Ischemia; Cerebral Infarction; Disease Models, Animal; Dizocilpine Maleate; Electric Stimulation; Evoked Potentials, Somatosensory; Excitatory Amino Acid Antagonists; Forelimb; Glycine Agents; Hindlimb; Indoles; Male; Neuroprotective Agents; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Somatosensory Cortex

Following cerebral ischemia, the extracellular concentration of excitatory amino acids increases, and the excitatory cell death may play an important role contributing to ischemic neuronal damage. Although sequential metabolic changes in permanent local cerebral ischemia have been reported, the effect of reperfusion in local cerebral ischemia on glucose metabolism is less clear. In order to investigate the time course change of glucose metabolism in a middle cerebral artery occlusion-reperfusion model and the effect of dizocilpin (MK-801) on glucose metabolism, the 14C-Deoxyglucose method was used. Hypermetabolism occurred at 30 min after the middle cerebral artery (MCA) occlusion, and reached a peak at 60 min after ischemia in both ischemic core and penumbra. The shift from hyper- to hypometabolism was observed after the ischemia. The reperfusion facilitated the decrease of cerebral glucose metabolism in the ischemic region following 2 h of MCA occlusion. The pretreatment of MK-801 (0.4 mg kg-1) inhibited both increased glucose metabolism during ischemia and decreased glucose metabolism during reperfusion. These findings support the hypothesis that excitation-induced hyper-metabolism plays a major role in the ischemic insult following focal cerebral vascular occlusion.

Topics: Animals; Arterial Occlusive Diseases; Blood Gas Analysis; Blood Glucose; Body Temperature; Brain Chemistry; Brain Ischemia; Cerebral Arteries; Disease Models, Animal; Dizocilpine Maleate; Glucose; Male; Neuroprotective Agents; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Reperfusion Injury; Time Factors

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

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

The functional integrity of the N-methyl-D-aspartate receptor complex following focal cerebral ischemia in the rat has been examined at a time when brain tissue is irreversibly damaged. Twelve hours after unilateral permanent middle cerebral artery occlusion, [3H]-MK-801 binding was not significantly altered in the ischemic cerebral cortex compared to sham-operated animals. Moreover, the enhancement of [3H]MK-801 binding by exogenous glutamate was preserved in an area of the brain that was permanently damaged by the ischemic insult.

Topics: Animals; Arterial Occlusive Diseases; Brain; Brain Ischemia; Cerebral Arteries; Dibenzocycloheptenes; Dizocilpine Maleate; Glutamates; Glutamic Acid; Male; Rats; Rats, Inbred Strains; Receptors, N-Methyl-D-Aspartate; Receptors, Neurotransmitter

The neuroprotective effects of MK-801, a noncompetitive antagonist of N-methyl-D-aspartate (NMDA) receptors, were evaluated in models of cerebral ischemia using Mongolian gerbils. Bilateral occlusion of the carotid arteries for a period of 5 min resulted in a consistent pattern of degeneration of hippocampal CA1 and CA2 pyramidal neurons, which was quantified using an image analyzer. Systemic administration of MK-801 (0.01-10 mg/kg, i.p.) 1 hr prior to the occlusion caused a dose-dependent protection of the CA1 and CA2 neurons. The ED50 value for neuroprotection by MK-801 was calculated to be 0.3 mg/kg, and at doses greater than or equal to 3 mg/kg the majority of animals were completely protected against the ischemic insult. Systemic administration of MK-801 (1 or 10 mg/kg, i.p.) 1 hr prior to unilateral occlusion of the right carotid artery resulted in significant protection against hippocampal neurodegeneration following 10 min of occlusion, and increased the survival rate after 30 min of occlusion. The potent neuroprotective effects of MK-801 in these cerebral ischemia models add further weight to the evidence that NMDA receptors are involved in the mechanism of ischemia-induced neuronal degeneration.

Topics: Animals; Arterial Occlusive Diseases; Brain Ischemia; Carotid Artery Diseases; Dibenzocycloheptenes; Dizocilpine Maleate; Female; Gerbillinae; Hippocampus; Male; Nerve Degeneration