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Showing papers in "Journal of Neural Transmission in 1999"


Journal ArticleDOI
TL;DR: The present data indicate an elevated kynurenine metabolism in AD brain and a marked increase of KYNA in the caudate nucleus and putamen may compensate the hyperactivity of the striato-frontal loop in AD brains.
Abstract: L-kynurenine (L-KYN) serves as a substrate for the synthesis of neurotoxic 3-OH-kynurenine (3-OH-KYN) and neuroprotective kynurenic acid (KYNA). KYNA is able to interact with ionotropic excitatory amino acid receptors that are involved in a variety of neurodegenerative disorders. The purpose of the present study was to investigate the biosynthetic machinery of KYNA in several regions of Alzheimer's disease (AD) brain. The endogenous levels of L-KYN, 3-OH-KYN and KYNA in frontal cortex, caudate nucleus, putamen, hippocampus, and cerebellum of 11 autopsy confirmed cases of AD and 13 age-matched controls were analyzed. Subsequently, the activity of two proteins responsible for the production of KYNA, kynurenine aminotransferases I and II (KAT I and KAT II), was investigated. There was a trend for a decrease of L-KYN and 3-OH-KYN in all examined regions of AD brain, as compared to controls. However, KYNA was increased significantly in the putamen and caudate nucleus of AD, by 192 and 177%, respectively. In other areas of AD brain only a minor increase of KYNA was present. Elevated KYNA in the caudate nucleus and putamen correlated with a significant increase of KAT I activities in both nuclei-157 and 147%, respectively. A minor increase of KAT II was measured only in the caudate nucleus of AD subjects. Kinetic analysis of KAT I and II performed in the caudate nucleus of AD patients revealed a marked increase of Vmax, by 207 and 274% of controls, respectively. Km value for L-KYN using pyruvate as amino acceptor was significantly higher for KAT II (247% of controls). The present data indicate an elevated kynurenine metabolism in AD brain. A marked increase of KYNA in the caudate nucleus and putamen may compensate the hyperactivity of the striato-frontal loop in AD brains. Blockade of NMDA receptors by KYNA may be responsible for impaired memory, learning and cognition in AD patients.

217 citations


Journal ArticleDOI
TL;DR: It is suggested that the increased activity of some glycolytic enzymes may be, at least in part, the result of the reactive astrocytosis developing in the course of AD.
Abstract: The activities of hexokinase, aldolase, pyruvate kinase, lactate dehydrogenase and glucose 6-phosphate dehydrogenase were determined in brains of patients with Alzheimer's disease (AD) and in age matched controls. For pyruvate kinase and lactate dehydrogenase a significant increase in specific activity was found in frontal and temporal cortex of AD brains, while the activities of aldolase and hexokinase are not changed. Glucose 6-phosphate dehydrogenase activity was significantly reduced in hippocampus. The increase of some glycolytic enzyme activities is correlated with increased contents of lactate dehydrogenase and glial fibrillary acidic protein (GFAP) in homogenates of frontal and temporal cortex and elevated phosphofructokinase (PFK) and GFAP in astrocytes from the same brain areas. The data extend previous findings on an increase in brain PFK specific activity in AD and suggest that the increased activity of some glycolytic enzymes may be, at least in part, the result of the reactive astrocytosis developing in the course of AD.

156 citations


Journal ArticleDOI
TL;DR: A global model was developed in which flupirtine stabilizes the resting membrane potential by activating inwardly rectifying K+ channels, thus indirectly inhibiting the activation of NMDA receptors.
Abstract: The spectrum of action of flupirtine includes analgesia, muscle relaxation and neuroprotection. N-methyl-D-aspartate (NMDA) receptor antagonism has been discussed as a possible mechanism of action of this compound with little direct evidence. The objective of the present study was to develop a plausible model to explain flupirtine's spectrum of action. A four-stage strategy was selected for this purpose: Firstly, the serum concentration of flupirtine under therapeutic conditions was determined on the basis of the current literature. The second stage involved assessing the known in-vitro effects in light of the therapeutic active concentration. Using whole cell patch clamp recordings from cultured rat superior colliculus neurones interactions between flupirtine and NMDA receptors were assessed. Only very high concentrations of flupirtine antagonized inward currents to NMDA (200 μM) at −70 mV with an lC50 against steady-state responses of 182.1 ± 12.1 μM. The effects of flupirtine were voltage-independent and not associated with receptor desensitization making actions within the NMDA receptor channel or at the glycine modulatory site unlikely. NMDA receptor antagonism probably has little relevance for the clinical efficacy of flupirtine as the concentrations needed were far higher than those achieved in clinical practice. However, the activation of a G-protein-regulated inwardly rectifying K+ channel was identified as an interesting molecular target site of flupirtine. In the next stage, the central nervous spectrum of action of experimental K+ channel openers (PCO) was considered. As far as they have been studied, experimental K+ channel openers display a spectrum of action comparable to that of flupirtine. In the final stage, a global model was developed in which flupirtine stabilizes the resting membrane potential by activating inwardly rectifying K+ channels, thus indirectly inhibiting the activation of NMDA receptors. The model presented here reconciles the known functional NMDA receptor antagonism of flupirtine with the activation of K+ channels that occurs at therapeutic concentrations, thus providing an understanding of flupirtine's spectrum of action. This makes flupirtine the prototype of a clinically applicable substance group with analgesic, muscle-relaxant and neuroprotective properties.

120 citations


Journal ArticleDOI
TL;DR: Findings point to a selective impairment of nigrostriatal and mesolimbic DA in aging rats, whereas reductions in NA were restricted to cell bodies region and 5-HT showed changes of different extent in areas of terminals and neuronal cell bodies.
Abstract: This study examines the age-associated changes in noradrenaline (NA), dopamine (DA), 3,4-dihydroxyphenyl-acetic acid (DOPAC), serotonin (5-HT) and 5-hydroxy-3-indoleacetic acid (5-HIAA) in different brain areas of rats DA and DOPAC concentrations in striatum increased at third month of age, remaining without significant variations until 12th month of age, and decreasing in 24-month-old rats DA concentration dropped in hippocampus, amygdala and brainstem of 24-month-old-rats, whereas DOPAC levels decreased only in hippocampus These changes suggest an age-dependent deficit of the dopaminergic system, presumably related to a reduced number/activity of DA nigrostriatal and mesolimbic neurons An age-induced decline in NA content was found in the pons-medulla, the area containing NA neuronal bodies Concentrations of 5-HT were reduced with aging in frontal cortex, showing a tendency to decrease in all brain areas examined The increased 5-HIAA/5-HT ratio found in frontal cortex, amygdala and striatum suggests an age-related decreased synthesis and an accelerated 5-HT metabolism The 5-HIAA content decreased in brainstem of the oldest rats These findings point to a selective impairment of nigrostriatal and mesolimbic DA in aging rats, whereas reductions in NA were restricted to cell bodies region and 5-HT showed changes of different extent in areas of terminals and neuronal cell bodies

111 citations


Journal ArticleDOI
TL;DR: It is concluded that neuronal loss and Lewy body formation in the nbM may contribute to the reduction in cortical ChAT in DLB.
Abstract: The biological substrate underlying the reduced cortical choline acetyltransferase (ChAT) in dementia with Lewy bodies (DLB) is incompletely understood. We compared cortical ChAT levels with Lewy body densities and neuronal loss in the nucleus basalis of Meynert (nbM) and cerebral cortex in six DLB, seven Alzheimer's disease (AD), and six control cases. We found greater neuronal loss in the nbM in DLB compared to AD (U = 9.500, p = 0.049). Mean ChAT levels in the cortex were lower in dementia patients than controls (t = 17.500, p = 0.001), and DLB cases had slightly lower ChAT levels than AD cases, but this difference was not significant (t = −0.332, p = 0.746). Overall, cortical ChAT levels correlated inversely with neuronal loss in the nbM (Spearman rank correlation coefficient = −0.53). The correlation between ChAT level and the combined factor of nbM LBs and neuronal loss was −0.59. A similar correlation between ChAT level and the combined factor of nbM neurofibrillary tangles and neuronal loss was −0.72. The correlation between ChAT and the combined factor of nbM LBs and neuronal loss was −0.81 when AD cases were excluded from the analysis. Local cortical pathology was not related to ChAT level. We conclude that neuronal loss and Lewy body formation in the nbM may contribute to the reduction in cortical ChAT in DLB.

106 citations


Journal ArticleDOI
TL;DR: The ongoing deterioration in behavior and the maintained deficit in cerebral energy metabolism occurring after a triplicate icv streptozotocin (STZ) injection were significantly slowed down by EGb761, underscoring the beneficial effect of EGb 761 that had been reported in dementia disorders.
Abstract: The standardized extract EGb 761 from the dried green leaves of Ginkgo biloba is a complex mixture of ingredients with an uniquely broad spectrum of pharmacological activities on the central nervous system e.g. in memory enhancing properties and in the regulation of cerebral glucose/energy metabolism. To test these effects on both behavioral and metabolic brain parameters, the animal model of intracerebroventricular (icv) streptozotocin (STZ) treatment was used. To quantify the experimental data more precisely, animals that were good performers were separated from poor performers by means of the holeboard test before icv administration of STZ. Good performers only were considered for the study. After a 1-week training period on the holeboard improvement was seen in all animals in learning, memory and cognition, and the improvement was maintained over the investigation period of 12 weeks in the control group. In this group, the energy pool in the cerebral parietotemporal cortex was found to be large and the energy turnover high. After triplicate icv STZ injection, working memory (WM), reference memory (RM), and passive avoidance (PA) behavior fell off and continued to deteriorate throughout the investigation period. Otherwise there were no significant differences in locomotor activity, excluding the possibility that activity per se might have contributed to the behavioral abnormalities. These were accompanied by a permanent deficit in cerebral energy metabolism. The ongoing deterioration in behavior and the maintained deficit in cerebral energy metabolism occurring after a triplicate icv STZ injection were significantly slowed down by EGb761. The deficits in learning, memory and cognition were partially compensated, and the disturbances in cerebral energy metabolism returned to almost completely normal values. These findings underscore the beneficial effect of EGb761 that had been reported in dementia disorders.

99 citations


Journal ArticleDOI
TL;DR: Management of PD includes pharmacological treatment or/and surgical intervention, and Disorders of the basal ganglia usually encompasses idiopathic and Parkinsonianlike syndromes.
Abstract: Disorders of the basal ganglia can be broadly divided into two: ones that manifest hypokinesia or those that elicit hyperkinesia. Parkinson's disease is the commonest form of hypokinetic disorder. The term Parkinson's disease (PD) usually encompasses idiopathic and Parkinsonianlike syndromes. PD is a chronic and progressive disease, in which the symptoms tend to appear unilateral to begin with. Subsequently subtle dysfunctions on the contralateral side may also be observed. Tremor, akinesia and rigidity are some of the classical features of the disease. Although many hypotheses have been proposed, the cause of PD largely remains obscure. Management of PD includes pharmacological treatment or/and surgical intervention.

90 citations


Journal Article
TL;DR: In this article, the authors present evidence to support the theory that the phenotypic traits of aneuploid syndromes, and DS in particular, result from the increased dosage of genes encoded on the triplicated chromosome.
Abstract: Two hypotheses exist to explain the Down syndrome (DS) phenotype. The “gene dosage effect” hypothesis states that the phenotype is a direct result of the cumulative effect of the imbalance of the individual genes located on the triplicated chromosome or chromosome region. In a nut shell, the phenotype results directly from the overexpression of specific chromosome 21 genes. The “amplified developmental instability” hypothesis contends that most manifestations of DS may be interpreted as the results of a non-specific disturbance of chromosome balance, resulting in a disruption of homeostasis. This hypothesis was proposed in an attempt to explain the similarities between the phenotypes of different aneuploid states and the observation that all of the phenotypic traits in DS are also seen in the general population but at lower frequency, with less severity and usually only present as a single trait. Herein, we review recent data and present evidence to support the theory that the phenotypic traits of aneuploid syndromes, and DS in particular, result from the increased dosage of genes encoded on the triplicated chromosome.

89 citations


Journal ArticleDOI
TL;DR: Data suggest that not only is oxidative stress a feature of Alzheimer's disease, but also that it occurs because of increased prooxidant activity rather than a diminished antioxidant capacity.
Abstract: In order to assess the integrity of antioxidant enzymes in Alzheimer's disease, the activities of glutathione peroxidase, glutathione reductase and two enzymes of the pentose phosphate pathway (glucose-6-phosphate dehydrogenase and 6-phosphonogluconate dehydrogenase) were determined in three regions of postmortem neocortex of controls and subjects with Alzheimer's disease. The activities of glutathione peroxidase and glutathione reductase were unaffected in Alzheimer's disease. By contrast, there was a selective increase in the activities of glucose-6-phosphate dehydrogenase and 6-phosphonogluconate dehydrogenase in the inferior temporal cortex of Alzheimer subjects. These changes negatively correlated with the Fe2+/ascorbate-induced lipid peroxidation which (in a previous study of the same subjects) was also found to be selectively elevated in the inferior temporal cortex. Increased activity of the pentose phosphate pathway probably occurs in response to increased prooxidant activity since both glucose-6-phosphate and 6-phosphonogluconate inhibited H2O2-induced lipid peroxidation in a concentration dependant fashion (IC50 = 504 +/- 105 microM and 88 +/- 12 microM, respectively). Together, these data suggest that not only is oxidative stress a feature of Alzheimer's disease, but also that it occurs because of increased prooxidant activity rather than a diminished antioxidant capacity.

88 citations


Journal ArticleDOI
TL;DR: It is drawn that a 5-HT2A receptor antagonist, due to i a the low side effect liability, could be the preferable treatment strategy in various disorders associated with hypoglutamatergia; such conditions might include schizophrenia, childhood autism and dementia disorders.
Abstract: The purpose of the present study was to compare the effectiveness of the selective 5-HT2A antagonist M100907 in different psychosis models. The classical neuroleptic haloperidol was used as reference compound. Two hyperdopaminergia and two hypoglutamatergia mouse models were used. Hyperdopaminergia was produced by the DA releaser d-amphetamine or the DA uptake inhibitor GBR 12909. Hypoglutamatergia was produced by the un-competitive NMDA receptor antagonist MK-801 or the competitive NMDA receptor antagonist D-CPPene. M100907 was found to counteract the locomotor stimulant effects of the NMDA receptor antagonists MK-801 and D-CPPene, but spontaneous locomotion, d-amphetamine- and GBR-12909-induced hyperactivity were not significantly affected. Haloperidol, on the other hand, antagonized both NMDA antagonist- and DA agonist-induced hyperactivity, as well as spontaneous locomotion in the highest dose used. Based on the present and previous results we draw the conclusion that 5-HT2A receptor antagonists are particularly effective against behavioural anomalies resulting from hypoglutamatergia of various origins. The clinical implications of our results and conclusions would be that a 5-HT2A receptor antagonist, due to i a the low side effect liability, could be the preferable treatment strategy in various disorders associated with hypoglutamatergia; such conditions might include schizophrenia, childhood autism and dementia disorders.

84 citations


Journal ArticleDOI
TL;DR: Rasagiline in repeat ip doses of 1–3 mg/kg within 16 h, or by sustained iv infusion to maintain a 3-h steady-state at corresponding levels, improved the outcome of permanent middle cerebral artery occlusion (MCAO) in the rat.
Abstract: Rasagiline, as the mesylate salt (TVP-1012), is a selective, potent, non-reversible MAO-B inhibitor of the propargylamine type. Current cellular and whole animal studies suggested a potential for neuroprotection by rasagiline. Rasagiline in repeat ip doses of 1-3mg/kg within 16h, or by sustained iv infusion to maintain a 3-h steady-state at corresponding levels, improved the outcome of permanent middle cerebral artery occlusion (MCAO) in the rat. In five independent studies using different protocols, rasagiline improved neurological severity score (NSS) with respect to saline from a high of 8.96 +/- 2.18 (n = 94) at 24h, and 7.64 +/- 2.52 (n +/- 49) at 48h, to a low of 7.13 +/- 2.32 (n = 88) at 24h, and 4.99 +/- 2.31 (n = 68) at 48h. Under the same conditions, there was a decrease in the volume of necrotic brain region determined at 48h by triphenyl tetrazolium chloride (TTC), from a high of 240 +/- 66 (n = 54) to a low of 176 +/- 77 mm(3) (n = 55); and by MRI scan at 48h, from a high of 297 +/- 62 (n = 25), to a low of 209 +/- 63 mm(3) (n = 28). Improvement in NSS was more obvious at 48h post MCAO, at the higher dose, when timing of drug administration was within the interval -30 min to 3 h from MCAO. A 3-h iv infusion of rasagiline caused a maximal reduction in infarct volume of about 49% of control. The (S)enantiomer of rasagiline TVP-1022, not a MAO inhibitor, was less effective, but still significantly different from saline, NSS at 48h 5.6 +/- 2.5 (n = 24) vs. 7.5 +/- 2.5 (n = 24), infarct volume 200 +/- 64 (n = 24) vs. 240 +/- 55 mm(3) (n = 24). Selegiline (n = 19) at corresponding ip doses was not different from saline. Dizocilpine decreased infarct volume from 277 +/- 65 (n = 20) to 203 +/- 52mm(3) (n = 21) but could not improve NSS at 24 or 48h. In this model, rasagiline could have exerted a neuroprotective effect independent of MAO inhibition.

Journal ArticleDOI
TL;DR: STN stimulation is a suitable functional neurosurgical procedure for the modulation and control of PD signs associated with severe motor fluctuations, in that they demonstrate a beneficial effect which was fully sustained over a one year follow-up period.
Abstract: Deep brain stimulation (DBS) of the subthalamic nucleus (STN) with a quadripolar electrode was carried out in 9 patients with advanced idiopathic Parkinson's disease (PD) affected with severe diurnal motor fluctuations The effect of bilateral STN stimulation was evaluated by clinical methods in all patients after 3 and 12 months Assessment was based on the Unified Parkinson's Disease Rating Scale (UPDRS), timed motor tests, the Schwab and England Activities of Daily Living and a diary chart to document motor fluctuations Alterations in parkinsonian signs, motor performance and functional outcome were recorded postoperatively (1) under temporary complete withdrawal of both STN stimulation and medication; (2) in the presence of STN stimulation only; and (3) in the presence of both STN stimulation and medication The results were compared with the preoperative data assessed in defined on-phase and defined off-phase STN stimulation on (compared to STN stimulation off) results in a significant improvement in UPDRS motor scores: after 3 months from 505 ± 143 to 278 ± 58, and after 12 months from 494 ± 141 to 271 ± 71 (p < 001) There was a significant decrease in the average duration of off-periods from 882 ± 247 hours to 100 ± 106 hours (p < 0001), a marked increase in on-periods without dyskinesia from 462 ± 272 to 1462 ± 151 hours (p < 001), and a sharp drop in on-periods with dyskinesia from 287 (± 418) to 025 (± 097) hours (p < 005), which remained stable up to 12 months (off-periods: 125 ± 158 hours, p < 0001; on-periods without: 1387 ± 195 hours, p < 0001; and on-periods wth dyskinesia: 037 ± 106 hours, p < 005) However, our first PD patient with an implanted DBS electrode within the STN died from cardiac infarction two days after surgery This sudden death was not linked either to surgery nor to stimulation – and happened by chance Our findings confirm that STN stimulation is a suitable functional neurosurgical procedure for the modulation and control of PD signs associated with severe motor fluctuations, in that they demonstrate a beneficial effect which was fully sustained over a one year follow-up period

Journal ArticleDOI
TL;DR: Evaluation of three housekeeping genes, as well as Trk B and Trk C demonstrated that the levels of mRNA transcripts were stable in brain samples at all time periods examined, demonstrating that this RT-PCR protocol is a sensitive and reliable method to study relative amounts of mRNAs.
Abstract: RNA isolated from frozen human post-mortem brain tissue was used for analysis of five gene products with a recently developed sensitive and competitive RT-PCR technique. Samples varying in post-mortem intervals up to four days from controls, schizophrenics and alcoholics were analyzed. Evaluation of three housekeeping genes, as well as Trk B and Trk C demonstrated that the levels of mRNA transcripts were stable in brain samples at all time periods (one to four days) examined. This observation demonstrates that this RT-PCR protocol is a sensitive and reliable method to study relative amounts of mRNAs. The overall stability of housekeeping transcripts implicates the value of post-mortem brain samples for differential gene expression studies.

Journal ArticleDOI
TL;DR: The data suggest that this developmental lesion alters function of the dopaminergic system in response to environmental and pharmacological challenge.
Abstract: In vivo microdialysis was used to study the effects of restraint stress (30 min) and amphetamine (AMPH) (5 mg/kg, i.p.) in awake adult male rats with neonatal ventral hippocampal (VH) damage. Extracellular levels of dopamine (DA), dihydrophenylacetate (DOPAC), homovanillate (HVA) and 5-hydroxyindolacetate (5-HIAA) were measured in the nucleus accumbens (NA). There were no differences in the baseline levels of DA, DOPAC, HVA or 5-HIAA in the lesioned as compared to the sham rats. Release from restraint resulted in increased extracellular levels of DA in the sham but not in the lesioned animals. AMPH increased DA release in both sham operated and lesioned animals, but this increase was significantly attenuated in the lesioned rats. Our data suggest that this developmental lesion alters function of the dopaminergic system in response to environmental and pharmacological challenge.

Journal ArticleDOI
TL;DR: While there are no differences between bipolars and controls in prefrontal cortical levels of glycogen synthase kinase-3β, β-catenin, or tau, tau isoform levels or phosphorylation states may be modified in bipolar disorder.
Abstract: Therapeutic concentrations of the anti-bipolar drug lithium inhibit the activity of glycogen synthase kinase-3β, which raises the possibility that this enzyme and its substrates may be altered in the brain of subjects with bipolar disorder. Therefore, in prefrontal cortical samples from subjects with bipolar disorder and age-matched control subjects, we examined the levels of glycogen synthase kinase 3β and of two proteins modified by it, β-catenin and the microtubule associated protein tau. There were no significant differences between subject groups among these measurements, but there was a tendency for the tau isoform profile to be modified in bipolar tissue. Thus, while there are no differences between bipolars and controls in prefrontal cortical levels of glycogen synthase kinase-3β, β-catenin, or tau, tau isoform levels or phosphorylation states may be modified in bipolar disorder.

Journal ArticleDOI
TL;DR: It is concluded that the lack of affinity for neurotransmitter receptors is of no importance to the development of adaptive changes in the studied systems, observed after repeated treatment of Venlafaxine.
Abstract: Venlafaxine (VEN) is a representative of a new class of antidepressants (SNRIs) which inhibit selectively the uptake of serotonin and noradrenaline, but--in contrast to tricyclics--show no affinity for neurotransmitter receptors. The present study was aimed at determining whether repeated VEN (given twice daily for 14 days) induced adaptive changes in the alpha 1-adrenergic, dopamine and serotonin systems, similar to those reported by us earlier for tricyclic antidepressants. The results indicate that VEN potentiates the clonidine-induced aggressiveness and the methoxamine-induced exploratory hyperactivity, both these effects being mediated by alpha 1-adrenoceptors. VEN increased the hyperlocomotion induced by D-amphetamine and (+/-)-7-OH-DPAT. Neither the apomorphine and quinpirole hyperlocomotion, nor the apomorphine and D-amphetamine stereotypies were changed. VEN did not affect the behavioural syndrome induced by 8-OH-DPAT (a 5-HT1A effect), and decreased both the head twitch reaction induced by L-5-HTP or (+/-)DOI and the hyperthermia induced by trifluoromethylphenylpiperazine, all those effects being mediated by 5-HT2 receptors. Repeated VEN did not change the hypothermia evoked by oxotremorine (a central cholinergic agonist). The above results indicate that repeated VEN increases--as do tricyclics--the responsiveness of alpha 1-adrenergic and dopaminergic (mainly D3) systems and decreases the responsiveness of the 5-HT2 system. It may be concluded that the lack of affinity for neurotransmitter receptors is of no importance to the development of adaptive changes in the studied systems, observed after repeated treatment.

Journal ArticleDOI
TL;DR: Serum levels of melatonin in healthy male volunteers, mirror the CSF concentrations when lumbar puncture is carried out using the described technique, calling in question the theory that melatonin is mainly released from the pineal gland into the bloodstream.
Abstract: Melatonin was determined in serum and cerebrospinal fluid (CSF) obtained from 13 healthy males lumbar-punctured in the sitting position without preceding bed rest. There was a significant correlation between the levels of melatonin in serum and the CSF. The serum concentration was lower than that in the CSF, a finding that calls in question the theory that melatonin is mainly released from the pineal gland into the bloodstream. In conclusion, serum levels of melatonin in healthy male volunteers, mirror the CSF concentrations when lumbar puncture is carried out using the described technique.

Journal ArticleDOI
TL;DR: The present study confirmed the differential vulnerability of the Nigrostriatal system of monkeys to MPTP, suggesting that if a high cumulative dose was needed to reach stable motor alterations, the cumulative dose-effect of the toxin independent of the nigrostRIatal system might be responsible for non-motor symptoms that also appear in Parkinson's disease besides the classic tetrad.
Abstract: The nocturnal sleep of three 1-Methyl, 4-phenyl, 1,2,3,6-tetrahydropyridine (MPTP) treated monkeys (one non-motor disabled and two severely motor disabled), while held in a primate chair was registered using a reversible system for head fixation and chronic recordings. Two electroencephalogram (EEG) channels, one electrooculogram (EOG) and one electromyogram (EMG) channel were monitored constantly and tape recorded during eight nights for posterior analyses. Subcutaneous temperature was registered each minute using a radio telemetry system. An analysis of sleep patterns and temperature parameters revealed lighter sleep, decreased amounts of slow wave and rapid eye movement (REM) sleep and lower temperature values in the two motor disabled MPTP-treated monkeys than in the non-motor disabled monkey. The temperature linear slope was negative in the case of one disabled monkey for just one night. Although the motor disability of the two monkeys was similar, their sleep organization patterns and temperatures slopes differed. The present study confirmed the differential vulnerability of the nigrostriatal system of monkeys to MPTP, suggesting that if a high cumulative dose was needed to reach stable motor alterations, the cumulative dose-effect of the toxin independent of the nigrostriatal system might be responsible for non-motor symptoms that also appear in Parkinson's disease besides the classic tetrad.

Journal ArticleDOI
TL;DR: The results suggest that the tested agonists primarily activate dopamine D2 receptors to induce emesis in the least shrew whereas activation of D3 sites potentiate the vomiting action of D2 dopamine receptors.
Abstract: This study introduces Cryptotis parva (the least shrew) as a new dopaminergic animal model of emesis. The potential emetogenic effects of a nonselective dopamine agonist [apomorphine], two D1 agonists [SKF-38393 and SKF-82958], a D2 preferring agonist [quinpirole], and two D3-preferring agonists [7-(OH) DPAT and PD 128, 907] were investigated. Intraperitoneal administration of D1 agonists failed to induce emesis. However, other agonists caused a dose-dependent increase in the percentage of animals vomiting as well as potentiating the mean frequency of emesis with the following ED50 potency order: 7-(OH) DPAT < apomorphine < quinpirole < PD 128, 907. For antagonist studies a 2 mg/kg dose of these agonists were used to in-duce emesis. Thus, the inhibitory dose-response effects of a D2-preferring [sulpride], a D3-preferring [U 99194A] and combination of varying doses of these antagonists [sulpride + U 99194A] were evaluated on the ability of the cited agonists to produce vomiting. Sulpride decreased the number of shrews vomiting and the mean vomiting frequency produced by the cited agonists in a dose-dependent fashion with the following ID50 order [apomorphine < PD 128, 907 < 7-(OH) DPAT < quinpirole]. By itself, U 99194A failed to significantly alter the emesis produced by any of the cited agonists, however, it potentiated (3–8 times) the antiemetic effects of sulpride both in reducing the number of shrews vomiting as well as decreasing the mean vomiting frequency with the following ID50 order: PD 128, 907 < 7-(OH) DPAT < quinpirole. However, U 99194A attenuated the potent antiemetic effect of sulpride on the apomorphine-induced emesis. The results suggest that the tested agonists primarily activate dopamine D2 receptors to induce emesis in the least shrew whereas activation of D3 sites potentiate the vomiting action of D2 dopamine receptors.

Journal ArticleDOI
TL;DR: It was found that a single neonatal dose of methamphetamine was a stimulus strong enough to significantly attenuate adult granule cell proliferation and acute doses of haloperidol might restore mitotic activity to control values.
Abstract: A single non-invasive dose of methamphetamine (50 mg/kg; i.p.) was administered to neonatal male gerbils (Meriones unguiculatus) aged 14 days. The first objective of the present study was to examine whether this early drug challenge, which has been shown to induce suppressive postnatal maturation of prefrontal dopamine (DA) innervation (Dawirs et al., 1994), interferes with adult granule cell proliferation in the dentate gyrus. Proliferation of granule cells was identified by in-vivo labeling with 5-bromo-2′-desoxyuridine (BrdU). BrdU-labeled granule cell nuclei were identified in consecutive horizontal sections along the mid-septotemporal axis of the hippocampus and light-microscopically quantified 7 days after BrdU-labeling. It was found that a single neonatal dose of methamphetamine was a stimulus strong enough to significantly attenuate adult granule cell proliferation. This effect was clearly lateralized with significant suppression of mitotic activity becoming apparent solely in the left dentate gyrus (−34%). The second objective of the present study was to examine whether acute doses of haloperidol, which have been found to stimulate granule cell proliferation in healthy adult animals (Dawirs et al., 1988), might restore mitotic activity to control values. For that purpose, at the age of postnatal day 90 adult animals which had been challenged with methamphetamine as juveniles received 4 doses of haloperidol (5 mg/kg; i.p.). Proliferation of granule cells was identified by BrdU-labeling. It was found that this neuroleptic treatment acutely restored granule cell proliferation rates to control values. The present results are discussed with regard to (1) factors, regulating mitotic activity in the hippocampus and (2) probable clues they may provide for understanding the neurobiological basis of psychotic behavior.

Journal ArticleDOI
TL;DR: A modulation of basal ganglia output by morphine with the possibility of reducing L-Dopa induced dyskinesia in patients treated with morphine for pain is indicated.
Abstract: In two patients with Parkinson's disease and L-Dopa induced dyskinesia we administered morphine orally to alleviate lumboradicular pain unresponsive to any other form of treatment. Besides an alleviation of the pain both patients showed a decrease in dyskinetic movements at very low doses of morphine and an increase in akinesia at higher doses. This observation indicates a modulation of basal ganglia output by morphine with the possibility of reducing L-Dopa induced dyskinesia in patients treated with morphine for pain.

Journal ArticleDOI
X. Li1, A. Y. Sun1
TL;DR: The results support the hypothesis that oxidative stress may be contributing to the apoptotic cell death of dopaminergic neurons, leading to the manifestation of Parkinson's disease.
Abstract: Drugs and certain environmental toxins may be responsible for the pathogenesis of Parkinson's disease. We have used paraquat as a model toxin for this study since paraquat has been shown to make its way to the nerve terminals and cause cell death of dopamine neurons by oxidative injury. We have shown by the electrophoretic mobility shift assay that paraquat, together with low concentrations of chelated iron (Fe++/DETAPAC), induced the activation of transcription factor AP-1 binding activity to DNA. Under similar conditions we also found by both a DNA laddering assay procedure and by terminal deoxynucleotidyl transferase assay (TUNEL assay) that paraquat also induces apoptotic cell death. Interestingly, both apoptotic cell death and AP-1/DNA binding activity induced by paraquat were blocked by cyclohexamide and genistein, indicating that both the AP-1/DNA binding activation and apoptosis induced by paraquat are closely related. Moreover, cells were also protected from paraquat toxicity in the presence of antioxidant defense enzymes SOD and catalase. The results support the hypothesis that oxidative stress may be contributing to the apoptotic cell death of dopaminergic neurons, leading to the manifestation of Parkinson's disease. Since paraquat was an important herbicide in the mid 20th Century, our results have the important implication that exposure to environmental toxins such as paraquat may induce Parkinson's disease.

Journal ArticleDOI
TL;DR: The results are in line with previous suggestions that a certain degree of tolerance to neuroleptics develops, in spite of profound D1 and D2 receptor changes that persist during the entire chronic treatment with these psychotropic agents.
Abstract: The effects of neuroleptics have been attributed to dopamine (DA) receptor blockade; however, other neurotransmitters, in particular serotonin (5-HT), have also been implicated. In this study, we examined the effects of clozapine and haloperidol on the distribution of DA and 5-HT transporters, on endogenous DA, 5-HT and their major metabolites, and on 5-HT1A receptors. Adult male Sprague-Dawley rats were treated with either haloperidol (1 mg/kg/day, i.p.), clozapine (20 mg/kg/day, i.p.) or saline for 21 days, and following 3 days of withdrawal, the brains were removed. Tissue levels of DA and 5-HT and their metabolites were measured by high-performance liquid chromatography in 16 brain regions, while quantitative autoradiography with [125I]RTI-121, [3H]citalopram and [3H]8-OH-DPAT was employed to label DA transporters, 5-HT transporters and 5-HT1A receptors, respectively. After haloperidol, densities of 5-HT transporters were increased in the dorsal insular cortex and in the ventral half of caudal neostriatum, while 5-HT1A receptors augmented in cingulate cortex but decreased in the entorhinal area. After clozapine, [3H]citalopram labelling was increased in ventral hippocampus, ventral caudal neostriatum and nucleus raphe dorsalis, but decreased in medio-dorsal and latero-dorsal neostriatum as well as in substantia nigra. Binding of [3H]8-OH-DPAT following clozapine was decreased in frontal, parietal, temporal and entorhinal cortices but increased in the CA3 division of Ammon's horn. The changes in 5-HT transporters in nucleus raphe dorsalis and substantia nigra, as well as the 5-HT1A receptor down-regulations caused by clozapine but not by haloperidol, may explain effects obtained with clozapine and other atypical neuroleptics. There were no modifications in densities of DA transporters, nor of tissue DA levels, after the chronic neuroleptic treatments. The results are in line with previous suggestions that a certain degree of tolerance to neuroleptics develops, in spite of profound D1 and D2 receptor changes that persist during the entire chronic treatment with these psychotropic agents.

Journal ArticleDOI
TL;DR: CSF selenium concentrations are apparently unrelated with the reported oxidative stress processes in patients with AD, and Weight and body mass index were significantly lower in AD patients than in controls.
Abstract: We compared CSF and serum selenium levels, measured by atomic absorption spectrophotometry, in 27 patients with Alzheimer's disease (AD) (13 females, 14 males, mean +/- SD age 73.6 +/- 7.4 years) without major clinical signs of undernutrition, and 34 matched controls (18 females, 16 males, mean +/- SD age 70.7 +/- 7.8 years). CSF and serum selenium levels did not differ significantly between AD-patient (11.4 +/- 7.8 ng/ml and 28.5 +/- 13.0 ng/ml, respectively) and control groups (13.3 +/- 7.0 ng/ml and 22.5 +/- 17.5 ng/ml). These values were not correlated with age, age at onset, duration of the disease, and scores of the MiniMental State Examination in the AD group. Weight and body mass index were significantly lower in AD patients than in controls. These results suggest that CSF selenium concentrations are apparently unrelated with the reported oxidative stress processes in patients with AD.

Journal ArticleDOI
TL;DR: Both phoenomena may be explained by the modifications of mitochondrial enzymes described in platelets, which could be used as a peripheral model of glutamatergic function in PD.
Abstract: Defects in mitochondrial enzymes have been found not only in substantia nigra, but also in platelets from Parkinson's Disease (PD) patients, suggesting a systemic impairment of energy metabolism. Since platelets present an energy-dependent glutamate uptake similar to that described in central nervous system, glutamate uptake was determined in platelets from 34 PD patients and 21 age-related normal controls, as Na+-dependent [3H]glutamate influx; glutamate level was also analyzed by reverse-phase HPLC. A 50% reduction of glutamate uptake (p < 0.001) was observed in idiopathic PD patients, respect to controls and secondary parkinsonian syndromes. The decrease correlated with the severity of PD, measured by the UPDRS (r = −0.54; P < 0.05). Glutamate level was increased in platelets of PD patients, but was not correlated to the uptake decrease. Both phoenomena may be explained by the modifications of mitochondrial enzymes described in platelets, which could be used as a peripheral model of glutamatergic function in PD.

Journal ArticleDOI
TL;DR: The results suggest that the increase inimmobility time in the forced swimming test is associated with presynaptic changes in noradrenaline availability, whereas the decrease in immobility observed after more complete denervation is associatedwith postsynaptic receptor supersensitivity.
Abstract: DSP-4 is a neurotoxin highly selective for the noradrenergic nerve terminals originating from the locus coeruleus. Preliminary data suggested that its effect in a typical screening test for antidepressant drugs, the forced swimming test, is biphasic dependent on the dose. In the present study, DSP-4 was administered in four doses (5, 10, 30 and 50 mg/kg) to male Wistar rats. Administration of the neurotoxin had a dose-dependent biphasic effect on immobility time in the forced swimming test 8 and 9 days later. Thus, DSP-4 at the dose of 10 mg/kg increased immobility, but higher doses reduced this measure. The reduction of noradrenaline concentration in the frontal cortex and hippocampus was dose-dependent starting from the dose 10 mg/kg. Cortical β-adrenoceptor binding was increased by DSP-4 treatment at the doses 30 mg/kg and 50 mg/kg. These results suggest that the increase in immobility time in the forced swimming test is associated with presynaptic changes in noradrenaline availability, whereas the decrease in immobility observed after more complete denervation is associated with postsynaptic receptor supersensitivity.

Journal ArticleDOI
TL;DR: It is demonstrated that chronic Ang II infusion enhances evoked release of NE from ISBAT sympathetic nerve terminals and responsiveness to the presynaptic effect of AngII was altered following chronic AngII infusion.
Abstract: Previous studies demonstrated that angiotensin II (AngII) decreases body weight. The purpose of this study was to determine if AngII-reductions in body weight result from stimulation of sympathetic neurotransmission to interscapular brown adipose tissue (ISBAT). Following 7 days of chronic AngII infusion (350 ng/kg/min), body weight decreased compared to controls. Using superfused ISBAT tissue slices preloaded with [3H]norepinephrine (NE), evoked [3H]overflow was greater in ISBAT slices from AngII-infused rats compared to controls. When AngII was included in the buffer, evoked [3H]overflow increased in a concentration-dependent manner in ISBAT slices from AngII-infused and control rats. The EC50 for the presynaptic effect of AngII was shifted to the left in ISBAT slices from AngII-infused rats compared to controls; however, the maximal response to AngII was decreased. These results demonstrate that chronic AngII infusion enhances evoked release of NE from ISBAT sympathetic nerve terminals. Moreover, responsiveness to the presynaptic effect of AngII was altered following chronic AngII infusion. Increased sympathetic neurotransmission to ISBAT may contribute to AngII-regulation of body weight.

Journal ArticleDOI
TL;DR: The data suggest that decreased neuronal activity and neuropathological hallmarks of AD, such as plaques and tangles, are basically independent phenomena and therapeutic strategies in AD should be focussed on reactivation of neuronal metabolism.
Abstract: An increasing number of studies have appeared in the literature suggesting that Alzheimer's disease (AD) is a hypometabolic brain disorder. Decreased metabolism in AD has been revealed by a variety of in vivo and postmortem methods and techniques including positron emission tomography and glucose metabolism. We used the size of the Golgi apparatus (GA) and cell profile area as indicators of neuronal activity in postmortem material. Using an antibody against MG-160, a sialoglycoprotein of the medial cisternae of the GA, we were able to visualize and quantify the GA area. In a series of experiments, we tried to relate neuronal metabolism to different hallmarks of AD, i.e. plaques and tangles, and also to genetic risk factors for AD like age and (apolipoprotein E) ApoE polymorphism. Our results showed that in AD there is indeed a clear reduction in brain metabolism in several severely affected brain regions including the nucleus basalis of Meynert (NBM), the CA1 area of the hippocampus and the hypothalamic tuberomamillary nucleus. However, the reduction in neuronal activity did not seem to be caused by the presence of neuropathological hallmarks of AD, i.e. plaques and tangles. There was, however, a clear relationship between the presence of ApoE e4 alleles and a decrease in GA size. Our data suggest that decreased neuronal activity and neuropathological hallmarks of AD, such as plaques and tangles, are basically independent phenomena. Moreover, ApoE e4 may participate in the pathogenesis of AD by decreasing neuronal metabolism. The main implication of these findings is that therapeutic strategies in AD should be focussed on reactivation of neuronal metabolism.

Journal ArticleDOI
TL;DR: Overnight switching of Parkinson's disease patients from per-golide or bromocriptine to ropinirole overnight may be a safe therapeutic approach that may reduce hospitalisation and related socio-economic costs.
Abstract: Patients with Parkinson's disease (n = 68) switched from per-golide or bromocriptine to ropinirole overnight (dose equivalence ratios – 1 : 6 and 10 : 6, respectively). The activities of daily living score for the Unified Parkinson's Disease Rating Scale (UPDRS) was significantly improved 4 weeks after the bromocriptine–ropinirole switch. All other UPDRS scores, including that for the side-effect component, were not significantly different after either switch. Overnight switching may be a safe therapeutic approach that may reduce hospitalisation and related socio-economic costs.

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TL;DR: Inositol has demonstrated antidepressant effects but in a controlled double blind augmentation trial did not improve depression in SSRI treatment failures.
Abstract: Some antidepressants, such as Lithium, can augment the antidepressant effect of serotonin selective uptake inhibitors (SSRI) in patients who have failed to respond to SSRI. Inositol has demonstrated antidepressant effects but in a controlled double blind augmentation trial did not improve depression in SSRI treatment failures.