RESUMEN
The neurotoxin 1-trichloromethyl-1,2,3,4-tetrahydro-beta-carboline (TaClo) has been reported, both in vitro and in vivo models, to produce neurodegeneration and parkinsonian symptoms after prolonged exposure in rats. The aim of the present study was to investigate the effects of TaClo on the cognitive performance of rats. We used the COGITAT hole board system where rats can find hidden pellets by exploring the board. TaClo-treated rats found as many pellets as control rats treated with saline. Furthermore, their search was as efficient as that of control animals since there were no differences between the groups regarding explorative activity, visits to non-baited holes and time needed to find the pellets. These results suggest that there is no deficit in spatial memory following the chronic administration of TaClo to rats.
Asunto(s)
Conducta Apetitiva/efectos de los fármacos , Carbolinas/toxicidad , Conducta Exploratoria/efectos de los fármacos , Recuerdo Mental/efectos de los fármacos , Neurotoxinas/toxicidad , Orientación/efectos de los fármacos , Animales , Masculino , Ratas , Ratas Wistar , Tiempo de Reacción/efectos de los fármacosRESUMEN
The consequences of short phases of restricted cerebral blood flow and iron enrichment of striatal tissues resulted in an animal model that could correspond to the basic features of a model for Parkinson's disease. An automatic and computerized hole-board offers simultaneous data on learning and cognitive memory capabilities, learning of distinct patterns of distributed food pellets found and eaten in a given time, switches between different locations of food in the holes and in different layout patterns. Wistar rats after 60 min of bilateral clamping of the carotid arteries (BCCA) under pentobarbital anesthesia received 1.5 microg FeCl3 injected one week after BCCA unilaterally into the ventrolateral striatum. The experiments showed that reduced cerebral blood flow and increased iron within the striatal tissue had the effect of retarding reactions. Rats after BCCA and iron need 180 s to find pellets deep inside holes that are distributed in a distinct pattern. During only 60 or 30s BCCA plus iron rats are no longer able to find the same number of pellets as over 180s. Rats after BCCA plus NaCl do not show such reduced success. These results point to the idea that cerebral oligemia and increased iron in the striatum stimulate the pathological symptoms of Parkinson's disease which need also more time to have reaction and success (see Fig. 5). The data covering abbreviated time-spans show how heavily the BCCA + Fe animals are dependent on longer times.
Asunto(s)
Corteza Cerebral/irrigación sanguínea , Corteza Cerebral/patología , Circulación Cerebrovascular , Hierro/toxicidad , Ataque Isquémico Transitorio/patología , Ataque Isquémico Transitorio/fisiopatología , Animales , Conducta Animal , Arterias Carótidas/fisiología , Aprendizaje/fisiología , Modelos Biológicos , Actividad Motora/efectos de los fármacos , Actividad Motora/fisiología , RatasRESUMEN
One BCCA-phase (bilateral clamping of carotid arteria) leads to an extensive release of striatal dopamine with a subsequent formation of free radicals (Heim et al., 200b). Early investigations did not show histological damage to cerebral structures after 24 and 60 min duration of a BCCA phase (Melzacka et al., 1994). The study here turned out that oligemic damage and an increase in iron (FeCl3) concentration in the ventral striatum was responsible for most of the defective performance of the animals investigated. Striatal damaged animals were unable to correct their deficient performance to the same extent as was possible for animals which had been damaged through BCCA and FeCl3 in the substantia nigra. Furthermore it turn out that with the use of a comprehensive behaviour profile which was able to gather 22 parameters simultaneously, 15 of these parameters did not correspond in the performance of the controls already after BCCA alone. Since during the ageing process, pathological effects may occur in vulnerable structures not only from disturbances to cerebral blood-perfusion but also from enrichment of iron in vulnerable structures (Connor, 1992) the question arose whether this situation did not reveal pathological mechanisms that might triggered the early symptoms of Parkinson's disease.
Asunto(s)
Conducta Animal/efectos de los fármacos , Conducta Animal/fisiología , Hierro/administración & dosificación , Ataque Isquémico Transitorio/fisiopatología , Enfermedad de Parkinson/fisiopatología , Animales , Arterias Carótidas/fisiología , Circulación Cerebrovascular/fisiología , Cognición/efectos de los fármacos , Cognición/fisiología , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/fisiopatología , Hipoxia Encefálica/etiología , Hipoxia Encefálica/metabolismo , Inyecciones Intraventriculares , Ataque Isquémico Transitorio/complicaciones , Actividad Motora/efectos de los fármacos , Actividad Motora/fisiología , Ratas , Sueño/efectos de los fármacos , Sueño/fisiología , Sustancia Negra/efectos de los fármacos , Sustancia Negra/fisiopatologíaRESUMEN
To test substances which might have protective effects on the dopaminergic system it is necessary to use models with a pathological symptomatology of the early beginning, i.e. models in which the chance exists to arrest the otherwise progressive pathological processes (see Heim et al., 2001). 6-hydroxydopamine (6-OHDA) injected unilaterally into the ventrolateral striatum of rats (6 microg dissolved in 2 microl 0.2% ascorbic acid) leads to specific stereotyped movements after subcutaneous injection of apomorphine both 3 and 13 weeks after surgery. Ten weeks after surgery decreased spontaneous motor activity could be observed. Twelve weeks after 6-hydroxydopamine injection, the animals had difficulties in performing a spatial navigation task when the submerged escape platform was moved to another position. The switching of motor programs was less pronounced. The application of tyrosine-hydroxylase-staining showed a loss of ipsilateral neurones of the substantia nigra compacta as well as of dendrites in the pars reticulata, neurones in the ventral tegmental area and in the retrorubral area ipsilaterally as well as a loss of dopaminergic fibres both ipsilaterally and contralaterally in the striatum which should belong to the contralateral acting substantia nigra afferents. The loss of the neurones and the afferents was induced by the retrograde denervation following the 6-OHDA injection within the ventrolateral striatum. The question arises whether the model used here with the partially loss of dopaminergic neurons and fibres reflects some of pathological symptoms of Parkinson's disease in the early states.
Asunto(s)
Dopamina/metabolismo , Neuronas/metabolismo , Enfermedad de Parkinson/metabolismo , Núcleo Rojo/metabolismo , Sustancia Negra/metabolismo , Sustancia Negra/patología , Tegmento Mesencefálico/metabolismo , Animales , Antiparkinsonianos/farmacología , Apomorfina/farmacología , Conducta Animal/efectos de los fármacos , Agonistas de Dopamina/farmacología , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Actividad Motora/efectos de los fármacos , Neuronas/patología , Oxidopamina , Enfermedad de Parkinson/patología , Enfermedad de Parkinson/psicología , Enfermedad de Parkinson Secundaria/inducido químicamente , Ratas , Ratas Wistar , Núcleo Rojo/patología , Natación , Tegmento Mesencefálico/patologíaRESUMEN
Inhibition of catechol catechol-O-methyltransferase (COMT) in the brains of subjects treated with L-DOPA (L-3,4-dihydroxylphenylalanine) and an aromatic amino acid decarboxylase (AADC) inhibitor is suggested to cause an increase of L-DOPA, which might lead to oxidative damage through enhanced formation of free radicals. To investigate this hypothesis, the acute effects of two doses of the systemically administered COMT inhibitors entacapone (peripheral) and tolcapone (peripheral and central) on the extracellular formation of hydroxyl radicals in vivo following treatment with L-DOPA and the AADC inhibitor carbidopa were examined. The formation of extracellular hydroxyl radicals were determined by the measurement of 2,3-dihydroxybenzoic acid (2,3-DHBA), a reaction product of hydroxyl radicals with sodium salicylate, using microdialysis in the striatum of anesthetised rats. The COMT inhibitors were administered together with 50 mg/kg i.p. carbidopa as 5% gum arabic suspensions intraperitoneally (i.p.) at doses of 0, 1.0, and 10 mg/kg body weight to a total of 36 male HAN-Wistars rats. L-DOPA was injected i.p. 40 min after drugs of interest. Microdialysis samples were collected every 20 min for 400 min at a perfusion rate of 1 microl/min. Systemically administered 10 mg/kg tolcapone, but not entacapone, induced an increase in hydroxyl radical formation in the striatum of anesthetised rats following treatment with L-DOPA/carbidopa. The increase in hydroxyl radical formation was reflected by higher extracellular concentrations of the hydroxylate product of salicylate, 2,3-DHBA, peaking at 192% of baseline at the end of the observation period. Similar results were also found using the AUC (area under the curve) value estimated for the observation period. We conclude that the increase in hydroxyl radical formation is likely to result from an increased rate of monoamine oxidase-mediated and non-enzymatic (autoxidation) dopamine metabolism following increased central availability caused by reduction in COMT-mediated metabolism. We cannot, however, exclude the possibility that hydroxyl radicals are produced by tolcapone as a result of uncoupling mitochondrial oxidative phosphorylation.
Asunto(s)
Antiparkinsonianos/farmacología , Benzofenonas/farmacología , Inhibidores de Catecol O-Metiltransferasa , Cuerpo Estriado/metabolismo , Trastornos Parkinsonianos/tratamiento farmacológico , Ácido 3,4-Dihidroxifenilacético/metabolismo , Animales , Carbidopa/farmacología , Catecoles/farmacología , Cuerpo Estriado/efectos de los fármacos , Dopamina/metabolismo , Relación Dosis-Respuesta a Droga , Radical Hidroxilo/metabolismo , Levodopa/farmacología , Masculino , Microdiálisis , Nitrilos , Nitrofenoles , Estrés Oxidativo/efectos de los fármacos , Estrés Oxidativo/fisiología , Trastornos Parkinsonianos/metabolismo , Ratas , Ratas Wistar , TolcaponaRESUMEN
6-Hydroxydopamine (6-OHDA) injected unilaterally into the striatum of rats induced contralateral circling, and increased the duration of stereotyped movements after subcutaneous (sc) injection of apomorphine both 3 and 13 weeks after surgery. Ten weeks after surgery, the spontaneous locomotor activity during 24 h of observation was decreased. Twelve weeks after 6-OHDA injection, the animals had difficulties in carrying out a spatial navigation task in the water maze when the submerged escape platform was moved to another position on each of four consecutive days. When learning to find a new platform position required switching behavior-strategies, latency and swim paths were increased because of significantly more perseverative crossings of the previous platform positions. Intraperitoneal (ip) injection of alpha-tocopherol for 8 days increased the ability of naive control animals to find the hidden platform positions in the water maze one week later. In intrastriatal sham-operated rats, 8 daily pre-injections of alpha-tocopherol significantly increased the duration and number of bursts of stereotyped movements during 30 min following a sc injection of apomorphine if measured 13 weeks after surgery. In 6-OHDA-lesioned rats, alpha-tocopherol prevented the increased response to apomorphine, reduced the apomorphine-induced circling at 3 and 13 weeks, and prevented the decrease in spontaneous locomotion at 10 weeks, as well as the perseverative platform crossings which are caused by an impairment in switching behavior-strategies in the navigation task 12 weeks after surgery. Alpha-Tocopherol has, however, no influence on 6-OHDA-induced changes in problem solving strategies. The used model reflects some of the pathological symptoms of Parkinson's disease, and it seems that alpha-tocopherol may be an effective drug in the early initial stages of the disease.
Asunto(s)
Adrenérgicos/toxicidad , Antioxidantes/farmacología , Cuerpo Estriado/efectos de los fármacos , Oxidopamina/toxicidad , alfa-Tocoferol/farmacología , Antagonistas Adrenérgicos/farmacología , Animales , Apomorfina/farmacología , Inyecciones , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Actividad Motora/efectos de los fármacos , Oxidopamina/antagonistas & inhibidores , Ratas , Ratas Wistar , Conducta Estereotipada/efectos de los fármacosRESUMEN
Oligemic episodes and increased iron concentration have both been proposed as being involved in neurodegenerative diseases. In animal models, a combination of both of these might therefore mimic the clinical pathology in humans. In rats, intrastriatal injections of ferric chloride, FeCl3, one week after a 60-minute oligemic episode, produced by bilateral clamping of the carotid arteries under pentobarbital anaesthesia (BCCA) impaired the animals' learning ability in a water maze task. Median adult rats, after intrastriatal 0.3 microg FeCl3, are impaired when challenged during the first three trial blocks, while after 0.06 microg FeCl3, an impairment is seen during the process of habituation to the challenge. Two-year-old animals do not show any learning effect at all after the combination of BCCA and intrastriatal FeCl3. Lazaroid U-74389G, a potent inhibitor of iron-induced lipid peroxidation, totally prevents the learning impairments in both median adult and aged animals, suggesting that iron-induced lipid peroxidation may be responsible for the late learning deficiencies. However, when U-74389G is applied one week after the oligemic episode but without the additional injection of iron, U-74389G on its own also impairs the animals' learning ability. The present animal model, when applied to clinical studies of lazaroids in humans, does seem able to give reliable information concerning the neuroprotective properties of such drugs.
Asunto(s)
Compuestos Férricos/farmacología , Hipoxia Encefálica/tratamiento farmacológico , Fármacos Neuroprotectores/farmacología , Pregnatrienos/farmacología , Percepción Espacial/efectos de los fármacos , Animales , Química Encefálica/efectos de los fármacos , Química Encefálica/fisiología , Arterias Carótidas , Circulación Cerebrovascular , Cloruros , Cuerpo Estriado/irrigación sanguínea , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/metabolismo , Reacción de Fuga/efectos de los fármacos , Hipoxia Encefálica/metabolismo , Peroxidación de Lípido/efectos de los fármacos , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Orientación/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Ratas , Ratas Wistar , Tiempo de Reacción/efectos de los fármacosRESUMEN
COGITAT is an automated hole board system that, following minimal experimental interventions, makes it possible to measure a variety of parameters associated with learning, memory, relearning, cognition, and cognitive shifts, but also changes in exploratory and sensorimotor performance in rodent models. The individual parameters--that is, overall exploratory activity, number of visits (deep in the hole) into or inspections of (at the upper surface) holes, number of baited, unbaited, or previously baited holes visited or inspected, reinspections of or revisits into any holes, number of pellets eaten, time to find pellets, serial order collection (without intermediate inspections or visits), and reference and working memory errors (visits, inspections, or total)--are obtained simultaneously, and the results are immediately available after the end of each experiment. The system appears to be well suited to neurophysiological, neuropharmacological, and gene-technological investigations in rodent models.
Asunto(s)
Trastornos del Conocimiento/diagnóstico , Procesamiento Automatizado de Datos , Animales , Conducta Animal/fisiología , Señales (Psicología) , Masculino , Ratas , Ratas Wistar , Factores de TiempoRESUMEN
Sixty minutes of cerebral oligaemic hypoxia, induced by bilateral clamping of the carotid arteries (BCCA) in pentobarbital-anaesthetized normotensive rats, induces a late progressive cognitive decline when compared with sham-operated controls. Analysis at BCCA of hippocampal metabolism using microdialysis showed increased release of glutamate, aspartate and gamma-aminobutyric acid, followed by a progressive rise in the formation of hydroxyl free radicals measured as 2,3-dihydroxybenzoic acid (2,3-DHBA), their reaction product with salicylate, though only in the re-perfusion phase. In the striatum increased dopamine release occurred during BCCA, whereas glutamate and aspartate showed an increase only during the late re-perfusion phase. gamma-Aminobutyric acid (GABA) concentration increased during BCCA and early re-perfusion. An increase in 2,3-DHBA was seen during BCCA, and persisted over 2 h of re-perfusion. Six and 13 months after surgery, though not as early as 3 months, BCCA-treated rats perform worse than sham-operated controls in a water-maze, where decreased swimming speed reveals striatal dysfunction, while hippocampal dysfunction manifested as diminished spatial bias. These results show that cerebral oligaemia, similarly to cerebral ischaemia, leads to increased extracellular dopamine, aspartate and glutamate, and the production of hydroxyl radicals in structures associated with learning and memory processes. Unlike cerebral ischaemia, in cerebral oligaemia the appearance of spatial memory deficits is delayed.
Asunto(s)
Trastornos del Conocimiento/etiología , Cuerpo Estriado/fisiopatología , Hipocampo/metabolismo , Radical Hidroxilo/metabolismo , Ataque Isquémico Transitorio/metabolismo , Ácido 3,4-Dihidroxifenilacético/metabolismo , Animales , Ácido Aspártico/metabolismo , Estenosis Carotídea/complicaciones , Modelos Animales de Enfermedad , Dopamina/metabolismo , Reacción de Fuga/fisiología , Ácido Glutámico/metabolismo , Hipocampo/fisiopatología , Ácido Homovanílico/metabolismo , Hidroxibenzoatos/metabolismo , Ataque Isquémico Transitorio/complicaciones , Ataque Isquémico Transitorio/psicología , Discapacidades para el Aprendizaje/etiología , Masculino , Aprendizaje por Laberinto/fisiología , Trastornos de la Memoria/etiología , Microdiálisis , Estrés Oxidativo , Desempeño Psicomotor , Ratas , Ratas Wistar , Tiempo de Reacción , Daño por Reperfusión/complicaciones , Daño por Reperfusión/metabolismo , Daño por Reperfusión/psicología , Conducta Espacial/fisiología , Natación , Factores de Tiempo , Ácido gamma-Aminobutírico/metabolismoRESUMEN
A reduction in cerebral blood flow to oligemic levels was achieved in pentobarbital-anesthetized adult rats by clamping both carotid arteries (BCCA) for 60 min. To assess the extent to which the animals' dopaminergic system was affected over an increasing time span, their spontaneous locomotor activity in an unfamiliar environment and in response to the subcutaneous administration of apomorphine was tested at various times after either BCCA or sham operation. Eight to 14 days after the operation, it was possible to observe a diminished locomotor activity in response to apomorphine injection in BCCA as compared with sham-operated animals, while oral stereotypical behavior such as licking was increased. At 3 months, there was only a subtle decrease in apomorphine-induced locomotor activity, and stereotypical behavior was similar in both groups. At 7 months, the BCCA rats covered shorter distances than sham-operated controls during the habituation phase; after apomorphine injection, more stereotypic movements, such as, e.g., sniffing, were observed, and less running. Twelve months after surgery, no further differences could be observed between the two groups during the habituation phase, but the injection of apomorphine led to increased stereotypic sniffing movements, rearing and locomotor activity in BCCA animals to a greater extent than in the controls. At 12 months, sensorimotor disturbances elicited by the rota rod test, which were only transiently observed at 11 weeks and 7 months, did not appear any different from the normal age-related motor decline of the sham-operated controls. The animals' motor co-ordination in the chimney test was not significantly disturbed during the time between 7 and 12 months after surgery. At 15 months, nocturnal locomotor activities in BCCA rats were significantly decreased. In situ hybridization (ISH) histochemistry revealed decreased D1 receptor mRNA (D1RmRNA) in striatal neurons 19 months after surgery, while D2 receptor mRNA (D2RmRNA) and the neuronal number remained the same. The present results show that just as is already known for the immature rat brain, the adult rat brain, too, reacts to a transient decrease in its blood supply by appearance of long-lasting alterations in function, and that even a single oligemic episode is capable of inducing progressive dopaminergic dysfunctions and ultimately the partial loss of striatal D1RmRNA.
Asunto(s)
Dopamina/metabolismo , Ataque Isquémico Transitorio/metabolismo , Actividad Motora/fisiología , ARN Mensajero/metabolismo , Receptores de Dopamina D1/metabolismo , Animales , Apomorfina/farmacología , Arterias Carótidas/cirugía , Agonistas de Dopamina/farmacología , Masculino , Actividad Motora/efectos de los fármacos , Degeneración Nerviosa/metabolismo , RatasRESUMEN
1-Trichloromethyl-1,2,3,4-tetrahydro-beta-carboline (TaClo), a neurotoxin structurally similar to the dopaminergic neurotoxin MPTP, may be formed in humans treated with chloral hydrate or exposed to trichloroethylene, a widely used industrial solvent. Systemically administered TaClo (0.4 mg/kg, i.p.) induced an immediate and transient release of dopamine (DA) and serotonin (5-HT) measured using microdialysis. However, only 5-HT was increased significantly (area under the curve, AUC, for the 1-2 h-period following TaClo administration: 400% compared with the respective control value; 2-3 h-period: 326%). This was followed by a progressive increase in hydroxyl radical formation reflected by higher extracellular concentrations of the hydroxylate product of salicylic acid, 2,3-dihydroxybenzoic acid (AUC for the 1-2 h period following TaClo administration: 182% compared with the respective control value; 2-3 h period: 190%). In contrast, extracellular glutamate and GABA were increased 2-3 h post-injection by 64 and 51%, respectively. These data suggest that TaClo stimulates the generation of hydroxyl free radicals via an acute release of 5-HT and perhaps DA.
Asunto(s)
Carbolinas/farmacología , Cuerpo Estriado/metabolismo , Espacio Extracelular/metabolismo , Radical Hidroxilo/metabolismo , Serotonina/metabolismo , Ácido 3,4-Dihidroxifenilacético/metabolismo , Animales , Ácido Aspártico/metabolismo , Cromatografía Líquida de Alta Presión , Cuerpo Estriado/efectos de los fármacos , Dopamina/metabolismo , Ácido Glutámico/metabolismo , Ácido Homovanílico/metabolismo , Hidroxibenzoatos/metabolismo , Ácido Hidroxiindolacético/metabolismo , Masculino , Microdiálisis , Ratas , Ratas Wistar , Ácido gamma-Aminobutírico/metabolismoRESUMEN
"TaClo", (1-trichloromethyl-1,2,3,4-tetrahydro-beta-carboline) which is structurally very similar to MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), increases the sensitivity to apomorphine in aging rats after subchronic daily application (0.2 mg/kg i.p.) for 7 weeks. Nine weeks after the last treatment with TaClo, the running speed of the animals during spontaneous nocturnal activity was significantly diminished, and 9 months after the last injection rats developed a pronounced hypersensitivity to apomorphine (0.4 mg/kg s.c.). TaClo, which can be readily produced from endogenous tryptamine and the non-natural aldehyde chloral, appears to be a drug that is able to induce a slowly-developing neurodegenerative process.
Asunto(s)
Carbolinas/toxicidad , Actividad Motora/efectos de los fármacos , Neurotoxinas/toxicidad , Enfermedad de Parkinson Secundaria/fisiopatología , Aclimatación , Animales , Apomorfina/farmacología , Ritmo Circadiano , Sinergismo Farmacológico , Enfermedad de Parkinson Secundaria/inducido químicamente , Ratas , Factores de TiempoRESUMEN
Highly chlorinated beta-carbolines have a potential in vivo relevance to Parkinson's disease. In this paper, a gas chromatographic method for the determination of the neurotoxic 1-trichloromethyl-1,2,3,4-tetrahydro-beta-carboline (TaClo), the condensation product of tryptamine and chloral hydrate, is described. The specific and sensitive assay involves purification of the biological samples by solid-phase extraction with C18 cartridges, derivatization with heptafluorobutyric anhydride, and chromatography on a non-polar fused-silica capillary column. Detection of TaClo was achieved by the registration of characteristic mass fragments of the TaClo heptafluorobutyric amide derivative using selected ion monitoring. The method was utilized to detect and quantify TaClo in blood, urine, bile, faeces, and brain tissue of rats treated with this alkaloid-type heterocycle. Four-fold deuterium-labelled TaClo was used as an internal standard.
Asunto(s)
Carbolinas/análisis , Cromatografía de Gases y Espectrometría de Masas , Animales , Carbolinas/farmacocinética , Carbolinas/toxicidad , Femenino , Humanos , Masculino , Sistema Nervioso/efectos de los fármacos , Ratas , Ratas Wistar , Distribución TisularRESUMEN
The spastic rat is a neurological mutant of the Han-Wistar strain with prominent spasticity, tremor, and ataxia. Neurodegeneration is found in the CA3 sector of the hippocampus and in Purkinje cells of the cerebellum. We examined the forebrain and cerebellum of spastic rats for glial reactions by using immunolabelling for the astrocytic marker, glial fibrillary acidic protein (GFAP). First, a map of the GFAP-distribution was made representing a systematic series of frontal sections in controls. Reactive astrocytes with increased GFAP should occur in the areas with established neuronal degeneration, but they could also demarcate further regions with pathology in this rat strain. Since the baseline levels of GFAP-immunoreactivity differ between brain regions, control rats and clinically normal littermates served as controls to judge relative increases in major structures. In the CA3 sector and hilus of the dorsal hippocampus, a massive gliosis was detected. In the cerebellum, a patchy increase of GFAP labelling in Bergmann glia was found. Further increases of GFAP-labelling in reactive astrocytes occurred in fiber tracts, the ventral thalamic nuclei, medial geniculate nuclei, pontine region and optic layer of the superior colliculus. Inconsistent changes were noted in cortex and pallidum. No defects of glial labelling or malformations in glial architectonics were found. The reactive changes of astroglial cells in hippocampus and cerebellum are in proportion to the neuronal degeneration. The glial reactions in the other brain regions possibly reflect a reaction to fiber degeneration and incipient neuronal degeneration or functional alterations of glial cells in response to neuronal dysfunction.
Asunto(s)
Cerebelo/química , Proteína Ácida Fibrilar de la Glía/análisis , Degeneración Nerviosa , Prosencéfalo/química , Ratas Mutantes/genética , Ratas Wistar/fisiología , Animales , Astrocitos/química , Astrocitos/patología , Biomarcadores , Química Encefálica , Modelos Animales de Enfermedad , Inmunohistoquímica , Mutación/fisiología , Ratas , Espasmo/fisiopatologíaRESUMEN
The aim of this study was to examine whether the non-competitive NMDA-antagonist memantine might have neuroprotective properties in an animal model of pro-gressive functional neurodegeneration, without producing NMDA-specific learning and memory deficiencies. Rats were subjected to bilateral clamping of the carotid arteries (BCCA) under pentobarbital anaesthesia for 24 min, and 8-10 days later estimates of their escape latency in finding a hidden platform in a Morris water maze indicated a significant increase. This BCCA-induced increase in escape latency is maximally ameliorated by preinjection of 5 mg/kg of memantine, while higher doses have a lesser effect. BCCA for 60 min produces deficiencies in the maze performance during the second experimental day only, when animals were tested 8-10 days after surgery, but results in severe deficits 6 months later. Intraperitoneal injection of 30 mg/kg memantine 10 minutes before BCCA prevents the development of these deficiencies. In parallel experiments, the apomorphine-induced hypersensitivity of the post-synaptic dopamine receptors, observed 12 months after BCCA, was also prevented by the memantine pre-treatment. No neuronal necrosis was observed after BCCA of either 24 minutes' or 60 minutes' duration. The results suggest that memantine complements the therapeutic value of NMDA antagonists. Further, they lend support to the idea that the glutamatergic NMDA-receptor might play a significant role in the BCCA-induced development of progressive "functional neurodegeneration", i.e. behavioural disturbances and dopamine-receptor hypersensitivity.
Asunto(s)
Antiparkinsonianos/farmacología , Antagonistas de Aminoácidos Excitadores/farmacología , Memantina/farmacología , Degeneración Nerviosa/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Análisis de Varianza , Animales , Apomorfina/farmacología , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Actividad Motora/efectos de los fármacos , Ratas , Ratas WistarRESUMEN
60 min of bilateral clamping of the carotid arteries (BCCA) in pentobarbital anaesthetized adult Wistar rats increases the lipid peroxidation in hippocampal tissue as estimated four weeks later. 1.5 micrograms FeCl3 in 2 microliters buffer injected unilaterally in the ventrolateral striatum enforced the effect when applicated one week after the BCCA treatment. During ageing, the explorative and locomotor behaviour of BCCA rats decreased earlier than the behaviour activities of the controls. These activities show no more changes 9 months after surgery but the BCCA treated rats were more sensitive to 2 mg/kg apomorphine s.c., demonstrated by the distance travelled during 1 hour of habituation in a new environment. BCCA treated rats rotate in response to apomorphine after an intrastriatal and ventrolateral injection of 0.3 microgram FeCl3 15 and 14 weeks, respectively, after BCCA and iron instead of 1.5 micrograms after iron injection alone. Transient BCCA leads to a dramatical increase of released DA. We assume, therefore, that during the autooxidation of released DA, free radicals trigger the increase of lipid peroxidation. Predamaged tissue due to increased lipid peroxidation reacts to very small amounts of iron and iron seems to be more toxic in such cerebral tissue.
Asunto(s)
Estenosis Carotídea/metabolismo , Hipocampo/metabolismo , Hipoxia Encefálica/metabolismo , Hierro/toxicidad , Peroxidación de Lípido/fisiología , Animales , Estenosis Carotídea/complicaciones , Cuerpo Estriado/efectos de los fármacos , Hipoxia Encefálica/etiología , Inyecciones , Masculino , Actividad Motora/efectos de los fármacos , Actividad Motora/fisiología , Ratas , Ratas WistarRESUMEN
The substantia nigra of parkinsonian brains is reported to contain increased amounts of iron as compared with age-matched controls. Since iron might be cytotoxic via radical mechanisms, we analyzed the effect of intranigral iron infusion on the dopaminergic activity in the striatum of the rat. The striatal dopamine metabolism of the rat was followed 1, 3, and 6 weeks after unilateral intranigral iron (III) (1.5 micrograms) application. A progressive decrease of extraneuronal 3,4-dihydroxyphenylacetic acid (DOPAC) levels was observed in the ipsilateral striatum by means of in vivo pulse voltammetry. The significant reduction of the DOPAC signal could be attenuated by pretreatment of the animals with the lazaroid U-74389G, applied ip 20 minutes before unilateral intranigral iron application. Our data indicate that a single iron application into the substantia nigra leads to a progressive loss of dopaminergic activity in the striatum, also observed in Parkinson patients. Furthermore, the Lazaroid U-74389G seems to be beneficial in this model of Parkinson's disease.
Asunto(s)
Antioxidantes/farmacología , Cuerpo Estriado/efectos de los fármacos , Dopamina/metabolismo , Hierro/farmacología , Fármacos Neuroprotectores/farmacología , Pregnatrienos/farmacología , Ácido 3,4-Dihidroxifenilacético/metabolismo , Animales , Cuerpo Estriado/metabolismo , Inyecciones , Peroxidación de Lípido/efectos de los fármacos , Masculino , Microelectrodos , Degeneración Nerviosa/efectos de los fármacos , Enfermedad de Parkinson Secundaria/inducido químicamente , Enfermedad de Parkinson Secundaria/metabolismo , Ratas , Ratas Wistar , Sustancia Negra/efectos de los fármacos , Sustancia Negra/metabolismoRESUMEN
Due to its structural analogy to the neurotoxin MPTP, "TaClo" (1-trichloromethyl-1,2,3,4-tetrahydro-beta-carboline), a compound readily originating in vitro from tryptamine ("Ta") and chloral ("Clo"), is discussed as a potential natural inducer of parkinsonian-like symptoms. Its spontaneous formation in man has to be taken into account after application of the drug chloral hydrate or after exposure to the solvent trichloroethylene. This first representative of chloral-derived heterocycles could now indeed be demonstrated to be formed in vivo after application of its putative precursors to rats. In vivo analysis of the nigrostriatal dopamine metabolism, behavioural studies, and histochemical findings as well as a strong inhibition of the complex I of the mitochondrial respiratory chain revealed the neurotoxic potential of TaClo on the dopaminergic system.
Asunto(s)
Carbolinas/toxicidad , Dopamina/fisiología , Neuronas/efectos de los fármacos , Neurotoxinas/toxicidad , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Carbolinas/metabolismo , Humanos , Inyecciones Intraperitoneales , Neuronas/metabolismo , Neurotoxinas/metabolismo , RatasRESUMEN
In vivo voltammetry with carbon fibre electrodes was used to study the effects of highly halogenated tetrahydro-beta-carbolines on the striatal dopamine (DA) metabolism of the rat. As representatives of chloral-derived heterocycles, "TaClo" (1-trichloro-1,2,3,4-tetrahydro-beta-carboline) and its N-methylated derivative. "N-methyl-TaClo", were investigated. After intranigral injection of 10 micrograms TaClo, the DA activity in the ipsilateral striatum was reduced compared with the intact side. Application of N-methyl-TaClo (10 micrograms) resulted in a nearly total reduction of the DOPAC signal. Furthermore, also "TaBro" (1-tribromomethyl-1,2,3,4-tetrahydro-beta-carboline), the bromal-derived analogue of TaClo, was tested. The impairment of the DA metabolism in rats achieved with 10 micrograms TaBro was found to be between that observed after application of TaClo and N-methyl-TaClo, respectively. The results demonstrate the toxic potential of chloral- and bromal-derived beta-carbolines towards dopaminergic neurons.
Asunto(s)
Carbolinas/toxicidad , Cuerpo Estriado/efectos de los fármacos , Dopamina/metabolismo , Neurotoxinas/toxicidad , Sustancia Negra/efectos de los fármacos , Ácido 3,4-Dihidroxifenilacético/metabolismo , Animales , Cuerpo Estriado/metabolismo , Electroquímica , Levodopa/metabolismo , Masculino , Ratas , Ratas Wistar , Sensibilidad y Especificidad , Sustancia Negra/metabolismoRESUMEN
1-Trichloromethyl-1,2,3,4-tetrahydro-beta-carboline (TaClo), which shows a great structural similarity to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), when administered to rats lead to enhanced spontaneous locomotion when they were tested 4-9 days after subchronic injection at a daily dose of 0.2 mg/kg over a seven week period. However, 9 weeks after the end of the course of injections animals walked more slowly during 12 hours of nocturnal activity, and apomorphine-induced locomotion was decreased 12 weeks later. These results suggest that the drug may exert a progressive neurotoxic effect.