dizocilpine-maleate and Brain-Diseases

Many N-methyl-D-aspartate (NMDA) antagonists cause vacuolization and necrosis in the posterior cingulate/retrosplenial (PC/RS) cortex of rats after single-dose administration. This article reviews a series of investigational studies that have characterized this effect. All the studies have used single doses of MK-801 in rats. Techniques employed were light microscopy, transmission electron microscopy, quantitative enzyme-linked immunosorbent assay (ELISA), and cell counting. Our studies demonstrated: (1) formation of vacuoles within 30 minutes of treatment, (2) dose-dependent necrosis of susceptible PC/RS neurons, (3) increased glial fibrillary acidic protein in response to neuronal necrosis, (4) significantly greater necrosis in female than in male rats, and (5) increases in necrosis along a rostrocaudal gradient within the PC/RS cortex. In addition, these studies illustrate a number of variables that impact the expression and detection of neuronal vacuolization and necrosis in rats after treatment with MK-801.

Topics: Animals; Brain Diseases; Cerebral Cortex; Dizocilpine Maleate; Female; Male; Rats

Compelling animal and clinical studies support the N-methyl-D-aspartate receptor (NMDAR) hypofunction hypothesis of schizophrenia and suggest promising pharmacological agents to ameliorate negative and cognitive symptoms of schizophrenia, including sarcosine, a glycine transporter-1 inhibitor.. It is imperative to evaluate the therapeutic potential of sarcosine in animal models, which provide indispensable tools for testing drug effects in detail and elucidating the underlying mechanisms. In this study, a series of seven experiments was conducted to investigate the effect of sarcosine in ameliorating behavioral deficits and the underlying mechanism in pharmacological (i.e., MK-801-induced) and genetic (i.e., serine racemase-null mutant (SR. In Experiment 1, the acute administration of 500/1000 mg/kg sarcosine (i.p.) had no adverse effects on motor function and serum biochemical responses. In Experiments 2-4, sarcosine significantly alleviated MK-801-induced (0.2 mg/kg) brain abnormalities and behavioral deficits in MK-801-induced and SR. Sarcosine effectively regulated the surface trafficking of NMDARs, NMDAR-evoked electrophysiological activity, brain glycine levels and MK-801-induced abnormalities in the brain, which contributed to the amelioration of behavioral deficits in mouse models of NMDAR hypofunction.

Topics: Animals; Behavioral Symptoms; Brain Diseases; Disease Models, Animal; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Glycine Plasma Membrane Transport Proteins; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Racemases and Epimerases; Receptors, N-Methyl-D-Aspartate; Sarcosine; Schizophrenia

In the developing mammalian brain, inhibition of NMDA receptor can induce widespread neuroapoptosis, inhibit neurogenesis and cause impairment of learning and memory. Although some mechanistic insights into adverse neurological actions of these NMDA receptor antagonists exist, our understanding of the full spectrum of developmental events affected by early exposure to these chemical agents in the brain is still limited. Here we attempt to gain insights into the impact of pharmacologically induced excitatory/inhibitory imbalance in infancy on the brain proteome using mass spectrometric imaging (MSI). Our goal was to study changes in protein expression in postnatal day 10 (P10) rat brains following neonatal exposure to the NMDA receptor antagonist dizocilpine (MK801). Analysis of rat brains exposed to vehicle or MK801 and comparison of their MALDI MS images revealed differential relative abundances of several proteins. We then identified these markers such as ubiquitin, purkinje cell protein 4 (PEP-19), cytochrome c oxidase subunits and calmodulin, by a combination of reversed-phase (RP) HPLC fractionation and top-down tandem MS platform. More in-depth large scale study along with validation experiments will be carried out in the future. Overall, our findings indicate that a brief neonatal exposure to a compound that alters excitatory/inhibitory balance in the brain has a long term effect on protein expression patterns during subsequent development, highlighting the utility of MALDI-MSI as a discovery tool for potential biomarkers.

Topics: Animals; Animals, Newborn; Biomarkers; Brain; Brain Chemistry; Brain Diseases; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Gene Expression Regulation; Mass Spectrometry; Nerve Tissue Proteins; Proteomics; Rats; Rats, Wistar

Abstract We have investigated the role of Ca2+ accumulation and neuronal injury in cerebellar granule neurons after glutamate receptor overactivation. After the removal of the free cytosolic Ca2+ we identified an extensive second Ca2+ fraction (SCF) that is retained within the neurons after glutamate receptor overactivation. The SCF reaches a plateau within 10 min with the magnitude of this SCF accumulation reflecting the extent of the neuronal injury that occurs within the neurons. The existence of this SCF is sensitive to both NMDA receptor antagonists and mitochondrial inhibitors but is unaffected by agents that deplete endoplasmic reticulum Ca2+, indicating that this Ca2+ fraction may be located within the mitochondria. Through the isolation of mitochondria from cerebellar granule neurons treated with glutamate we have shown that the majority of the SCF is mitochondrial in location. On the removal of the glutamate stimulus the SCF recovers at a slower rate than the free Ca2+ concentration within the neuron. This is intriguing, as it implies a capacity to remember previous excitatory events. Most significantly we have shown that a short pre-application of subthreshold glutamate or kainate blocks both SCF Ca2+ accumulation and extensive neuronal injury in response to high concentrations of glutamate. These findings may be relevant to the observations of pre-conditioning in the brain and heart.

Topics: Age Factors; Alamethicin; Analysis of Variance; Animals; Animals, Newborn; Brain Diseases; Calcium; Calcium Isotopes; Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone; Cell Count; Cell Death; Cell Fractionation; Cells, Cultured; Cerebellum; Diagnostic Imaging; Dizocilpine Maleate; Dose-Response Relationship, Drug; Drug Interactions; Enzyme Inhibitors; Excitatory Amino Acid Antagonists; Female; Fura-2; Glutamic Acid; Glycine; Hydro-Lyases; Indoles; Intracellular Space; Ionophores; Male; Mitochondria; Neurons; Propidium; Quinoxalines; Rats; Rats, Wistar; Time Factors

We examined the expression of TNF-alpha within the substantia nigra pars reticulata (SNR) following intrastriatal injection of quinolinic acid (QA) and studied the effect of rolipram, a TNF-alpha-inhibitor, on the secondary neuronal damage. QA (240 nmol in 1 microl) was injected stereotactically into the striatum of male Wistar rats. After survival of 1, 3 or 10 days, the animals were sacrificed and immunohistochemical staining with an antibody against TNF-alpha was performed. From day 1 to day 10 after striatal QA injection TNF-alpha positive cells were observed within ipsilateral substantia nigra which were neither present on the contralateral side nor in sham-operated controls. Double labeling with antibodies against TNF-alpha and NeuN, keratan sulfate proteoglycan or GFAP displayed a good overlap between TNF-alpha and NeuN, which suggests that TNF-alpha positive cells are neurons. For the pharmacological approach, three groups of QA rats were treated intraperitoneally with either solvent (n=5), the NMDA receptor antagonist MK 801 (4 mg/kg, n=6) or the TNF-alpha inhibitor rolipram (0.3 mg/kg, n=6), which was started 24 h after QA-injection and continued with daily applications for 14 days. The amount of striatal damage did not differ between the three groups. The number of intact neurons within the ipsilateral substantia nigra of the solvent treated group was reduced by approximately 30% compared to the contralateral side. Both MK 801 and rolipram ameliorated this secondary damage and reduced the number of TNF-alpha positive cells. The observed association between expression of TNF-alpha and secondary neuronal damage within the substantia nigra induced by intrastriatal QA application might hint towards an involvement of this cytokine in transneuronal degeneration.

Topics: Animals; Brain Diseases; Cell Count; Chondroitin Sulfate Proteoglycans; Corpus Striatum; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Functional Laterality; Glial Fibrillary Acidic Protein; Immunohistochemistry; Inflammation; Keratan Sulfate; Lumican; Male; Phosphodiesterase Inhibitors; Phosphopyruvate Hydratase; Quinolinic Acid; Rats; Rats, Wistar; Rolipram; Substantia Nigra; Time Factors; Tumor Necrosis Factor-alpha

The neurotoxic effect following a single intraperitoneal injection of MK-801 (10 mg/kg) in adult female Wistar rats at different survival times was studied with the 1994 version of de Olmos' Amino-Cupric-Silver (A-Cu-Ag) technique for detection of neural degeneration. In addition to the well documented somatodendritic degeneration observable in cortical olfactory structures, dentate gyrus, retrosplenial and sensory cortices, we detected this type of neuronal degeneration also in the main olfactory bulb, motor and anterior cingulate cortices, thalamus and cerebellum. Terminal degeneration, not reported by previous authors, was detected in cortical olfactory structures, hippocampal formation, sensory, infralimbic, prelimbic, agranular insular, ectorhinal, perirhinal and lateral orbital cortices. These results demonstrate that the A-Cu-Ag procedure is more efficient than other silver methods for detecting the degeneration induced by MK-801. In fact, the use of the A-Cu-Ag method has made it possible to infer the connectional relations between the damaged cell bodies and corresponding terminal degeneration. Our results also indicate that the A-Cu-Ag technique may be a suitable method for the staining of neurons undergoing apoptotic-like degeneration. The probable degenerative mechanism of MK-801 in the main olfactory system is discussed.

Topics: Animals; Apoptosis; Brain; Brain Diseases; Copper; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Female; Nerve Degeneration; Rats; Rats, Wistar; Silver; Staining and Labeling; Time Factors

The strain and sex of a species under investigation may influence the animal's physiological response to a variety of stimuli. Strain and sex differences are important considerations when evaluating animal models. In the rodent MK-801 model of schizophrenia, degenerative changes occur widely in the main olfactory system and in a number of cortical brain regions. In the present report, we compare the effects of MK-801 neurotoxicity in two strains of female rats and also two lines within each strain. The magnitude and regional extent of the neurodegeneration detected with the amino-cupric-silver method varied markedly both between the Sprague-Dawley and Wistar rat strains and also between two lines derived from each strain. For example, terminal degeneration occurred in layer VI of somatosensory cortex and the central extended amygdala in Sprague-Dawley but not Wistar rats. Moreover, MK-801 treatment led to somatodendritic degeneration in the dentate gyrus of the dorsal hippocampus and basolateral amygdala in Wistar rats from Charles River Laboratories but not those from Ferreyra Institute. There are thus both strain and intrastrain differences in the magnitude of the neurodegenerative response to MK-801 treatment. The differing neurotoxicity of MK-801 between rat strains and between lines within a strain may reflect genetic variation and/or differences in hepatic biotransformation and thus the bioavailability of the drug between strains and lines within a strain.

Topics: Animals; Brain; Brain Diseases; Copper; Disease Models, Animal; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Female; Genetic Predisposition to Disease; Nerve Degeneration; Rats; Rats, Sprague-Dawley; Rats, Wistar; Silver; Species Specificity; Staining and Labeling

Intrastriatal injection of the reversible succinate dehydrogenase inhibitor malonate results in both chemically induced hypoxia and striatal lesions that are similar to those seen in Huntington's disease and cerebral ischaemia. The mechanisms leading to neuronal death involve secondary excitotoxicity, the release of dopamine from nigrostriatal fibres and the generation of reactive oxygen species (ROS) including nitric oxide (NO) and hydroxyl radicals. Here, we further investigated the contribution and mechanism of dopamine on malonate-induced striatal lesions. Prior lesions of the nigrostriatal pathway with 6-OHDA or the depletion of striatal dopamine stores by pretreatment with reserpine, an inhibitor or the vesicular monoamine transporter type-2 (VMAT2), in combination with alpha-methyl-p-tyrosine resulted in a significant reduction of malonate-induced striatal lesion volumes. This was paralleled by block or reduction of the malonate-induced generation of ROS, as measured by the conversions of salicylate to 2,3-dihydroxybenzoic acid (2,3-DHBA) using microdialysis. Systemic or intrastriatal application of L-DOPA or dopamine, respectively, reconstituted malonate toxicity and the generation of ROS in 6-OHDA-lesioned rats. Block of the dopamine transporter by GBR12909 did not result in a reduction of malonate-induced dopamine release, but significantly reduced the generation of hydroxyl radicals. The D2 receptor agonist lisuride and the mixed D1 and D2 receptor agonist apomorphine, but not the D1 receptor agonist SKF38393, partially restored malonate toxicity in 6-OHDA-lesioned rats without increasing the generation of ROS. In line with these results sulpiride, an inhibitor of D2 receptors, reduced the malonate-induced lesion volume, whereas SCH23390, an inhbitor of D1 receptors, was ineffective. Our data suggest that malonate-induced dopamine toxicity to energetically impaired neurons is mediated by two independent pathways: (i) dopamine transporter uptake-dependent, dopamine receptor-independent generation of ROS, and (ii) excessive stimulation of D2 receptors.

Topics: 3,4-Dihydroxyphenylacetic Acid; alpha-Methyltyrosine; Animals; Benzazepines; Brain Diseases; Carbidopa; Carrier Proteins; Corpus Striatum; Dizocilpine Maleate; Dopamine; Dopamine D2 Receptor Antagonists; Dopamine Plasma Membrane Transport Proteins; Enzyme Inhibitors; Homovanillic Acid; Levodopa; Male; Malonates; Membrane Glycoproteins; Membrane Transport Proteins; Nerve Tissue Proteins; Neuropeptides; Oxidopamine; Rats; Rats, Wistar; Reactive Oxygen Species; Receptors, Dopamine; Receptors, Dopamine D1; Receptors, Dopamine D2; Receptors, N-Methyl-D-Aspartate; Reserpine; Succinate Dehydrogenase; Sulpiride; Vesicular Biogenic Amine Transport Proteins; Vesicular Monoamine Transport Proteins

The reduction of the apparent diffusion coefficient (ADC) of brain tissue water in acute cerebral ischemia, as measured by diffusion-weighted magnetic resonance imaging, is generally associated with the development of cytotoxic edema. However, the underlying mechanism is still unknown. Our aim was to elucidate diffusion changes in the intracellular environment in cytotoxic edematous tissue. The ADC of intracellular metabolites was measured by use of diffusion-weighted 1H-magnetic resonance spectroscopy after (1) unilateral N-methyl-D-aspartate (NMDA) injection and (2) cardiac arrest-induced global ischemia in neonatal rat brain. The distinct water ADC drop early after global ischemia was accompanied by a significant reduction of the ADC of all measured metabolites (P < 0.01, n = 8). In the first hours after excitotoxic injury, the ADC of water and the metabolites taurine and N-acetylaspartate dropped significantly (P < 0.05, n = 8). At 24 and 72 hours after NMDA injection brain metabolite levels were diminished and metabolite ADC approached contralateral values. Administration of the NMDA-antagonist MK-801 1.5 hours after NMDA injection completely normalized the water ADC but not the metabolite ADC after 1 to 2 hours (n = 8). No damage was detected 72 hours later and, water and metabolite ADC had normal values (n = 8). The contribution of brain temperature changes (calculated from the chemical shift between the water and N-acetylaspartate signals) and tissue deoxygenation to ischemia-induced intracellular ADC changes was minor. These data lend support to previous suggestions that the ischemia-induced brain water ADC drop may partly be caused by reduced diffusional displacement of intracellular water, possibly involving early alterations in intracellular tortuosity, cytoplasmic streaming, or intracellular molecular interactions.

Topics: Animals; Animals, Newborn; Body Water; Brain Diseases; Brain Ischemia; Diffusion; Dizocilpine Maleate; Excitatory Amino Acid Agonists; Excitatory Amino Acid Antagonists; Intracellular Fluid; N-Methylaspartate; Rats; Rats, Wistar

Serum protein levels in LP-BM5 infected mouse brains were investigated to gain insight into the contribution of blood-brain barrier (BBB) patency to the pathogenesis of retroviral encephalopathy. Evans blue uptake by the forebrain and cerebellum was significantly increased between 8-12 weeks post inoculation. Immunohistochemistry revealed foci of albumin, transferrin, alpha(2)-macroglobulin and IgG transudation around blood vessels particularly in the cerebral cortex and cerebellar vermis. These leaks were often associated with astrocytosis and apoptotic cells. Unlike the other serum proteins, IgG immunoreactivity extended from the circumventricular organs and disseminated throughout the brain parenchyma, accumulating on the plasma membranes of hippocampal and cortical neurons. Consistent with the chronic elevation of free glutamate levels in LP-BM5 infected mice, the increase in Evans blue uptake into the forebrain was completely reversed following dizocilpine administration. Thus, the chronic increase in free glutamate levels in LP-BM5 infected mouse brain contributes to BBB disruption. Furthermore, the CNS accumulation of serum proteins, particularly IgG, observed in these mice may increase osmotic load, impair neuronal function, and cause white matter pallor. Administration of NMDA receptor antagonists may prove useful in managing BBB permeability in those neuropathologies, such as HIV-associated dementia/cognitive/motor complex, having a glutamatergic component.

Topics: Animals; Blood Proteins; Blood-Brain Barrier; Brain Diseases; Coloring Agents; Dizocilpine Maleate; Evans Blue; Excitatory Amino Acid Antagonists; Glutamic Acid; Immunohistochemistry; Leukemia, Experimental; Male; Mice; Mice, Inbred C57BL; Prosencephalon; Receptors, N-Methyl-D-Aspartate; Retroviridae Infections

Intrastriatal injection of the excitotoxin N-methyl-D-aspartate (NMDA) in neonatal rat brain resulted in an acute ipsilateral decrease of the apparent diffusion coefficient (ADC) of brain tissue water, as measured with diffusion-weighted MRI. The early diffusion changes were accompanied by only mild changes in the overall metabolic status as measured by in vivo 1H MRS and 31P MRS and metabolic imaging of brain sections. Minimal decreases in the high-energy phosphate levels and a small hemispheric acidosis were observed in the first 6 h after NMDA administration. In addition, there was very modest lactate accumulation. Twenty-four hours after the induction of the excitotoxic injury the tissue energy status was still only moderately affected, whereas an overall decrease of 1H MRS-detected brain metabolites was found. Treatment with the non-competitive NMDA-antagonist MK-801 given within 90 min after NMDA injection rapidly reversed the NMDA-induced changes in the entire ipsilateral hemisphere. The effect of the competitive NMDA-antagonist D-CPPene was restricted to the cortical areas and was accomplished on a slower time scale. Our results indicate that; (i) early excitotoxicity in the neonatal rat brain does not lead to profound changes in the metabolic status; and (ii) brain tissue water ADC changes are not necessarily associated with a metabolic energy failure.

Topics: Animals; Brain Diseases; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Fluoroscopy; Luminescent Measurements; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; N-Methylaspartate; Phosphorus; Rats; Rats, Wistar

Although the mechanism of neuronal death in neurodegenerative diseases remains unknown, it has been hypothesized that relatively minor metabolic defects may predispose neurons to N-methyl-D-aspartate (NMDA) receptor-mediated excitotoxic damage in these disorders. To further investigate this possibility, we have characterized the excitotoxic potential of the reversible succinate dehydrogenase (SDH) inhibitor malonate. After its intrastriatal stereotaxic injection into male Sprague-Dawley rats, malonate produced a dose-dependent lesion when assessed 3 days after surgery using cytochrome oxidase histochemistry. This lesion was attenuated by coadministration of excess succinate, indicating that it was caused by specific inhibition of SDH. The lesion was also prevented by administration of the noncompetitive NMDA antagonist MK-801. MK-801 did not induce hypothermia, and hypothermia itself was not neuroprotective, suggesting that the neuroprotective effect of MK-801 was due to blockade of the NMDA receptor ion channel and not to any nonspecific effect. The competitive NMDA antagonist LY274614 and the glycine site antagonist 7-chlorokynurenate also profoundly attenuated malonate neurotoxicity, further indicating an NMDA receptor-mediated event. Finally, the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) antagonist NBQX (2,3-dihydroxy-6-nitro-7-sulfamoylbenzo(f)-quinoxaline) was ineffective at preventing malonate toxicity at a dose that effectively reduced S-AMPA toxicity, indicating that non-NMDA receptors are involved minimally, if at all, in the production of the malonate lesion. We conclude that inhibition of SDH by malonate results in NMDA receptor-mediated excitotoxic neuronal death. If this mechanism of "secondary" or "weak" excitotoxicity plays a role in neurodegenerative disease, NMDA antagonists and other "antiexcitotoxic" strategies may have therapeutic potential for these diseases.

Topics: alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Animals; Body Temperature; Brain Diseases; Cell Death; Corpus Striatum; Dizocilpine Maleate; Dose-Response Relationship, Drug; Glutamic Acid; Glycine; Isoquinolines; Male; Malonates; Neurons; Quinoxalines; Rats; Rats, Sprague-Dawley; Receptors, Kainic Acid; Receptors, N-Methyl-D-Aspartate; Succinate Dehydrogenase

We report that a subtoxic dose of the succinate dehydrogenase (SDH) inhibitor malonate greatly enhances the neurotoxicity of three different excitatory amino acid agonists: N-methyl-D-aspartate (NMDA), S-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (S-AMPA), and L-glutamate. In male Sprague-Dawley rats, intrastriatal stereotaxic injection of malonate alone (0.6 mumol), NMDA alone (15 nmol), S-AMPA alone (1 nmol), or glutamate alone (0.6 mumol) produced negligible toxicity as assessed by measurement of lesion volume. Coinjection of subtoxic malonate with NMDA produced a large lesion (15.2 +/- 1.4 mm3), as did coinjection of malonate with S-AMPA (11.0 +/- 1.0 mm3) or glutamate (12.8 +/- 0.7 mm3). Administration of the noncompetitive NMDA antagonist MK-801 (5 mg/kg i.p.) completely blocked the toxicity of malonate plus NMDA (0.5 +/- 0.3 mm3). This dose of MK-801 had little effect on the lesion produced by malonate plus S-AMPA (9.0 +/- 0.7 mm3), but it attenuated the toxicity of malonate plus glutamate by approximately 40% (7.5 +/- 0.9 mm3). Coinjection of the AMPA antagonist 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo(f)-quinoxaline (NBQX; 2 nmol) had no effect on malonate plus NMDA or malonate plus glutamate toxicity (12.3 +/- 1.8 and 14.0 +/- 0.9 mm3, respectively) but greatly attenuated malonate plus S-AMPA toxicity (1.5 +/- 0.9 mm3). Combination of the two antagonists conferred no additional neuroprotection in any paradigm. These results indicate that metabolic inhibition exacerbates both NMDA receptor- and non-NMDA receptor-mediated excitotoxicity.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Animals; Brain; Brain Diseases; Dizocilpine Maleate; Drug Synergism; Glutamic Acid; Male; Malonates; N-Methylaspartate; Quinoxalines; Rats; Rats, Sprague-Dawley; Succinate Dehydrogenase

The present study was carried out to compare the neuroprotective effect of the novel noncompetitive NMDA antagonist, FR115427, with that of(+)MK-801 in rat focal cerebral ischemia. Focal cerebral ischemia was produced by permanent occlusion of the left middle cerebral artery (MCA). Drugs were administered intraperitoneally immediately after ischemia and once a day for 6 successive days. FR115427 (10 mg/kg, i.p.) significantly improved neurologic deficit at 1 day after ischemia and reduced total infarct volume (54%) at 7 days after ischemia. Although FR115427 (10 mg/kg, s.c.) produced neuronal vacuolization similar to (+)MK-801, FR115427 did not produce adverse effects such as a loss of body weight, mortality, and hypothermia, in contrast to (+)MK-801. These results suggest that FR115427 may be useful in the treatment of stroke.

Topics: Animals; Brain Diseases; Brain Ischemia; Dizocilpine Maleate; Isoquinolines; Male; Neuroprotective Agents; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Tetrahydroisoquinolines

The purpose of this study was to compare the effects of dizocilipine maleate (MK-801) and NG-nitro-L-arginine methyl ester (L-NAME) on focal excitotoxic brain injury and associated hemodynamic response in the newborn lamb. A 27 gauge needle was placed into the right striatum in 28 anesthetized newborn lambs. Seven animals were placed in each group. A negative control group received 0.2 mL of buffered saline, a positive control group received 5 mumol of N-methyl-D-aspartic acid (NMDA) alone, and two groups received NMDA and pretreatment with L-NAME. Ultrasound images and cerebral blood flow determinations (microspheres) were obtained before, and at 20, 40, and 60 min after, intrastrial injection. Three animals in each group underwent histopathologic evaluation. Sonographic lesions were visible immediately after intracerebral injection. Saline injection resulted in small lesions (mean volume; 13.6 +/- 5 mm3) without hyperemia. NMDA alone resulted in larger lesions (92.9 +/- 24 mm3) and hyperemia to both hemispheres, whereas pretreatment with MK-801 reduced lesion size (11.7 +/- 6 mm3) and completely ablated cerebral hyperemia. Pretreatment with L-NAME showed no effect on lesion size (69.9 +/- 20 mm3) and hyperemia only in the ipsilateral hemisphere. Sonographic lesions correlated well with gross and histopathologic appearance. We concluded that NMDA-induced focal brain injury and associated hyperemia in the newborn lamb appear to be specific NMDA receptor-mediated events. NO production probably does not play a major part in NMDA-induced neonatal neuronal injury, and may be only partly responsible for regional hyperemia during NMDA injection.

Topics: Animals; Animals, Newborn; Arginine; Brain Diseases; Cattle; Disease Models, Animal; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Hemodynamics; Hyperemia; N-Methylaspartate; Neuroprotective Agents; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Receptors, N-Methyl-D-Aspartate; Sheep

The possibility that compounds which interact with the putative sigma receptor might influence the dopaminergic neuropathology produced by the administration of methamphetamine (METH) to mice was investigated. (+/-)-BMY 14802 [alpha-(4-fluorophenyl)-4-(5-fluoro-2-pyrimidinyl)-1-piperazine-butanol hydrochloride] attenuated METH-induced dopaminergic neuropathology whereas several other sigma-acting compounds such as R-(+)-3-(3-hydroxyphenyl)-N-propylpiperidine hydrochloride, 1,3-di-o-tolyl-guanidine, rimcazole, clorgyline or (-)-butaclamol did not alter neurotoxicity produced by this central nervous system stimulant. (-)-BMY 14802, which has a lower affinity for the sigma site than (+)-BMY 14802, was more potent than (+)-BMY 14802 in antagonizing METH-induced neuropathology. In addition, the ketone metabolite (BMY 14786; alpha-(4-fluorophenyl)-4-(5-fluoro-2-pyrimidinyl)-1-piperazine-butanone hydrochloride), which is a major metabolite formed from (-)-BMY 14802, also attenuated the METH-induced effects. (+/-)-BMY 14802 pretreatment of mice prevented the reduction in D1 and D2 dopamine receptor number produced by the systemic administration of N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline and demonstrates that (+/-)-BMY 14802 and/or its metabolites interact with the dopamine receptor subtypes. Taken together, these findings suggest that the protective effect of (+/-)-BMY 14802 against METH-induced neuropathology is mediated, at least in part, through dopamine receptor antagonism. Furthermore, the failure of other sigma-acting compounds to alter METH-induced neurotoxicity indicates that the putative sigma receptor is unlikely to be an important mediator in this type of neuropathology.

Topics: Animals; Anticonvulsants; Antipsychotic Agents; Brain Diseases; Butaclamol; Carbazoles; Dizocilpine Maleate; Dopamine; Dopamine Agents; Drug Interactions; Drug Synergism; Guanidines; Ligands; Male; Methamphetamine; Mice; MPTP Poisoning; Neostriatum; Piperidines; Psychotropic Drugs; Pyrimidines; Receptors, Dopamine; Receptors, sigma; Stereoisomerism; Tyrosine 3-Monooxygenase

The effects of bilateral 6-hydroxydopamine-induced destruction of the dopamine nerve terminals in the ventral striatum (nucleus accumbens) or pharmacological blockade of dopamine receptors with haloperidol injected locally into this area were examined on the locomotor hyperactivity induced by systemic administration of the non-competitive NMDA receptor antagonist, MK-801 ((+)-5-methyl-10,11-dihydro-5H-dibenzo(a,d) cyclohepten-5,10-imine hydrogen maleate salt). The locomotor stimulation induced by two doses of MK-801 (0.15 and 0.3 mg/kg, i.p.) was not attenuated by 6-hydroxydopamine bilateral lesions to the ventral striatum, either 7 or 14 days after the operation. The same lesion however reduced the locomotor activation induced by 0.5 mg/kg d-amphetamine 14 days after surgery. Bilateral intra-accumbens injection of haloperidol at a dose (2.5 micrograms/side) that blocked d-amphetamine-induced hypermotility did not reduce the locomotor response to 0.3 mg/kg MK-801, while 5 micrograms/side haloperidol decreased the MK-801-induced locomotor stimulation. These results suggest that the locomotor response to MK-801 is dependent on an interaction between dopaminergic and excitatory amino acid transmission occurring postsynaptically rather than presynaptically in the ventral striatum.

Topics: Amphetamine; Animals; Brain; Brain Diseases; Corpus Striatum; Dizocilpine Maleate; Dopamine; Dopamine Antagonists; Drug Interactions; Haloperidol; Male; Microinjections; Motor Activity; Nucleus Accumbens; Oxidopamine; Rats; Rats, Wistar; Receptors, Dopamine; Receptors, N-Methyl-D-Aspartate; Stimulation, Chemical; Synapses

The neuroprotective effects of 2,3-dihydroxy-6-nitro-7- sulfamoylbenzo(f)quinoxaline (NBQX), GYKI 52466, and MK-801 were tested following severe forebrain ischemia. Wistar rats were subjected to 10 min of normothermic ischemia and reperfused for 7 days. Necrotic hippocampal CA1 neurons were counted and expressed as a percentage (mean +/- SD). In Experiment 1, saline-treated rats sustained 81 +/- 20% damage to dorsal CA1. Rats given NBQX 30 mg/kg i.p. x3 lost 21 +/- 27% (p < 0.01). Neither MK-801 1 mg i.p. x3 alone, nor in combination with the cytoprotective dose of NBQX protected CA1, with 83 +/- 18 and 54 +/- 34% damage, respectively (NS). Giving NBQX 90 mg/kg i.v. did not protect cells (94 +/- 5%) and resulted in nephrotoxicity. In Experiment 2, rats were given saline or three doses of NBQX 30 mg/kg i.p. immediately at reperfusion (RP) or after a 6-, 12-, or 24-h delay. Saline-treated rats suffered 79 +/- 16% injury. NBQX given immediately resulted in 17 +/- 17% injury, and even if treatment was delayed by either 6 or 12 h, there was marked protection with only 27 +/- 32 and 25 +/- 17% injury, respectively (all p < 0.01). Delaying the initiation of treatment to 24 h was not successful, resulting in 50 +/- 28% injury (NS). In Experiment 3, saline-treated rats lost 81 +/- 19% of CA1 cells, while those given GYKI 52466 10 mg/kg i.p. x5 starting immediately following RP lost 80 +/- 14%.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Animals; Anti-Anxiety Agents; Benzodiazepines; Brain Diseases; Dizocilpine Maleate; Hippocampus; Ischemic Attack, Transient; Male; Neurons; Prosencephalon; Quinoxalines; Rats; Rats, Wistar

The potential antiparkinson activity of N-methyl-D-aspartate antagonists was investigated by examining the effects of dizocilpine (MK-801) on rats with 6-hydroxydopamine-induced lesions of the nigrostriatal pathway. MK-801, when administered alone to these animals, elicited ipsilateral rotation, which could be blocked by haloperidol. MK-801, at doses that did not produce rotation when given alone, inhibited the contralateral rotation produced by the D2 receptor agonist quinpirole but had no effect on the rotation induced by the D1 agonist SKF 38393 [(+-)-1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8- diolhydrochloride]. However, exposure to levodopa 3 days previously resulted in a subsensitive rotational response to SKF 38393 and this subsensitivity to the D1 agonist was reversed by MK-801. The subsensitive rotational response to SKF 38393 was not evident 7 days after exposure to levodopa and MK-801 had no effect on the response to SKF 38393 at this time. These data suggest that N-methyl-D-aspartate receptor blockade can exert differential effects on dopamine agonist-induced rotational behavior that depend on which dopamine receptor subtype is activated and the previous exposure of the animal to dopamine agonists.

Topics: 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; Animals; Behavior, Animal; Brain Diseases; Dizocilpine Maleate; Dopamine Agents; Dose-Response Relationship, Drug; Drug Interactions; Levodopa; Male; Motor Activity; N-Methylaspartate; Oxidopamine; Parkinson Disease; Rats; Rats, Sprague-Dawley; Receptors, Dopamine D1; Receptors, Dopamine D2

N-methyl-D-aspartate receptor antagonists are potent neuroprotectants in experimental focal cerebral ischemia, but behavioral and neuropathologic changes seen with these drugs in rodent models may limit the clinical utility of these compounds. Glycine's modulation of N-methyl-D-aspartate channel function offers another pharmacologic approach to excitotoxicity in ischemia. The potent glycine antagonist 7 Chlorothiokynurenic acid (7-Cl-Thio-Kyna) was studied in a permanent middle cerebral artery occlusion stroke model in the rat. The compound was effective, in a dose-dependent manner, in attenuating infarct size when administered before or after permanent middle cerebral artery occlusion. Its activity was mainly due to glycine antagonism inasmuch as 5 Chlorothiokynurenic acid, a compound having other pharmacological activities in common with 7-CI-Thio-Kyna (for instance the radical scavenger action), was inactive in this model. 7-Cl-Thio-Kyna did not produce cytological changes similar to MK 801.

Topics: Animals; Brain; Brain Chemistry; Brain Diseases; Brain Ischemia; Disease Models, Animal; Dizocilpine Maleate; Dose-Response Relationship, Drug; Free Radical Scavengers; Heat-Shock Proteins; Immunohistochemistry; Kynurenic Acid; Male; Rats; Rats, Sprague-Dawley; Receptors, Glycine

Magnetic resonance imaging has been used to follow the time course of lesions induced in the rat brain as an animal model for characterization of the volume of the lesion. The dispersion in spin-spin relaxation has been used to characterize the nature of the brain lesion. Parameter selective estimation of T2, quantitative determination of the lesion size and volume selective in vivo proton spectroscopy have been employed for the purpose. The work has been carried out on rats which were subject to lesioning by ibotenic acid as a model for excitotoxicity and also on rats which received doses of ibotenic acid and subsequent doses of the NMDA antagonist drug MK 801 (dizocilpine). The time course of the progress of the lesions in untreated animals and the effect of neuroprotection by MK 801 was continuously monitored in all test animals. Further, a relatively new inhalation anesthetic agent, isoflurane, has been employed. A more logical and semiquantitative T2 bandwidth demarkation useful in distinguishing different degrees of lesioning from the onset and up to the 'edema' stage through penumbra (mild lesion), medium degree lesion and severe lesion has been proposed.

Topics: Animals; Brain Diseases; Dizocilpine Maleate; Ibotenic Acid; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Male; Rats; Rats, Wistar; Time Factors

The aim of this study is to characterize the evolution of excitotoxic damage in neonatal rat brain by diffusion-weighted and T2-weighted magnetic resonance imaging. Results are compared with histological findings. Magnetic resonance imaging was performed at various times (15 min, 24 h, 3 days and 5 days) after intrastriatal microinjection of N-methyl-D-aspartate (NMDA) at postnatal day 8. The transverse relaxation time (T2) and apparent diffusion coefficient of water were determined. The results show an acute reduction of the apparent diffusion coefficient, reflected by an ipsilateral hyperintensity in the diffusion-weighted images, within 15 min after intrastriatal NMDA injection. At this time no changes in the T2-weighted images were apparent. The volume of the hyperintensity was relatively large with a radius of approximately 2 mm and coincided with histological signs of pronounced karyo-dendritic swelling. Subcutaneous administration of MK-801 25 min after the intracerebral NMDA injection readily reversed the hyperintensity and resulted in complete protection as verified by histology. Areas with increased T2 values were observed 1 day after NMDA microinjection and corresponded to regions with obvious cell necrosis. Five days after NMDA injection the lesion was evident using both diffusion- and T2-weighted images and coincided with an overt lesion comprising areas of cell loss and dilatation of the ipsilateral ventricle. In conclusion, this study illustrates the possibility of using diffusion-weighted imaging as a tool to monitor efficacy of treatment strategies at an early stage of excitotoxic injury.

Topics: Animals; Animals, Newborn; Brain Diseases; Corpus Striatum; Diffusion; Dizocilpine Maleate; Histocytochemistry; Magnetic Resonance Spectroscopy; Microinjections; N-Methylaspartate; Necrosis; Rats

We investigated the neuroprotective potential of MK-801 (dizocilpine), a noncompetitive N-methyl-D-aspartate (NMDA) antagonist, in the setting of three 5-min periods of global cerebral ischemia separated by 1-h intervals in halothane-anesthetized rats. Each ischemic insult was produced by bilateral carotid artery occlusions plus hypotension (50 mm Hg). Brain temperature was maintained at normothermic levels (36.5-37.0 degrees C) throughout the experiment. MK-801 (3 mg/kg) (n = 6) or saline (n = 6) was injected intraperitoneally 45 min following the end of the first ischemic insult. Following 7-day survival, quantitative neuronal counts of perfusion-fixed brains revealed severe ischemic damage in hippocampal CA1 area, neocortex, ventrolateral thalamus, and striatum of untreated rats. By contrast, significant protection was observed in MK-801-treated rats. In area CA1 of the hippocampus, numbers of normal neurons were increased 11- to 14-fold by MK-801 treatment (p < 0.01). The ventrolateral thalamus of MK-801-treated rats showed almost complete histologic protection, and neocortical damage was reduced by 71% (p < 0.01). The degree of MK-801 protection of striatal neurons was less complete than that seen in other vulnerable structures, amounting to 63% for central striatum (p = 0.02, Mann-Whitney U test) and 48% in the dorsolateral striatum (NS). A repeated-measures analysis of variance demonstrated a highly significant overall protective effect of MK-801 treatment (F1,10 = 37.2, p = 0.0001).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Blood Glucose; Brain Diseases; Carotid Arteries; Cerebral Cortex; Constriction; Corpus Striatum; Dizocilpine Maleate; Hippocampus; Ischemic Attack, Transient; Male; Neurons; Rats; Rats, Wistar; Thalamus; Time Factors

To study the molecular mechanisms contributing to glial fibrillary acidic protein (GFAP) accumulation after neuronal injury in the developing brain, we used a reproducible and pharmacologically modifiable model of excitotoxic injury, intracerebral injection of N-methyl-D-aspartate (NMDA) in Postnatal Day 7 rats. Injection of NMDA into the posterior striatum elicits dose-dependent ipsilateral injury to striatum, hippocampus, and overlying cortex; treatment with the non-competitive NMDA antagonist MK-801 is neuroprotective. To examine regionally specific changes in GFAP mRNA expression after lesioning, GFAP mRNA content was assayed, by Northern analysis, in pooled tissue samples of striatum, hippocampus, and cortex, derived from the injected and contralateral hemispheres of animals killed 1-16 days after lesioning with NMDA (12.5 nmol), and in samples derived from lesioned animals and littermates treated with MK-801. In addition, in situ hybridization assays were done to visualize the anatomic distribution of GFAP mRNA expression in NMDA-lesioned (n = 5) and lesioned/MK-801-treated animals (n = 3) 5 days postinjection. There was a marked rise in GFAP mRNA in lesioned cortex within 24 h, and increases were sustained over the next 2 weeks. In contrast, in striatum and hippocampus, in which severe histologic damage evolves, at 24 h postlesioning there was little stimulation of GFAP mRNA expression. Subsequently, 5-16 days postinjury increases in GFAP mRNA were detected in both brain regions. In animals examined 5 days postlesioning, MK-801 treatment markedly attenuated stimulation of GFAP mRNA expression.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Brain Diseases; Dizocilpine Maleate; Glial Fibrillary Acidic Protein; In Situ Hybridization; N-Methylaspartate; Rats

Cerebral cortex tissue was obtained at autopsy from neonatal Poll Hereford calves with clinically confirmed maple syrup urine disease (MSUD), neonatal Holstein-Friesian calves with clinically confirmed citrullinemia, and matched controls. From this, synaptosomes were prepared for studies of neurotransmitter amino acid uptake and stimulus-induced release, and synaptic plasma membranes were obtained for studies of associated postsynaptic receptor binding sites. As well as having abnormal brain tissue concentrations of the pathognomic plasma amino acids (markedly increased levels of the branched-chain compounds valine, isoleucine, and leucine in MSUD; marked elevation of citrulline levels in citrullinemia), both groups of diseased animals showed reduced brain tissue concentrations of each of the transmitter amino acids glutamate, aspartate, and gamma-aminobutyric acid (GABA). Nontransmitter amino acids were generally unaffected in either disease. Citrullinemic calves showed a marked increase in brain glutamine concentration; in calves with MSUD, the glutamine concentration was raised, but to a much lesser extent. The Na(+)-dependent synaptosomal uptake of both glutamate and GABA was markedly reduced (to less than 50% of control values in both cases) in citrullinemic calves but was unaltered in calves with MSUD. Whereas synaptosomes from normal calves showed the expected stimulus-coupled release of transmitter amino acids, especially glutamate and aspartate, and no response to stimulus of nontransmitter amino acids, there was no increased release of transmitter amino acids in response to depolarization in synaptosomes from citrullinemic calves.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Acute-Phase Reaction; Animals; Animals, Newborn; Aspartic Acid; Brain Diseases; Cattle; Cattle Diseases; Cerebral Cortex; Citrulline; Dizocilpine Maleate; Female; gamma-Aminobutyric Acid; Glutamates; Male; Maple Syrup Urine Disease; Neurotransmitter Agents; Receptors, GABA-A; Receptors, N-Methyl-D-Aspartate

alpha-Dendrotoxin (Dtx), a snake polypeptide, increases neuronal excitability by blocking certain fast-activating, voltage-dependent K+ channels. Thus, the behavioural, electrocortical (ECoG) and neuropathological effects of Dtx, injected into rat brain areas, were studied. A unilateral injection of 35 pmol of Dtx into the CA1 hippocampal area or the dendate gyrus (DG; upper blade) immediately produced motor and ECoG seizures, followed at 24 h by multi-focal brain damage and significant neuronal loss. Whilst brain damage was seen bilaterally, significant neuronal loss occurred only in regions (CA1, CA3, CA4 and DG) ipsilateral to the site of injection. A lower dose (3.5 pmol) of toxin elicited motor and ECoG seizures but failed to produce brain damage. Seizures were observed 50 min after injecting Dtx (35 pmol) into the amygdala, though significant neuronal loss was not evident. 4-Aminopyridine (100 nmol), given into the CA1 area elicited a similar motor and ECoG pattern to that of Dtx except no brain damage could be seen at 24 h. Systemic pretreatment with antagonists of N-methyl-D-aspartate receptors (MK-801 or CGP 37849) did not protect against the effects typically evoked by injecting Dtx into the CA1 area.

Topics: 2-Amino-5-phosphonovalerate; Animals; Brain Diseases; Dizocilpine Maleate; Elapid Venoms; Electroencephalography; Hippocampus; Injections; Male; Nerve Degeneration; Neurotoxins; Potassium Channels; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Seizures

The neuroprotective characteristics of the functional antagonist of metabotropic stimulated phosphoinositide hydrolysis, 2-amino-3-phosphonoproprionate (D,L-AP3), were examined alone and in combination with the non-competitive N-methyl-D-aspartate (NMDA) antagonist, MK-801, against ibotenate induced brain injury. Postnatal day (PND) 7 rats received unilateral stereotaxic intrastriatal injections of 10 nmol ibotenate and treated with either D,L-AP3 (600 nmol i.c.), MK-801 (1 mg/kg i.p.) or both. The severity of brain injury was assessed on PND 12 by comparison of the weights of injected and contralateral cerebral hemispheres. Ibotenate induced injury was partially reduced by treatment with MK-801 (34.0 +/- 4.4% protection, P < 0.05 vs. PBS treated, independent t-test) but not D,L-AP3. However, combined treatment with both MK-801 and D,L-AP3 produced marked synergistic neuroprotection (83.5 +/- 7.6% protection, P < 0.001 vs. PBS treated, independent t-test). The data suggest that metabotropic stimulated phosphoinositide hydrolysis contributes to excitotoxic neuronal injury in the presence of concurrent ionotropic receptor activation.

Topics: 6-Cyano-7-nitroquinoxaline-2,3-dione; Alanine; Animals; Brain; Brain Diseases; Dizocilpine Maleate; Drug Synergism; Female; Ibotenic Acid; Injections; Male; Organ Size; Quinoxalines; Rats; Rats, Sprague-Dawley

The effects of the N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 and the dihydropyridine calcium antagonist nimodipine on NMDA-induced phenomena were investigated using an in vivo fluorometric technique with indo-1. Indo-1, a fluorescent cytosolic free calcium ([Ca2+]i) indicator, was loaded into the cat cortex approximately 500 microns in depth by superfusion with the membrane-permeant indo-1 acetoxy-methyl ester (indo-1-AM). Changes in [Ca2+]i signals (400 and 506 nm) and reduced nicotinamide adenine dinucleotide (NADH) fluorescence (464 nm) were simultaneously measured directly from the cortex during ultraviolet excitation (340 nm). Superfusion of 100 microM NMDA over the exposed cortex induced an elevation of the [Ca2+]i signal ratio (400/506 nm), biphasic changes in NAD/NADH redox state (initial oxidation followed by progressive reduction), and characteristic changes in the EEG (abrupt depression in amplitude followed by an excitatory pattern of 18-22 Hz polyspikes or sharp waves). These changes were completely blocked by treatment with MK-801 and reduced by nimodipine. The mechanism underlying the protective effects of systemically administered MK-801 on the NMDA-induced neuronal injury was verified in vivo.

Topics: Animals; Brain Diseases; Calcium; Cats; Cerebral Cortex; Cytosol; Dizocilpine Maleate; Ion Channels; Male; N-Methylaspartate; NAD; Neurons; Receptors, N-Methyl-D-Aspartate

Topics: Animals; Animals, Newborn; Brain Diseases; Dizocilpine Maleate; Hypothermia, Induced; Hypoxia; Ischemia; Nervous System; Rats; Rats, Inbred Strains

A quantitative dot immunobinding procedure was used to quantify glial [the S-100 protein and the glial fibrillary acidic (GFA) protein] and neuronal (the 68- and 200-kDa neurofilament polypeptides, neuron-specific enolase, and neuronal cell adhesion molecule) markers. A single intraperitoneal administration of 10 mg/kg of MK 801 blocked the increase of glial parameters and the decrease in content of neuronal marker proteins that occurred as the response to an N-methyl-D-aspartate (NMDA) lesion in the rat hippocampus. The degradation products of GFA protein and the 68-kDa neurofilament polypeptide that were induced by the NMDA lesion did not appear after MK 801 treatment. This study shows that brain-specific proteins are a set of precise tools for the evaluation of neuroprotective effects of antagonists to excitatory amino acids.

Topics: Animals; Behavior, Animal; Biomarkers; Body Weight; Brain Diseases; Dizocilpine Maleate; Glial Fibrillary Acidic Protein; Immunoblotting; Intermediate Filament Proteins; Male; Nerve Tissue Proteins; Neuroglia; Neurons; Rats; Rats, Inbred Strains

Topics: Animals; Anticonvulsants; Body Temperature; Brain; Brain Diseases; Carotid Arteries; Corpus Striatum; Disease Models, Animal; Dizocilpine Maleate; Gerbillinae; Hippocampus; Hypothermia; Ischemic Attack, Transient; Male; Pipecolic Acids; Pyramidal Tracts; Receptors, N-Methyl-D-Aspartate; Triazoles

Histologic evidence suggests that drugs acting as noncompetitive antagonists at the N-methyl-D-aspartate receptor can have beneficial or pathologic effects on central nervous system neurons. In the present experiments we examined the effects of MK-801 on recovery of behavioral function after unilateral lesions in the rat somatic sensorimotor cortex. In the first experiment, rats with unilateral sensorimotor cortex lesions were given either MK-801 (1 mg/kg) or saline 12-16 hours after surgery. Additional injections were given on postoperative days 2, 4, and 6. Behavioral tests measured somatosensory asymmetries (i.e., bilateral tactile stimulation tests) and forelimb placing. After creation of sensorimotor cortex lesions, rats showed an ipsilateral somatosensory bias and an impairment in placing the contralateral forelimb. Rats treated with MK-801 recovered slightly faster than saline-treated animals as measured by a bilateral tactile stimulation test (p less than 0.05). In contrast, there was no significant difference between the groups in the recovery of forelimb placing. In a second experiment, rats with sensorimotor cortex lesions were treated with a single injection of MK-801 after behavioral recovery. Twenty hours after the MK-801 injection, rats with sensorimotor cortex lesions showed a reinstatement of the placing deficits. The impairment endured for at least 7 days after injection. These behavioral data support the idea that MK-801 can have either beneficial or detrimental effects when administered after brain damage.

Topics: Animals; Brain Diseases; Dizocilpine Maleate; Forelimb; Male; Movement; Nervous System; Neural Pathways; Physical Stimulation; Rats; Rats, Inbred Strains; Somatosensory Cortex; Vibrissae

8319, ((+-)-2-Amino-N-ethyl-alpha-(3-methyl-2-thienyl)benzeneethanamine 2HCl), is a novel compound with the profile of a non-competitive NMDA antagonist. The compound displaced [3H] TCP with high affinity (IC50 = 43 nM), but was inactive at the NMDA, benzodiazepine and GABA sites; in vivo, 8319 showed good efficacy as an anticonvulsant and potential neuroprotective agent. It blocked seizures induced by NMDLA, supramaximal electroshock, pentylenetetrazol (PTZ), picrotoxin, and thiosemicarbazide with ED50's of 1-20 mg/kg ip. As a neuroprotective agent, 8319 (30-100 mg/kg sc) prevented the death of dorsal hippocampal pyramidal cells induced by direct injection of 20 nmol NMDA. At 15 mg/kg ip, the compound was also effective against hippocampal neuronal necrosis induced via bilateral occlusion of the carotid arteries in gerbils. In summary, 8319 is a noncompetitive NMDA antagonist with good anticonvulsant activity and may possess neuroprotective properties useful in the treatment of brain ischemia.

Topics: Aniline Compounds; Animals; Anticonvulsants; Binding, Competitive; Brain Diseases; Brain Ischemia; Dizocilpine Maleate; Gerbillinae; Hippocampus; Male; Mice; Mice, Inbred Strains; N-Methylaspartate; Rats; Rats, Inbred Strains; Thiophenes; Tritium

In immature rodent brain, unilateral intrastriatal injections of selected excitatory amino acid (EAA) receptor agonists, such as N-methyl-D-aspartate (NMDA), produce prominent ipsilateral forebrain lesions. In Postnatal Day (PND) 7 rats that receive a right intrastriatal injection of NMDA (25 nmol) and are sacrificed 5 days later, there is a considerable and consistent reduction in the weight of the injected cerebral hemisphere relative to that of the contralateral side (-28.5 +/- 1.9%, n = 6). In animals treated with specific NMDA receptor antagonists, the severity of NMDA-induced damage is markedly reduced. We have previously reported that the efficacy of potential neuroprotective drugs in limiting NMDA-induced lesions can be assessed quantitatively by comparison of hemisphere weights after a unilateral NMDA injection. In this study, we compared three quantitative methods to evaluate the severity of NMDA-induced brain injury and the degree of neuroprotection provided by NMDA receptor antagonists. We characterized the severity of brain injury resulting from intrastriatal injections of 1-50 nmol NMDA in PND 7 rats sacrificed on PND 12 by (i) comparison of cerebral hemisphere weights; (ii) assay of the activity of the cholinergic neuronal marker, choline acetyltransferase (ChAT) activity; and (iii) measurement of regional brain cross-sectional areas. The severity of the resulting brain injury as assessed by comparison of hemisphere weights increased linearly with the amount of NMDA injected into the striatum up to 25 nmol NMDA. The magnitude of injury was highly correlated with the degree of reduction in ChAT activity (r2 = 0.97).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Aspartic Acid; Brain; Brain Diseases; Choline O-Acetyltransferase; Corpus Striatum; Dibenzocycloheptenes; Dizocilpine Maleate; Dose-Response Relationship, Drug; Female; Ketamine; Male; N-Methylaspartate; Piperazines; Rats; Rats, Inbred Strains; Regression Analysis