dizocilpine-maleate and Cerebrovascular-Disorders

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

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

Recent clinical trials with non-competitive and competitive N-methyl-D-aspartate (NMDA) receptor antagonists in patients with stroke have shown that these patients develop more adverse effects, particularly psychomimetic effects such as hallucinations and agitation, than normal volunteers at equivalent doses. We therefore examined whether such increased adverse effect potential of NMDA antagonists also occurs in a rat model of permanent focal ischemia. For this purpose, the right middle cerebral artery was occluded under halothane anesthesia, and behavioral alterations in response to the non-competitive NMDA antagonist, MK-801 (dizocilpine), were recorded after recovery from anesthesia. Behavioral alterations in ischemic rats were compared with those in sham-lesioned rats in a blinded fashion. MK-801 (0.4 mg/kg) induced psychomimetic-like stereotyped behaviors which were about twice as intense in ischemic than in non-ischemic rats. A similar trend for enhanced adverse effects was seen with the competitive NMDA antagonist CGS 19755 (Selfotel). Although more NMDA antagonists have to be tested to draw definite conclusions, the present data may indicate that enhanced sensitivity of stroke patients to adverse effects of NMDA antagonists can be predicted by use of a focal ischemia model in rats, thus allowing use of this model for developing novel cytoprotective strategies targeted to minimize glutamatergic excitotoxicity with reduced adverse effect potential.

Topics: Animals; Behavior, Animal; Binding, Competitive; Brain; Brain Ischemia; Cerebrovascular Disorders; Dizocilpine Maleate; Injections, Intraperitoneal; Male; Pipecolic Acids; Piperazines; Rats; Rats, Inbred Strains; Receptors, N-Methyl-D-Aspartate

Although N-methyl-D-aspartate (NMDA) antagonism may be a useful therapeutic approach in stroke treatment, it has been found that these pharmacological agents cause neuronal necrosis in restricted cortical regions of the rodent brain.. To test the hypothesis that age and sex influence NMDA antagonist-induced neuronal necrosis, male and female rats were studied at 2 months (young), 12 months (middle-aged), and 24 months (old) of age. A dose of 5 mg/kg MK-801 was administered, followed by quantitation of neuronal necrosis at nine coronal levels in the cingulate and retrosplenial cortex at 1 week of survival.. Mortality was dependent on age but not sex and was higher in the old rats (P<.01). The number of necrotic neurons per hemisphere was greater in female than in male rats at all ages (P<.0001). Female rats also showed increasing neuronal necrosis with age (P<.05).. The results indicate a major sex difference in neuronal cytotoxicity caused by NMDA antagonists and a minor increase in susceptibility with increasing age in females. The findings may be relevant to development of drugs with NMDA antagonist properties for use in human stroke.

Topics: Age Factors; Animals; Brain; Cerebrovascular Disorders; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Female; Gyrus Cinguli; Humans; Male; N-Methylaspartate; Necrosis; Neurons; Rats; Rats, Sprague-Dawley; Rats, Wistar; Sex Characteristics; Sex Factors

Topics: Animals; Cerebral Infarction; Cerebrovascular Disorders; Dizocilpine Maleate; Fibrinolytic Agents; Humans; Neuroprotective Agents

Experimental studies of stroke in animal models have traditionally relied on histological endpoints for the measurement of neuroprotection. In this study, we used in vivo and dynamic MRI to quantify the neuroprotective effects of the non-competitive NMDA antagonist MK801. Four hours of occlusion followed by 6 h of reperfusion was performed in a rabbit model of focal cerebral ischemia. Spin-echo T2-weighted (T2W) MRI was used to quantify ischemic lesion volumes. Hemispheric measurements of perfusion deficits were assessed by using dynamic susceptibility-contrast MRI to map the first-pass transit of injected GdDTPA. Histological correlates of infarction were quantified using tetrazolium staining. Animals treated with 2 mg/kg MK801 infused immediately post-occlusion (n = 6) were compared with untreated controls (n = 8). T2W MRI scans obtained after 6 h of reperfusion showed high-intensity lesions in the ischemic basal ganglia and cortex. MK801-treated animals showed significantly decreased lesion volumes compared to untreated controls (7.3 +/- 3.2% treated vs 20.7 +/- 4.8% control, p < 0.05). Lesion volumes measured with MRI were significantly correlated with tetrazolium-defined infarct volumes (r = 0.766, p = 0.004). Dynamic MRI demonstrated the phenomenon of delayed hypoperfusion in the ischemic hemisphere during the late reperfusion phase; relative cerebral blood volume (rCBV) was 45.2 +/- 10.3% in untreated animals. MK801 slightly improved these deficits although the differences did not reach statistical significance (rCBV = 77.0 +/- 9.7%, p = 0.128).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Brain Ischemia; Cerebrovascular Disorders; Coloring Agents; Disease Models, Animal; Dizocilpine Maleate; Magnetic Resonance Imaging; N-Methylaspartate; Neurons; Neuroprotective Agents; Rabbits; Tetrazolium Salts

We sought to extend the therapeutic window for acute stroke therapy using the combination of a glutamate antagonist and a GABA agonist, which in prior studies was effective if given 5 min after stroke. We used a quantal bioassay to measure neuroprotective potency after injection of several thousand microspheres into the cerebral circulation of rats. The GABA-A agonist muscimol, but not MK-801, was effective if given 30, 45, or 60 min after embolization (potency ratio compared with saline of 3.0, 2.3, 1.8, respectively). If muscimol was combined with MK-801 at lower doses of each drug, the combination was neuroprotective (potency ratio of 4.2). Agonists of GABA-A, but not GABA-B, receptors blocked the toxic vacuolization seen in the cingulate and retrosplenial cortex after MK-801 treatment. Combination chemotherapy appears to extend the time window for acute stroke therapy in rats to 1 h and to result in fewer side effects.

Topics: Animals; Brain; Cerebrovascular Disorders; Dizocilpine Maleate; Drug Therapy, Combination; Excitatory Amino Acid Antagonists; GABA Agonists; GABA-A Receptor Agonists; GABA-B Receptor Agonists; Male; Microspheres; Muscimol; Neuroprotective Agents; Rats; Rats, Sprague-Dawley; Time Factors; Vacuoles

A novel experimental model of stroke has been developed using the powerful vasoconstrictor peptide, endothelin-1, to occlude the middle cerebral artery (MCA) of anaesthetised rats. Intracerebral microinjections of endothelin-1 were administered under stereotaxic guidance adjacent to the MCA, and after 3 days rats were perfusion fixed for histopathological determination of ischaemic brain damage. The pattern of brain damage noted using this model was similar to that reported following permanent surgical occlusion of the MCA. Brain damage was apparent in the dorsal and lateral neocortex (98 +/- 12 mm3) and striatum (32 +/- 3 mm3) ipsilateral to the insult. Rats anaesthetised with halothane and barbiturate exhibited a similar volume of brain damage. However, infarct volume increased when the duration of halothane anaesthesia was extended from 5 to 180 min post-occlusion. Neuroprotection studies demonstrated that dizocilpine (5 mg/kg, i.p.), administered 30 min prior to MCA occlusion, reduced the volume of cortical brain damage by 51% (P < 0.05) but did not alter the volume of striatal brain damage. The present results demonstrate that microinjections of endothelin-1 adjacent to the rat MCA result in a reproducible pattern of focal cerebral infarction which is sensitive to the duration of anaesthesia and can be reduced by dizocilpine.

Topics: Anesthesia; Animals; Brain Ischemia; Cerebral Arteries; Cerebral Cortex; Cerebral Infarction; Cerebrovascular Disorders; Disease Models, Animal; Dizocilpine Maleate; Endothelins; Excitatory Amino Acid Antagonists; Injections, Intra-Arterial; Male; Microinjections; Rats; Rats, Sprague-Dawley; Stereotaxic Techniques

The cytoprotective effects of MK-801 and NBQX, selective N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor antagonists, respectively, were compared both singularly and in combination in models of transient severe forebrain and transient focal cerebral ischemia. After 10 minutes of four-vessel occlusion ischemia, the sodium salt of NBQX (30 mg/kg IP) given at the time of reperfusion and, subsequently, 15 and 30 minutes later produced a dramatic reduction in CA1 hippocampal necrosis at 7 days. This effect was not obtained with the intraperitoneal administration of either MK-801 (1 mg/kg x 3) or the combination of both NBQX and MK-801 given at the same time intervals. This effect of intraperitoneal NBQX alone was reproduced in a two-vessel occlusion/hypotension model using this same drug administration. Delayed treatment with both NBQX and GYKI 52466, but neither MK-801 nor the combination of NBQX and MK-801 given after a delay, produced a significant reduction in the mean volume of neocortical infarction after transient focal ischemia. We conclude that the AMPA receptor may play a more important role than the NMDA receptor in both selective ischemic necrosis of hippocampal neurons and in neocortical infarction. AMPA antagonists should be subjected to clinical stroke trials.

Topics: alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Animals; Anti-Anxiety Agents; Benzodiazepines; Cerebral Infarction; Cerebrovascular Disorders; Dizocilpine Maleate; Drug Administration Schedule; Injections, Intraperitoneal; Male; N-Methylaspartate; Quinoxalines; Rats; Rats, Wistar; Reperfusion

A focal, unilateral thrombotic stroke was produced in the rat sensorimotor cortex. The time course of expression and localization of the immediate early inducible genes: c-fos, c-jun, zif268; nerve growth factor, brain-derived neurotrophic factor and the related tyrosine kinase high-affinity receptor (trkB) messenger RNAs were studied by in situ hybridization. The levels of messenger RNAs for c-fos, zif268, brain-derived neurotrophic factor (but not nerve growth factor) and trkB were consistently increased in cortex ipsilaterally to the lesion, while c-jun messenger RNA content was only slightly increased. The brain-derived neurotrophic factor messenger RNA was increased from 2 to 18 h following the stroke, mainly in cells having a normal morphological appearance. The trkB messenger RNA displayed temporal and spatial increases similar to brain-derived neurotrophic factor messenger RNA. The time course and pattern of expression of immediate early inducible gene and trophic factor messenger RNAs did not clearly support a causal relationship between these two families of factors. The observed messenger RNA increases were greatly attenuated by the non-competitive N-methyl-D-aspartate-sensitive glutamate receptor antagonist (+)-5-methyl-10,11-dihydroxy-5H-dibenzo(a,d)cyclohepten-5,10-imine , but substantially unaffected by the non-N-methyl-D-aspartate receptor antagonist 2,3-dihydroxy-6-nitrosulphanoylbenzoquinoxaline. The results suggest a major contribution of N-methyl-D-aspartate-sensitive glutamate receptor activation to the transcriptionally directed events subsequent to stroke. Future studies should clarify the contribution of these processes to either the progression of neuronal degeneration or the establishment of protective compensatory responses.

Topics: Animals; Brain; Brain-Derived Neurotrophic Factor; Cerebrovascular Disorders; Dizocilpine Maleate; DNA-Binding Proteins; Early Growth Response Protein 1; Gene Expression; Genes, fos; Genes, jun; Immediate-Early Proteins; In Situ Hybridization; Kinetics; Male; Membrane Proteins; Nerve Growth Factors; Nerve Tissue Proteins; Photochemistry; Protein-Tyrosine Kinases; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-fos; Proto-Oncogene Proteins c-jun; Proto-Oncogenes; Quinoxalines; Rats; Rats, Sprague-Dawley; Receptor, Ciliary Neurotrophic Factor; RNA, Messenger; Rose Bengal; Time Factors; Transcription Factors

The non-competitive N-methyl-D-aspartate receptor/channel antagonist dizocilipine maleate (MK-801) has been reported to reduce infarct volume in a variety of focal stroke models. We examined the effect of MK-801 on infarct volume and cerebral blood flow in temporary and permanent focal ischemia in rats. In Wistar rats exposed to permanent right common carotid artery and 2 h of transient right middle cerebral and left common carotid artery occlusion followed by 22 h of reperfusion, MK-801 reduced infarct volume by 73% (P less than 0.05) and significantly increased cerebral blood flow to the ischemic core throughout the 2-h period of ischemia. In spontaneously hypertensive rats (SHRs) exposed to permanent right common carotid artery occlusion and 2 h of transient right middle cerebral artery occlusion followed by 22 h of reperfusion, MK-801 decreased infarct volume by 13% (P greater than 0.05) and increased cerebral blood flow to the penumbral region. In SHRs subjected to permanent right common carotid and middle cerebral artery occlusion MK-801 reduced infarct volume by 18% at 3 h (P greater than 0.05), by 25% at 6 h (P less than 0.01) and by 18% at 24 h (P less than 0.05). MK-801-treated SHRs had no difference in cerebral blood flow to the ischemic core, but increased cerebral blood flow to penumbral zones as compared with untreated SHRs. These results suggest that the protective effect of MK-801, at least in part, relates to improved cerebral blood flow.

Topics: Animals; Cerebral Infarction; Cerebrovascular Circulation; Cerebrovascular Disorders; Dizocilpine Maleate; Ischemic Attack, Transient; Male; Rats; Rats, Inbred Strains; Receptors, N-Methyl-D-Aspartate

Thrombolytic therapy is likely to be effective in some patients with stroke, but further improvements may require combination treatment with neuroprotective agents that can be given rapidly with relative safety. We tested the effects of tissue plasminogen activator (t-PA) with the glutamate antagonist MK-801 or the calcium channel blocker nimodipine in an embolic stroke model. We found that MK-801, followed by t-PA, was more effective than t-PA alone in reducing neurologic damage. Nimodipine plus t-PA was not better than t-PA alone. Combined glutamate antagonist and thrombolytic therapy may provide increased efficacy and safety for stroke treatment.

Topics: Animals; Cerebrovascular Disorders; Dizocilpine Maleate; Drug Therapy, Combination; Excitatory Amino Acid Antagonists; Glutamic Acid; Intracranial Embolism and Thrombosis; Nervous System Diseases; Nimodipine; Rabbits; Tissue Plasminogen Activator

The role of calcium as a mediator in neuronal death during ischemia is now quite strong. Evidence supporting this link includes studies in cell cultures and measurements of calcium accumulation in the mitochondria during ischemia, as well as direct measurements of shifts in extracellular calcium using microelectrodes. Since it is dangerously high concentrations of the intracellular free calcium that have been hypothesized to lead to neuronal damage, direct in vivo measurements of this parameter in ischemia are important. A technique for the measurement of intracellular free calcium is described, along with data from studies that dramatically demonstrate the time course of changes in intracellular free calcium induced by focal ischemia. Additional data are also presented that indicate that cellular damage can be attenuated by the use of agents that block calcium channels (nimodipine, which blocks voltage-sensitive calcium channels, and MK-801, which blocks receptor-operated channels) and support the concept that these agents owe their beneficial effects to their ability to reduce the accumulation of intracellular calcium.

Topics: Animals; Calcium; Cats; Cerebral Arteries; Cerebrovascular Circulation; Cerebrovascular Disorders; Cytosol; Dizocilpine Maleate; Electroencephalography; Ischemic Attack, Transient; Nimodipine

Topics: Anesthesia; Animals; Barbiturates; Cats; Cerebrovascular Disorders; Dibenzocycloheptenes; Disease Models, Animal; Dizocilpine Maleate; Dogs; Evaluation Studies as Topic; Humans; Primates; Rats

MK-801 is an indirect antagonist of the NMDA excitatory amino acid receptor which is being considered for possible clinical development for treatment of epilepsy and stroke. MK-801 was evaluated for its effects on regional brain energy metabolism by means of Sokoloff's 2-deoxyglucose (2-DG) autoradiography method. MK-801 produced dramatic alterations in regional energy metabolism, exciting Papez circuit and dopaminergic structures most intensely. The pattern of metabolic alterations was virtually indistinguishable from that previously described for the psychotomimetic drug of abuse, phencyclidine (PCP). It is concluded that MK-801 is at risk for possibly producing PCP-like psychotomimetic effects.

Topics: Animals; Anticonvulsants; Autoradiography; Brain; Cerebrovascular Disorders; Dibenzocycloheptenes; Dizocilpine Maleate; Energy Metabolism; Male; Phencyclidine; Rats; Rats, Inbred Strains