dizocilpine-maleate and Huntington-Disease

3-nitropropionic acid (3-NP), a substance used for modelling Huntington's disease, was given to male Wistar rats in a single 20 mg/kg b.w. dose, and the resulting behavioral alterations in spontaneous locomotor activity were measured after 30 minutes. To detect the involvement of neurotransmitter systems in this immediate effect, the NMDA antagonist MK-801 (0.8 mg/kg); as well as an agonist, quinpirole (QP, 5 mg/kg) and an antagonist, sulpiride (SP, 80 mg/kg) of the dopamine D2 receptors, were given before 3-NP to separate groups of rats. Controls were given saline. All substances were injected ip. 3-NP decreased the rats' locomotor, especially vertical, activity, whereas local activity was increased. Based on the further changes of 3-NP effects in the combination groups it could be concluded that dopaminergic rather than glutamatergic mechanisms were possibly involved in the acute behavioral effect of 3-NP.

Topics: Animals; Behavior, Animal; Disease Models, Animal; Dizocilpine Maleate; Dopamine Agents; Dopamine D2 Receptor Antagonists; Excitatory Amino Acid Agents; Huntington Disease; Male; Motor Activity; N-Methylaspartate; Nitro Compounds; Propionates; Quinpirole; Rats; Rats, Wistar; Receptors, Dopamine; Receptors, Dopamine D2; Receptors, Glutamate; Sulpiride

1. Caspases, key enzymes in the apoptosis pathway, have been detected in the brain of HD patients and in animal models of the disease. In the present study, we investigated the neuroprotective properties of a new, reversible, caspase-3-specific inhibitor, M826 (3-([(2S)-2-[5-tert-butyl-3-[[(4-methyl-1,2,5-oxadiazol-3-yl)methyl]amino]-2-oxopyrazin-1(2H)-yl]butanoyl]amino)-5-[hexyl(methyl)amino]-4-oxopentanoic acid), in a rat malonate model of HD. 2. Pharmacokinetic and autoradiography studies after intrastriatal (i.str.) injection of 1.5 nmol of M826 or its tritiated analogue [(3)H]M826 indicated that the compound diffused within the entire striatum. The elimination half-life (T(1/2)) of M826 in the rat striatum was 3 h. 3. I.str. injection of 1.5 nmol of M826 10 min after malonate infusion induced a significant reduction (66%) in the number of neurones expressing active caspase-3 in the ipsilateral striatum. 4. Inhibition of active caspase-3 translated into a significant but moderate reduction (39%) of the lesion volume, and of cell death (24%), 24 h after injury. The efficacy of M826 at inhibiting cell death was comparable to that of the noncompetitive NMDA receptor antagonist MK801. 5. These data provide in vivo proof-of-concept of the neuroprotective effects of reversible caspase-3 inhibitors in a model of malonate-induced striatal injury in the adult rat.

Topics: Animals; Autoradiography; Caspase 3; Caspase Inhibitors; Cell Count; Cell Death; Diffusion; Dizocilpine Maleate; Enzyme Inhibitors; Enzyme-Linked Immunosorbent Assay; Excitatory Amino Acid Antagonists; Half-Life; Huntington Disease; Male; Malonates; Neostriatum; Neurons; Neuroprotective Agents; Oxadiazoles; Pyrazines; Rats; Rats, Sprague-Dawley

Transplanting fetal striatal tissue is currently considered to be an important alternative strategy in the treatment of Huntington's disease. Although grafted striatal tissue differentiates and shows certain structural and neurochemical features of the normal striatum and receives host afferents, it is not clear whether host-derived afferent inputs can modulate the activity of neurotransmitter receptors and their signaling in the graft. An intricate interaction between dopaminergic and glutamatergic systems is pivotal for striatal function. In the present study, the modulation of D(2) receptors in the graft by host-derived glutamatergic afferents via NMDA receptors was investigated using haloperidol-induced c-Fos expression. The results indicate that haloperidol induces c-Fos in a large number of neurons in the P-zones of the graft and this induction is significantly suppressed by pretreatment with the NMDA receptor antagonist, MK-801. Therefore, the NMDA receptor-mediated modulation of D(2) receptor function seen in the normal striatum is established in the striatostriatal grafts.

Topics: Animals; Brain Injuries; Brain Tissue Transplantation; Corpus Striatum; Disease Models, Animal; Dizocilpine Maleate; Dopamine Antagonists; Excitatory Amino Acid Antagonists; Fetal Tissue Transplantation; Fluorescent Antibody Technique; Glutamine; Haloperidol; Huntington Disease; Immunohistochemistry; Male; Neurons, Afferent; Proto-Oncogene Proteins c-fos; Quinolinic Acid; Rats; Rats, Sprague-Dawley; Receptors, Dopamine D2; Receptors, N-Methyl-D-Aspartate

Transgenic Huntington's disease (HD) mice, expressing exon 1 of the HD gene with an expanded CAG repeat, are totally resistant to striatal lesion induced by excessive NMDA receptor activation. We now show that striatal lesions induced by the mitochondrial toxin malonate are reduced by 70-80% in transgenic HD mice compared with wild-type littermate controls. This occurred in 6- and 12-week-old HD mice with 150 CAG repeats (line R6/2) and in 18-week-old, but not 6-week-old, HD mice with 115 CAG repeats (line R6/1). Therefore, we show for the first time that the resistance to neurotoxin in transgenic HD mice is dependent on both the CAG repeat length and the age of the mice. Importantly, most HD patients develop symptoms in adulthood and exhibit an inverse relationship between CAG repeat length and age of onset. Transgenic mice expressing a normal CAG repeat (18 CAG) were not resistant to malonate. Although endogenous glutamate release has been implicated in malonate-induced cell death, glutamate release from striatal synaptosomes was not decreased in HD mice. Malonate-induced striatal cell death was reduced by 50-60% in wild-type mice when they were treated with either the NMDA receptor antagonist MK-801 or the caspase inhibitor zVAD-fmk. These two compounds did not reduce lesion size in transgenic R6/1 mice. This might suggest that NMDA receptor- and caspase-mediated cell death pathways are inhibited and that the limited malonate-induced cell death still occurring in HD mice is independent of these pathways. There were no changes in striatal levels of the two anti cell death proteins Bcl-X(L) and X-linked inhibitor of apoptosis protein (XIAP), before or after the lesion in transgenic HD mice. We propose that mutant huntingtin causes a sublethal grade of metabolic stress which is CAG repeat length-dependent and results in up-regulation over time of cellular defense mechanisms against impaired energy metabolism and excitotoxicity.

Topics: Aging; Amino Acid Chloromethyl Ketones; Animals; bcl-X Protein; Blood Glucose; Cell Death; Corpus Striatum; Disease Models, Animal; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Female; Glutamic Acid; Humans; Huntingtin Protein; Huntington Disease; Immunoblotting; Immunohistochemistry; Male; Malonates; Mice; Mice, Inbred C57BL; Mice, Inbred CBA; Mice, Transgenic; Nerve Tissue Proteins; Neurons; Neuroprotective Agents; Nuclear Proteins; Proteins; Proto-Oncogene Proteins c-bcl-2; Succinate Dehydrogenase; Synaptosomes; Trinucleotide Repeats; X-Linked Inhibitor of Apoptosis Protein

At different times post-lesion, the excitotoxically lesioned striatum has been shown to undergo significant neuroanatomical and neurochemical changes, which could be expressed behaviorally. Gender and dose of excitotoxin are other variables that may modify the behavioral effects of the lesion. Consequently, the purpose of this study was to determine the effect of dose, gender, and time post-lesion on spontaneous and drug-induced locomotor behavior after intrastriatal KA lesions. Results showed that dose and time post-lesion had a significant effect on the deficits observed. Hyperactivity induced by the lesion with KA (5 nm) subsided as time post-lesion increased. Both the pattern of spontaneous and MK-801-induced locomotor activity were different for male and female rats. In female animals with KA lesions (5 nm), MK-801 did not stimulate ambulatory activity nor reduce vertical activity. Both female and male rats lesioned with KA (5 nm) showed an exaggerated response to amphetamine, at a time when spontaneous locomotor activity was reduced to control levels. Haloperidol significantly reduced locomotor activity in all groups.

Topics: Animals; Disease Models, Animal; Dizocilpine Maleate; Excitatory Amino Acid Agonists; Excitatory Amino Acid Antagonists; Female; Huntington Disease; Hyperkinesis; Kainic Acid; Male; Motor Activity; Neostriatum; Neurons; Neurotoxins; Rats; Rats, Wistar; Sex Characteristics

Injection of the excitatory amino-acid analog quinolinic acid into the striatum of rats produces neuropathological and neurochemical alterations that are reminiscent of those observed in Huntington's disease. In the present study, we evaluated quinolinic acid-induced striatal changes using quantitative autoradiographic binding assays for [3H]MK-801-labeled NMDA receptors, [3H]SCH 23390-labeled dopamine D1 and [3H]sulpiride-labeled dopamine D2 receptors, [3H]CGS 21680-labeled adenosine A2a receptors, [3H]mazindol-labeled dopamine uptake sites, [3H]hemicholinium-3-labeled high affinity choline uptake sites and [3H]PK 11195-labeled peripheral-type benzodiazepine binding sites, as markers of different cellular populations of the striatum. We found that decrease in [3H]MK 801 and [3H]SCH 23390 binding, and increase in [3H]PK 11195 binding were the most significant alterations induced by the intrastriatal injection of quinolinic acid. Concentrations of [3H]CGS 21680 and [3H]hemicholinium-3 bindings were also decreased, however, to a lesser extent, and [3H]sulpiride binding was not significantly affected. Quinolinic acid also produced an increase in [3H]mazindol binding. We tested the specificity of the N-methyl-D-aspartate receptor-mediated mechanism of quinolinic acid neurotoxicity using MK 801 pretreatment, an N-methyl-D-aspartate receptor antagonist, and it prevented all quinolinic acid-induced binding changes. Because anticholinergic drugs were proposed to prevent the neurotoxic side-effects of MK 801, we also tested the effect of scopolamine pretreatment and found that it altered neither the neurotoxicity induced by quinolinic acid nor the neuroprotective effect of MK 801.

Topics: Animals; Autoradiography; Benzazepines; Binding, Competitive; Cholinergic Agents; Corpus Striatum; Disease Models, Animal; Dizocilpine Maleate; Dopamine Antagonists; Dopamine Uptake Inhibitors; Excitatory Amino Acid Antagonists; Hemicholinium 3; Huntington Disease; Isoquinolines; Male; Mazindol; Muscarinic Antagonists; Neurons; Quinolinic Acid; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Scopolamine; Sulpiride; Tritium

Huntington's disease is a dominantly inherited, progressive neurodegenerative disorder causing marked pathology in the basal ganglia. The pathophysiology of the selective neuronal death is as yet unknown, but evidence suggests that the neurotoxicity may result from endogenous substances acting at excitatory amino acid receptors. Previous data have shown a selective decrease in binding to one class of glutamate receptors, the N-methyl-D-aspartate (NMDA) receptor in the putamen of Huntington's disease. The present study was undertaken to determine the relative density of binding to all of the currently defined subpopulations of excitatory amino acid receptors in the caudate nuclei and frontal cortex of patients with Huntington's disease and of control subjects, using quantitative in vitro autoradiography. NMDA, MK-801, glycine, kainate, and alpha-amino-3-hydroxy-5-methylisoxazole propionic acid (AMPA) receptor binding were all decreased to a similar extent (50-60%). Binding to the metabotropic quisqualate receptor and to the non-NMDA, nonkainate, nonquisqualate (NNKQ) site was decreased nonsignificantly by 31% and 26%, respectively. Autoradiograms of NMDA, MK-801, AMPA, kainate, metabotropic, and NNKQ receptors in caudates revealed an inhomogeneous pattern of binding that is different from the binding pattern seen in control caudates. Binding to all receptor subtypes was the same in the frontal cortex from Huntington's disease patients and control subjects. The data suggest that no single excitatory amino acid receptor is selectively decreased in the caudate of Huntington's disease.

Topics: Adolescent; Adult; Age Factors; Aged; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Binding, Competitive; Caudate Nucleus; Cell Death; Child; Dizocilpine Maleate; Frontal Lobe; Glycine; Humans; Huntington Disease; Ibotenic Acid; Kainic Acid; Middle Aged; N-Methylaspartate; Phencyclidine; Receptors, AMPA; Receptors, Glutamate; Receptors, Glycine; Receptors, Kainic Acid; Receptors, Metabotropic Glutamate; Receptors, N-Methyl-D-Aspartate; Receptors, Neurotransmitter; Receptors, Phencyclidine

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Aging; Alzheimer Disease; Animals; Dizocilpine Maleate; Haplorhini; Humans; Huntington Disease; Nerve Degeneration; Neurotoxins; Parkinson Disease; Quinolinic Acid; Quinolinic Acids; Receptors, Dopamine

Using the excitotoxic animal model of Huntington's disease, two experimental treatments were evaluated. The first experiment explored the effect of MK801 (a systemically active anticonvulsant, and noncompetitive NMDA antagonist) pretreatment on quinolinic acid (QA)-induced striatal degeneration and behavioral deficits. MK801 prevented QA-induced neuropathological changes in the striatum and the anatomical protection was correlated with the absence of deficits in the cataleptic response to haloperidol. The second experiment tested the ability of three types of fetal grafts to reverse behavioral deficits induced by kainic acid (KA) lesion. Fetal (E15-16) striatal, cortical and tectal grafts were delivered into the KA-lesioned striatum one week or one month after lesion. Animals in this experiment were evaluated on a motor coordination task, haloperidol-induced catalepsy and amphetamine-induced locomotor activity. Striatal grafts attenuated the deficits induced by KA in all of the tasks observed, and no effect of time of grafting was detected. Tectal grafts had a partial beneficial effect, attenuating the decrease in the cataleptic response to haloperidol observed after KA lesions. No effect of time of grafting was detected for these grafts. In contrast, a clear effect of time of grafting was detected for the cortical grafts. Early cortical grafts reversed the exaggerated response to amphetamine observed after KA lesions whereas late cortical grafts resulted in sham-like scores on the catalepsy test. Histochemical analysis showed that most of the grafts survived, had acetylcholinesterase (AChE) positive fibers and cell bodies, and were metabolically active as indicated by cytochrome oxidase (CO) positive staining. It is suggested that striatal grafts may have restored to some extent the striatal GABAergic control over output structures, and that trophic factors play a role in behavioral recovery as is evident from the beneficial effects of the tectal grafts. Although the mechanisms underlying the differential effects observed after early or late cortical grafts are unknown, the interaction between the cellular components and trophic factors present in the cortical grafts and the condition of the lesioned host at the time of grafting may yield a host-graft complex with a unique profile.

Topics: Acetylcholinesterase; Amphetamine; Animals; Brain Tissue Transplantation; Catalepsy; Cerebral Cortex; Corpus Striatum; Dizocilpine Maleate; Electron Transport Complex IV; Female; Fetal Tissue Transplantation; Huntington Disease; Immunohistochemistry; Kainic Acid; Motor Activity; Nerve Degeneration; Pregnancy; Quinolinic Acid; Quinolinic Acids; Rats; Rats, Inbred Strains

Despite several decades of research aimed at elucidating the mechanisms underlying neuronal degeneration in Parkinson's and Huntington's diseases, these mysteries remain unfathomed. The brain contains high concentrations of the putative transmitters, glutamate and aspartate, which have neurotoxic (excitotoxic) potential and are thought to cause neuronal degeneration in certain acute neurological disorders. However, no mechanism has been identified by which these diffusely distributed agents might cause the regionally selective patterns of neuronal degeneration characterizing Parkinson's and Huntington's diseases. Here we report that L-DOPA, the natural precursor to dopamine, is a weak excitotoxin and its ortho-hydroxylated derivative, 6-OH-DOPA, is a powerful excitotoxin. We propose that an excitotoxic process mediated by L-DOPA or an acidic derivative such as 6-OH-DOPA might be responsible for degeneration of nigral neurons in Parkinson's disease or striatal neurons in Huntington's disease.

Topics: 2-Amino-5-phosphonovalerate; 6-Cyano-7-nitroquinoxaline-2,3-dione; Animals; Chick Embryo; Dibenzocycloheptenes; Dihydroxyphenylalanine; Dizocilpine Maleate; Hippocampus; Huntington Disease; Levodopa; Neurons; Parkinson Disease; Quinoxalines; Receptors, Neurotransmitter; Retina

Quinolinic acid (QA) is an endogenous excitotoxin present in mammalian brain that reproduces many of the histologic and neurochemical features of Huntington's disease (HD). In the present study we have examined the ability of a variety of systemically administered compounds to modify striatal QA neurotoxicity. Lesions were assessed by measurements of the intrinsic striatal neurotransmitters substance P, somatostatin, neuropeptide Y, and GABA. Histologic examination was performed with Nissl stains. The antioxidants ascorbic acid, beta-carotene, and alpha-tocopherol administered s.c. for 3 d prior to striatal QA lesions had no significant effect. Other drugs were administered i.p. 1/2 hr prior to QA striatal lesions. The following were ineffective in blocking QA excitotoxicity: allopurinol, 50 and 100 mg/kg; ketamine, 75 mg/kg; nimodipine, 2.4, and 10 mg/kg; baclofen, 10 mg/kg; 2-amino-5-phosphonovalerate, 50 mg/kg; and 2-amino-7-phosphonoheptanoate, 50 mg/kg. Oral taurine administration for 4 weeks resulted in significantly increased levels of brain taurine but had no significant effect in blocking QA neurotoxicity. Systemic administration of the noncompetitive N-methyl-D-aspartate (NMDA) antagonist MK-801 resulted in a dose-responsive protection against QA toxicity, with complete block at a dose of 4 mg/kg. If the pathogenesis of HD involves QA or another excitotoxin acting at the NMDA receptor, it is possible that MK-801 could retard the degenerative process.

Topics: 2-Amino-5-phosphonovalerate; Allopurinol; Amino Acids; Animals; Antioxidants; Baclofen; Corpus Striatum; Dibenzocycloheptenes; Disease Models, Animal; Dizocilpine Maleate; Huntington Disease; Ketamine; Male; Neuropeptide Y; Nimodipine; Peptides; Pyridines; Quinolinic Acid; Quinolinic Acids; Rats; Rats, Inbred Strains; Substance P; Taurine; Valine