dizocilpine-maleate and Neurodegenerative-Diseases

Icariin, a major bioactive compound found in the

Topics: Animals; Dizocilpine Maleate; Flavonoids; Mice; Molecular Docking Simulation; Neurodegenerative Diseases; Schizophrenia

Functional disorders of the glymphatic system and Aquaporin-4 (AQP-4) channels take part in the pathophysiology of neurodegenerative disease. The aim of this study was to describe the distribution of AQP-4 channels in the prefrontal cortex and hippocampus in a mouse model of NMDA receptor blocking agent-induced schizophrenia-like behavior model. NMDA receptor antagonist MK-801 was used to produce the experimental schizophrenia model. MK-801 injections were administered for eleven days to Balb/c mice intraperitoneally. Beginning from the sixth day of injection, the spatial learning and memory of the mice were tested by the Morris water maze (MWM) task. A group of mice was injected with MK-801 for ten days without the MWM task. Hippocampus and prefrontal specimens were collected from this group. Tissue samples were stained immunohistochemically and AQP-4 channels were examined by electron microscope. Time to find the platform was significantly longer at MK-801 injected group than the control group at the MWM task. Also, time spent at the target quadrant by the MK-801 group was shorter compared to the control group. AQP-4 expression increased significantly at MK-801 group glial cells, neuronal perikaryon, perineuronal and pericapillary spaces. In the MK-801 group, there was remarkable damage in neurons and glial cells. Increased AQP-4 channel expression and neurodegeneration at the MK-801 group induced with schizophrenia-like behavior model. MK-801 induced NMDA receptor blockade causes a decline in cognitive and memory functions. Increased AQP-4 expression at the prefrontal cortex and hippocampus to elicit and transport products of synaptic neurotransmitters and end metabolites is suggested.

Topics: Animals; Aquaporins; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Hippocampus; Mice; Mice, Inbred BALB C; Neurodegenerative Diseases; Prefrontal Cortex

Olfactory dysfunction is an early symptom of neurodegenerative disease. Amyloid-beta oligomers (AβOs), the pathologic protein of Alzheimer's disease (AD), have been confirmed to be firstly deposited in olfactory bulb (OB), causing smell to malfunction. However, the detailed mechanisms underlying pathogenic nature of AβOs-induced olfactory neuronal degeneration in AD are not completely realized. Here, an early-stage olfactory dysfunction pathological model of AD in vitro based on biomimetic OB neuronal network chip was established for dynamic multi-site detection of neuronal electrical activity and network connection. We found both spike firing and correlation of overall neuronal network change regularly displayed gradually active state and then rapidly decay state after AβOs induction. Moreover, MK-801 and memantine were administrated at early-stage to detect alteration of OB neurons simulating nasal administration for AD treatment, which showed an almost recovery through the intermittent firing pattern. Together, this neuronal network-on-chip has revealed synaptic impairment and network neurodegeneration of olfactory dysfunction in AD, providing potential mechanisms information for early-stage progressive olfactory amyloidogenic pathology.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Biomimetics; Biosensing Techniques; Dizocilpine Maleate; Humans; Memantine; Neurodegenerative Diseases; Neurons; Olfaction Disorders; Olfactory Bulb; Smell

Glutamic acid decarboxylase (GAD), the enzyme responsible for GABA synthesis, requires pyridoxal phosphate (PLP) as a cofactor. Thiosemicarbazide (TSC) and γ-glutamyl-hydrazone (PLPGH) inhibit the free PLP-dependent isoform (GAD65) activity after systemic administration, leading to epilepsy in mice and in young, but not in adult rats. However, the competitive GAD inhibitor 3-mercaptopropionic acid (MPA) induces convulsions in both immature and adult rats. In the present study we tested comparatively the epileptogenic and neurotoxic effects of PLPGH, TSC and MPA, administered by microdialysis in the hippocampus of adult awake rats. Cortical EEG and motor behavior were analyzed during the next 2h, and aspartate, glutamate and GABA were measured by HPLC in the microdialysis-collected fractions. Twenty-four hours after drug administration rats were fixed for histological analysis of the hippocampus. PLPGH or TSC did not affect the motor behavior, EEG or cellular morphology, although the extracellular concentration of GABA was decreased. In contrast, MPA produced intense wet-dog shakes, EEG epileptiform discharges, a >75% reduction of extracellular GABA levels and remarkable neurodegeneration of the CA1 region, with >80% neuronal loss. The systemic administration of the NMDA glutamate receptor antagonist MK-801 30 min before MPA did not prevent the MPA-induced epilepsy but significantly protected against its neurotoxic effect, reducing neuronal loss to <30%. We conclude that in adult awake rats, drugs acting on PLP availability have only a weak effect on GABA neurotransmission, whereas direct GAD inhibition produced by MPA induces hyperexcitation leading to epilepsy and hippocampal neurodegeneration. Because this degeneration was prevented by the blockade of NMDA receptors, we conclude that it is due to glutamate-mediated excitotoxicity consequent to disinhibition of the hippocampal excitatory circuits.

Topics: Amino Acids; Animals; Disease Models, Animal; Dizocilpine Maleate; Dose-Response Relationship, Drug; Enzyme Inhibitors; Epilepsy; Hippocampus; Male; Microdialysis; Neurodegenerative Diseases; Neuroprotective Agents; Phenylacetates; Pyridoxal Phosphate; Rats; Rats, Wistar; Semicarbazides; Time Factors; Wakefulness

Excitotoxicity due to excessive glutamatergic neurotransmission is a well-studied phenomenon that has been related to the mechanisms of neuronal death occurring in some disorders of the CNS. We have previously shown that the intrahippocampal perfusion by microdialysis of 4-aminopyridine (4-AP) in rats stimulates endogenous glutamate release from nerve endings and this results in excitotoxic effects such as immediate seizures and delayed neuronal death, due to the overactivation of N-methyl-D-aspartate (NMDA) receptors. To study whether mitochondrial energy dysfunction and oxidative stress could be involved in this 4-AP-induced excitotoxicity, we evaluated in awake rats the protective effect of several energy substrates and antioxidant compounds, using microdialysis, electroencephalographic (EEG) recording and histological analysis. The 4-AP-induced behavioral and EEG seizures, which progressed to status epilepticus in about 30 min, were prevented by the NMDA receptor antagonist MK-801, whereas acetoacetate, DL- and L-β-hydroxybutyrate did not protect against seizures but increased the latency to the onset of status epilepticus; pyruvate, α-ketoglutarate and glutathione ethyl ester did not show any protective effect. 4-AP also produced nearly complete loss of pyramidal neurons in CA1 and CA3 regions of the ipsilateral hippocampus 24 h after the experiment. MK-801 totally prevented this neuronal death and the energy substrates tested protected by about 50%, whereas the antioxidants showed only a weak protection. We conclude that ketone bodies possess weak anticonvulsant effects and that energy metabolism impairment plays a more important role than oxidative stress in the delayed hippocampal neurodegeneration resulting from the excitotoxic action of 4-AP mediated by endogenous glutamate.

Topics: Animals; Dizocilpine Maleate; Energy Metabolism; Excitatory Amino Acid Antagonists; Glutamic Acid; Hippocampus; Male; Neurodegenerative Diseases; Rats; Rats, Wistar; Wakefulness

Several years after the diagnosis of Parkinson's disease (PD), 20-30% of PD patients develop dementia, known as Parkinson's disease dementia (PDD), the features of which include impairment of short-term memory and recognition function. Hyperactivation of the glutamatergic system is implicated in the neurodegeneration seen in PD. The aim of this study was to determine the effects of MK-801, an N-methyl-d-aspartate (NMDA) receptor antagonist, on short-term memory and object recognition in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD rat animal model. MPTP was injected stereotaxically into the substantia nigra pars compacta (SNc) of male Wistar rats, then, starting 1 day later (day 1), the rats were injected daily with MK-801 (0.2 mg/kg/day, i.p.) and rats underwent a bar test on days 1-7, a T-maze test on days 8-10, and object recognition test on days 12-14. On day 1, the animals showed motor dysfunction, which recovered to control levels on day 7. MPTP-lesioned rats showed impairment of working memory in the T-maze test and of recognition in the object recognition test, both of which were prevented by MK-801 treatment. Furthermore, MPTP lesion-induced dopaminergic degeneration in the nigrostriatal system, microglial activation in the SNc, and cell loss in the hippocampal CA1 area were all improved by MK-801 treatment. These results suggest that NMDA receptors are involved in PD-related neuronal and behavioral dysfunction.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Analysis of Variance; Animals; Brain; Disease Models, Animal; Dizocilpine Maleate; Gene Expression Regulation; Male; Maze Learning; Memory Disorders; MPTP Poisoning; Neurodegenerative Diseases; Neuroprotective Agents; Rats; Rats, Wistar; Recognition, Psychology; Time Factors; Tyrosine 3-Monooxygenase

Nerve cell death is the key event in all neurodegenerative disorders, with apoptosis and necrosis being central to both acute and chronic degenerative processes. However, until now, it has not been possible to study these dynamically and in real time. In this study, we use spectrally distinct, well-recognised fluorescent cell death markers to enable the temporal resolution and quantification of the early and late phases of apoptosis and necrosis of single nerve cells in different disease models. The tracking of single-cell death profiles in the same living eye over hours, days, weeks and months is a significant advancement on currently available techniques. We identified a numerical preponderance of late-phase versus early-phase apoptotic cells in chronic models, reinforcing the commonalities between cellular mechanisms in different disease models. We showed that MK801 effectively inhibited both apoptosis and necrosis, but our findings support the use of our technique to investigate more specific anti-apoptotic and anti-necrotic strategies with well-defined targets, with potentially greater clinical application. The optical properties of the eye provide compelling opportunities for the quantitative monitoring of disease mechanisms and dynamics in experimental neurodegeneration. Our findings also help to directly observe retinal nerve cell death in patients as an adjunct to refining diagnosis, tracking disease status and assessing therapeutic intervention.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Apoptosis; Disease Models, Animal; Dizocilpine Maleate; Mice; Necrosis; Neurodegenerative Diseases; Retinal Ganglion Cells

The K+ channel blocker 4-aminopyridine (4-AP) stimulates the release of glutamate from nerve endings and induces seizures and neurodegeneration when perfused by microdialysis in rat hippocampus. In addition, there is a temporal correlation between the progress of neurodegeneration in the perfused hippocampus and the expression of the inducible cellular stress marker heat shock protein 70 (HSP70) in the non-damaged contralateral hippocampus. All these effects of 4-AP are prevented by the NMDA receptor antagonists 3-phosphonopropyl-piperazine-2-carboxilic acid (CPP) and (+)5-methyl-10,11-dyhydro-5H-dibenzo(a,d)cyclohepten-5,10-imine maleate (MK-801), indicating that they are due to NMDA receptor overactivation by excessive extracellular synaptic glutamate. We hypothesized that the induction of HSP70 in the non-damaged contralateral hippocampus should have a protective action against this excitotoxic effect. Here we demonstrate that 4-AP perfusion in one hippocampus prevented the neurotoxic effect of 4-AP when perfused by microdialysis in the contralateral hippocampus 24h later. However, both the stimulation of glutamate release and the EEG epileptiform discharges, which occur immediately after 4-AP perfusion, were similar after the first and the second perfusions. When CPP was coperfused with 4-AP during the first microdialysis, HSP70 induction in the contralateral hippocampus was prevented and the protection against the second 4-AP perfusion was abolished in 50% of the rats. These results suggest that HSP70 induction is an important cellular mechanism to protect vulnerable neurons from excitotoxic overactivation of glutamate receptors by endogenous glutamate, and may be relevant to pathological conditions in which extracellular endogenous glutamate is augmented, such as ischemia.

Topics: 4-Aminopyridine; Animals; Cell Count; Disease Models, Animal; Dizocilpine Maleate; Electroencephalography; Functional Laterality; Glutamic Acid; Hippocampus; HSP70 Heat-Shock Proteins; Male; Neurodegenerative Diseases; Neuroprotective Agents; Piperazines; Rats; Rats, Wistar; Time Factors

The postmortem and magnetic resonance imaging studies for schizophrenic patients showed neuropathological abnormalities including neuron loss and volume reduction in ventral hippocampus (VH), some longitudinal studies suggest these changes may be a neurodegenerative process.. The present study examined the effects of adult bilateral VH lesions on a dopaminergic stimulant, methamphetamine (METH)-induced and an N-methyl-(D)-aspartate (NMDA) receptor antagonist, dizocilpine (MK-801)-induced behavioral and neurochemical changes in rats, in order to evaluate a potential of adult VH lesion animals for a model of schizophrenia.. To study the behavioral effects after bilateral VH lesions in adult rats, locomotor activity was measured individually by an infra-red sensor. Extracellular concentrations of dopamine in the nucleus accumbens (NAc) were measured using in vivo brain microdialysis.. The bilateral adult VH lesion rats showed a significant enhanced hyperlocomotion in response to METH but no changes to MK-801 and phencyclidine; while bilateral adult VH lesion enhanced METH-induced increasing dopamine levels in the NAc.. The bilateral adult VH lesions enhanced locomotor activity, which related to increased dopamine releases in the NAc, induced by a dopaminergic stimulant; these findings may suggest a potential of adult VH lesion animal for a model reflecting dopamine D2 receptor antagonist-responsive pathophysiology of schizophrenia by way of neurodegenerative processes.

Topics: Animals; Behavior, Animal; Disease Models, Animal; Dizocilpine Maleate; Dopamine; Hippocampus; Male; Methamphetamine; Motor Activity; Neurodegenerative Diseases; Neurotoxins; Rats; Rats, Sprague-Dawley; Schizophrenia

Fetal alcohol exposure results in cognitive and neurobehavioral deficits, but the effects of modifying genetic loci on the severity of these sequelas have not been well characterized. Although the cAMP signaling pathway has been shown to be an important modulator of ethanol sensitivity in adult mice, its potential role in modulating ethanol-induced neurodegeneration has not been examined. Adenylyl cyclases (ACs) 1 and 8 produce cAMP in response to intracellular calcium elevation and modulate several aspects of neuronal function, including ethanol sensitivity. AC1 and AC8 are expressed widely throughout the brain of neonatal mice, and genetic deletion of both AC1 and AC8 in double-knock-out (DKO) mice enhances ethanol-induced neurodegeneration in the brains of neonatal mice. In addition, ethanol treatment induces significantly greater levels of caspase-3 activation in the brains of DKO mice compared with wild-type (WT) mice, reflecting higher numbers of apoptotic neurons. Administration of the NMDA receptor antagonist MK801 [(+)-5-methyl-10,11-dihydro-5H-dibenzo [a,d] cyclohepten-5,10-imine hydrogen maleate] or the GABA(A) receptor potentiator phenobarbital, which mimics components of the effects of ethanol on neurons, results in significantly greater neurodegeneration in the brains of neonatal DKO mice than WT mice. Furthermore, loss of a single calcium-stimulated AC isoform potentiates neurodegeneration after administration of ethanol, MK801, or phenobarbital. In contrast, the levels of physiological cell death, death after hypoxia/ischemia, and excitotoxic cell death are not increased in the brains of DKO mice. Thus, AC1 and AC8 are critical modulators of neurodegeneration induced by activity blockade in the neonatal brain and represent genetic loci that may potentially modify the severity of fetal alcohol syndrome.

Topics: Adenylyl Cyclases; Anilides; Animals; Animals, Newborn; Behavior, Animal; Blotting, Western; Brain; Calcium; Caspase 3; Caspases; Dizocilpine Maleate; Dose-Response Relationship, Drug; Drug Interactions; Ethanol; GABA Modulators; Hippocampus; Hypoxia; In Situ Hybridization; In Vitro Techniques; Mice; Mice, Inbred C57BL; Neurodegenerative Diseases; Neurons; Neuroprotective Agents; Oligopeptides; Phenobarbital; Silver Staining; Time Factors

Medical measures that bear no known danger for the adult brain may trigger active neuronal death in the developing brain. Pharmacological blockade of N-methyl-D-aspartate or activation of GABA(A) receptors, blockade of voltage-dependent sodium channels, and oxygen induce widespread apoptotic neurodegeneration during the period of rapid brain growth in rodents. Because such measures are often necessary in critically ill infants and toddlers, search for adjunctive neuroprotective strategies is warranted. We report that 17beta-estradiol ameliorates neurotoxicity of drugs that block N-methyl-D-aspartate receptors, activate GABA(A) receptors, or block voltage-gated sodium channels and reduces neurotoxicity of oxygen in the infant rat brain. This neuroprotective effect is reversed by tamoxifen and cannot be reproduced by 17alpha-estradiol. 17Beta-estradiol did not affect GABA(A) or N-methyl-D-aspartate currents in hippocampal neuronal cultures, indicating that direct modulation of neurotransmitter receptor/channel properties by this compound cannot explain neuroprotective effect. 17beta-Estradiol did, however, increase levels of phosphorylated extracellular signal-regulated kinase 1/2 and AKT, suggesting that activation of these prosurvival proteins may represent one mechanism for its neuroprotective action. 17Beta-estradiol and related compounds may be neuroprotective agents suitable for use in critically ill infants and toddlers. Its supplementation may particularly help to improve neurocognitive outcome in preterm infants who are prematurely deprived of maternal estrogen.

Topics: Animals; Animals, Newborn; Apoptosis; Bicuculline; Blotting, Western; Brain; Caenorhabditis elegans Proteins; Cell Count; Cells, Cultured; Cerebral Cortex; Disease Models, Animal; Dizocilpine Maleate; Dose-Response Relationship, Drug; Drug Interactions; Estradiol; Estrogen Antagonists; Extracellular Signal-Regulated MAP Kinases; GABA Antagonists; Hypoxia; Immunohistochemistry; In Situ Nick-End Labeling; Membrane Potentials; Neurodegenerative Diseases; Neurons; Neuroprotective Agents; Patch-Clamp Techniques; Phenobarbital; Phenytoin; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-akt; Rats; Rats, Wistar; Receptors, GABA-A; Silver Staining; Tamoxifen

Drugs that block NMDA receptors, thereby inducing an NMDA receptor hypofunctional (NRHypo) state, can cause a disseminated pattern of irreversible neurodegeneration. Based on several lines of evidence, an N-methyl-D-aspartate receptor hypofunction (NRHypo) mechanism has been postulated to contribute to neurodegenerative changes in Alzheimer disease (AD). Because estrogen putatively exerts a neuroprotective effect in AD, we examined whether estrogen protects against NRHypo-induced neurodegeneration. We administered estradiol benzoate in three separate experiments to adult female rats: (1) 100 microg subcutaneously as a onetime dose, (2) 100 microg bid twice daily for 4.5 or 14 d, and 3) 300 microg twice daily for 4.5 d. Two hours after the last estradiol dose, MK-801 was administered (0.5 mg/kg subcutaneously) to produce a robust neurotoxic injury. Controls received MK-801, but no estradiol. Four hours after administration of MK-801, the severity of injury was evaluated histologically by quantitative methods previously described. Compared to controls, a single dose of estradiol produced no change in the severity of injury (p = 0.24). Chronic treatment with estradiol was associated with a 25-35% reduction in the number of injured neurons (p < 0.05 in all cases). We conclude that chronic but not acute estradiol treatment reduces the severity of NRHypo-induced neurodegeneration.

Topics: Animals; Brain; Dizocilpine Maleate; Estradiol; Excitatory Amino Acid Antagonists; Female; Neurodegenerative Diseases; Neurons; Neuroprotective Agents; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate

The neurotoxic effect of the pro-inflammatory cytokine interleukin (IL)-1beta was studied in monolayer cultures, obtained using roller-drum incubation of hippocampal slices from neonatal Sprague Dawley rats. Following exposure to recombinant rat IL-1beta for four days, a concentration dependent loss was observed in the number of NMDAR1 receptor subunit immunoreactive pyramidal neurons in the cultures, reaching significance at 10 ng/ml rIL-1beta. Also incubation with recombinant mouse IL-1beta caused a loss of pyramidal neurons, with a significant effect at a concentration of 30 pg/ml. The vitamin E analog trolox (30 microM) was found to exert a protective effect against the rIL-1beta induced neuronal degeneration. A neuroprotective action against rIL-1beta was also found after co-incubation with the NMDA antagonist dizocilpine (MK-801; 30 microM), while no protection was found with the GABAA mimetic clomethiazole. Hence, the pro-inflammatory cytokine IL-1beta is neurotoxic to hippocampal pyramidal neurons when studied in an in vitro system with advanced phenotypic characteristics. The neuroprotective effects exerted by trolox and MK-801 suggest that free radicals and NMDA receptor-mediated processes are involved in IL-1beta -induced neurodegeneration.

Topics: Animals; Animals, Newborn; Antioxidants; Chlormethiazole; Chromans; Dizocilpine Maleate; Excitatory Amino Acid Agonists; GABA Modulators; Hippocampus; Immunohistochemistry; Interleukin-1; N-Methylaspartate; Neurodegenerative Diseases; Neuroprotective Agents; Organ Culture Techniques; Pyramidal Cells; Rats; Rats, Sprague-Dawley; Receptors, GABA-A

It has been demonstrated that the endogenous cannabinoid receptor ligand, anandamide, and other N-acylethanolamines (NAEs), accumulate during neuronal injury in vitro, a process that may be linked to the neuroprotective effects of NAEs. The crucial step for generation of NAEs is the synthesis of the corresponding precursors, N-acylethanolamine phospholipids (NAPEs). However, it is unknown whether this key event for NAE formation is regulated differently in the context of insults causing necrotic or apoptotic neuronal death. To address this question, we monitored a range of cortical NAPE species in three infant rat models of in vivo neurodegeneration: (i) necrosis caused by intrastriatal injection of NMDA (25 nmol); (ii) apoptosis induced by systemic administration of the NMDA-receptor antagonist (+)MK-801 (3 x 0.5 mg/kg, i.p.); and (iii) apoptosis following focal necrosis triggered by concussive head trauma. A marked increase of all NAPE species was observed in both hemispheres 4 and 24 h after NMDA-induced injury, with a relatively larger increase in N-stearoyl-containing NAPE species. Thus, the percentage of the anandamide precursor fell from 1.1 to 0.5 mol %. In contrast, administration of (+)MK-801 did not alter cortical NAPE levels. Concussion head trauma resulted in a similar but less pronounced upregulation of NAPE levels at both 4 and 24 h as compared to NMDA injections. Increased levels of NAPE 24 h post-trauma possibly reflect that necrosis is still ongoing at this time point. Consequently, our data suggest that excitotoxic necrotic mechanisms of neurodegeneration, as opposed to apoptotic neurodegeneration, have a profound effect on in vivo NAE precursor homeostasis.

Topics: Animals; Apoptosis; Arachidonic Acids; Brain Injuries; Cerebral Cortex; Corpus Striatum; Disease Models, Animal; Dizocilpine Maleate; Endocannabinoids; Ethanolamines; Male; N-Methylaspartate; Necrosis; Neurodegenerative Diseases; Neurons; Phospholipids; Polyunsaturated Alkamides; Rats; Rats, Sprague-Dawley; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Species Specificity; Wounds, Nonpenetrating

There is growing evidence that mitochondrial dysfunction is an important factor in a cascade of neurotoxic events as observed during pathogenesis of various neurodegenerative diseases. In the neurodegenerative disease amyotrophic lateral sclerosis (ALS) both spinal and cortical motoneurons degenerate, but in experimental studies most attention so far has been focussed on the spinal motoneurons. In order to study the role of mitochondrial dysfunction in the pathways leading to cortical (upper) motoneuron (CMN) death, a long-term culture system of rat cortical explants was used. CMNs were visualized by immunocytochemical labeling with antibodies directed against nonphosphorylated neurofilament, SMI-32, and for their identification we also used their location in layer V of the explant, their size, and their morphological appearance. In this model the effect of mitochondrial inhibition was studied through chronic malonate treatment. For 2 weeks, low doses of complex II inhibitor malonate were added to the cultures twice a week. The malonate-induced chronic mitochondrial inhibition resulted in a dose-dependent increase of CMN death in the slices. Neuroprotection was achieved with the NMDA antagonist MK-801 and the non-NMDA antagonist CNQX indicating the involvement of glutamate in the malonate-induced CMN death. Furthermore, our data indicate that chronic mitochondrial inhibition results in CMN death, which is mediated by glutamate excitotoxicity via both non-NMDA and NMDA receptors. In this respect the present in vitro approach may act as a model for understanding mechanisms underlying CMN death in ALS.

Topics: Animals; Antigens, Differentiation; Cell Death; Cell Size; Cells, Cultured; Cerebral Cortex; Dizocilpine Maleate; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Glutamic Acid; Immunohistochemistry; In Vitro Techniques; Malonates; Mitochondria; Models, Biological; Motor Neurons; Neurodegenerative Diseases; Neurofilament Proteins; Neuroprotective Agents; Pyramidal Cells; Rats; Rats, Wistar; Time Factors

The neuroprotective effects of the NMDA antagonists MK-801 and ketamine were analyzed in a mutant strain of Han-Wistar rats which develop neurodegeneration in the hippocampus and cerebellum. Previous experiments have shown that the progressive neuronal degeneration observed in this mutant may be the result of a dysfunctional glutamatergic system. For MK-801 studies, mutants were injected in a chronic paradigm with (+)MK-801 or its weaker acting isomer (-)MK-801 at a dose of 1 mg/kg. Ketamine studies consisted of both acute (50 mg/kg once) and chronic (10 mg/kg multiple times) injection paradigms. MK-801-treated mutants exhibited longer life spans (8-23%) compared to saline-injected mutants. Ketamine-injected mutants in both paradigms also lived slightly longer (6-9%) than the saline mutants. Motor skill deterioration was monitored in an open-field test, and after 50 days of age the MK-801 and ketamine mutants displayed over 20% greater motor skill activity than the saline mutants. In the cerebellum, mutants treated with ketamine and both forms of MK-801 had 10-20% more Purkinje cells surviving at 55 days than the saline mutants. Further, the density of CA3c pyramidal hippocampal neurons in ketamine and MK-801-treated mutants as compared to saline mutants appeared to be greater upon qualitative analysis. This study shows that these mutants derive some protective effects from the NMDA antagonists MK-801 and ketamine, confirming glutamate-induced excitotoxicity as a possible cause of neuronal degeneration in this mutant strain of rat.

Topics: Animals; Cell Survival; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Glutamic Acid; Hippocampus; Ketamine; Longevity; Muscle Spasticity; Neurodegenerative Diseases; Neuroprotective Agents; Neurotoxins; Purkinje Cells; Pyramidal Cells; Rats; Rats, Mutant Strains; Rats, Wistar; Receptors, N-Methyl-D-Aspartate