Browsing by Author "Zlokovic, B.V. (7005891585)"

Blood-brain barrier permeability to homologous serum125I-IgG and to D-[3H]mannitol was studied by means of the brain vascular perfusion method in guinea pigs with experimental allergic encephalomyelitis (EAE). EAE was induced with homologous myelin basic protein (MBP) after pretreatment with foreign protein and muramyl dipeptide (MDP). The results suggest a significant comparable increase in IgG blood-to-brain clearance in the parietal cortex, hippocampus, and caudate nucleus, during vascular perfusion of the brains of animals, after 7 and 20 days of EAE. On the other hand, unidirectional transfer of mannitol in the same period of EAE was markedly augmented only in the hippocampus, but no significant changes in the parietal cortex or caudate nucleus were observed. Cerebrospinal fluid (CSF)/serum ratios for IgG and albumin were both significantly increased, suggesting an increase in blood-CSF barrier permeability, but more for albumin than for IgG. The results were confirmed by immunohistochemical determination of the IgG deposits in the brains of EAE animals, during vascular perfusion with unlabeled homologous IgG. An important role of the blood-brain barrier for the central nervous system immunoglobulin homeostasis during EAE is suggested. © 1989 Plenum Publishing Corporation.

Blood-brain barrier permeability to homologous serum125I-IgG and to D-[3H]mannitol was studied by means of the brain vascular perfusion method in guinea pigs with experimental allergic encephalomyelitis (EAE). EAE was induced with homologous myelin basic protein (MBP) after pretreatment with foreign protein and muramyl dipeptide (MDP). The results suggest a significant comparable increase in IgG blood-to-brain clearance in the parietal cortex, hippocampus, and caudate nucleus, during vascular perfusion of the brains of animals, after 7 and 20 days of EAE. On the other hand, unidirectional transfer of mannitol in the same period of EAE was markedly augmented only in the hippocampus, but no significant changes in the parietal cortex or caudate nucleus were observed. Cerebrospinal fluid (CSF)/serum ratios for IgG and albumin were both significantly increased, suggesting an increase in blood-CSF barrier permeability, but more for albumin than for IgG. The results were confirmed by immunohistochemical determination of the IgG deposits in the brains of EAE animals, during vascular perfusion with unlabeled homologous IgG. An important role of the blood-brain barrier for the central nervous system immunoglobulin homeostasis during EAE is suggested. © 1989 Plenum Publishing Corporation.

Effects of sensory-motor cortical lesions on the function of the blood-brain barrier in distant brain areas are poorly understood. Therefore a brain vascular perfusion method has been used to measure simultaneously the kinetics of entry of two inert polar molecules, D[14C]mannitol (MW 180) and [3H]polyethylene glycol (PEG; MW 4000), into the parietal cortex, hippocampus, and caudate nucleus in guinea pigs with ipsilateral and contralateral sensorymotor cortical lesions. The graphically determined cerebral capillary unidirectional constant, Kin, indicated a marked increase in blood-to-brain transport of both molecules in all regions studied, the changes being significantly higher after contralateral lesion. The mannitol/PEG cerebrovascular permeability constant ratio, Pman/PPEG, suggested the opening up of channels that permit a flow of fluid carrying substances either with respect to (2 days after ipsilateral lesion) or irrespective of their molecular size, depending on the time after lesion. Amphetamine treatment in the guinea pigs with sensory-motor lesions induced more pronounced blood-brain barrier permeability changes for both molecules in distant brain areas. © 1989 Plenum Publishing Corporation.

Effects of sensory-motor cortical lesions on the function of the blood-brain barrier in distant brain areas are poorly understood. Therefore a brain vascular perfusion method has been used to measure simultaneously the kinetics of entry of two inert polar molecules, D[14C]mannitol (MW 180) and [3H]polyethylene glycol (PEG; MW 4000), into the parietal cortex, hippocampus, and caudate nucleus in guinea pigs with ipsilateral and contralateral sensorymotor cortical lesions. The graphically determined cerebral capillary unidirectional constant, Kin, indicated a marked increase in blood-to-brain transport of both molecules in all regions studied, the changes being significantly higher after contralateral lesion. The mannitol/PEG cerebrovascular permeability constant ratio, Pman/PPEG, suggested the opening up of channels that permit a flow of fluid carrying substances either with respect to (2 days after ipsilateral lesion) or irrespective of their molecular size, depending on the time after lesion. Amphetamine treatment in the guinea pigs with sensory-motor lesions induced more pronounced blood-brain barrier permeability changes for both molecules in distant brain areas. © 1989 Plenum Publishing Corporation.

Summary: Adult male mice, rats, and guinea pigs were subjected to intense sound stimulation of an electric bell (100 dB, 12 kHz for 60 s) after a single intraperitoneal (i.p.) injection of metaphit (1‐(1‐(3 isothiocyanatophenyl)‐cyclohexyl)piperidine) (50 mg/kg). When the animals were tested 24 h after administration of metaphit, audiogenic seizures were observed. None of the control saline‐injected animals had convulsions. EEG recordings demonstrated the appearance of paroxysmal activity and spike‐wave complexes in the trace from cortical and hip‐pocampal electrodes, with frequency and amplitude increasing with time. Behaviorally, myoclonic jerks of facial muscles, ears, and neck appeared, but no correlation was noted between EEG and the motor phenomena. Auditory stimulation was necessary to elicit the full‐blown sequence of seizure responses consisting of wild running followed by clonic and then tonic extension. At the time of seizures, repetitive high‐amplitude spikes and waves appeared in the EEG, followed by profound EEG and behavioral depression. None of the animals died during or immediately after seizures. The seizure response to sound stimulation of mice, rats, and guinea pigs was phe‐nomenologically similar, with minor differences in quantitative pattern of convulsive components, which suggests that all three animal species share the common property of extreme susceptibility to audiogenic stimulation caused by metaphit administration. Des souris, rats et cobayes adultes mâles ont été exposés à une stimulation sonore intense par sonnerie électrique (100 dB, 12 kHz pendant 60 s) apres injection intrapéritonéale unique de metaphit (50 mg/kg). Des crises audiogéniques ont été observers 24 heures après 1'administration de metaphit. Aucun des animaux contrôles traités par sérum physiologique n'a présenté de convulsion. Les énregistrements électroencéphalographiques (EEG) ont montré l'apparition d'une activité paroxystique et de complexes de PO sur les électrodes corticales et hippocampiques, avec une fréquence et une amplitude qui augmentaient avec le temps. Sur le plan comportemental, les auteurs ont noté l'apparition de secousses myocloniques des muscles faciaux, des oreillś et du cou, mais n'ont pas observé de corrélation entre l'EEG et les phénomènes moteurs. Une stimulation auditive a été nécessaire pour provoquer une séquence critique compléte, qui a consisté en une course folle suivie d'une extension clonique puis tonique. Au moment des crises, des pointes ondes de grande amplitude sont apparues sur l'EEG, suivies d'une dépression EEG et comportementale profond. Aucun des animaux n'est mort pendant ou immédiatement après les crises. La réponse critique à la stimulation sonore des souris, rats et cobayes a été semblable sur le plan phénoménologique, avec des differences mineures dans l'organisation quantitative des composantes critiques. Ceci suggère que les trois espèces animales ont en commun une propriété de susceptibilityé extréme à la stimulation audiogénique après administration de metaphit. Tras la inyección única intraperitoneal de metaphit (50 mg/kg) ratones macho adultos, ratas y cobayas fueron sometidos a una estimulación sonora muy intensa mediante una campana eléctrica (100 dB, 12 kHz durante 60 s). Cuando se estudiaron 24 horas depués de la administración de metaphit, se observaron ataques audiogénicos. Ninguno de los animales control inyectados con salino tuvieron convulsiones. Los registros electroence‐falográficos (EEG) demostraron la aparición de actividad paroxística y complejos punta‐onda en los trazados de los electro‐dos corticales e hipocampicos con un incremento, en el tiempo, de la frecuencia y de la amplitud. Observando el compor‐tamiento, se detectaron mioclonías de la musculature facial, orejas y cuello pero no se observó ninguna correlación entre el EEG y estos fenómenos motores. La estimulación auditiva fue nece‐saria para conseguir la secuencia completa de ataques que consistía en carrera desordenada seguida de movimientos clónicos y, después, de extensión tónica. En el momenta de las convulsiones, en el EEG aparecieron puntas y ondas repetitivas de alta amplitud seguidas de depresión profunda del EEG y del compor‐tamiento. Ninguno de los animales murio durante o inmediatamente después de los ataques. Las respuestas de ataques a la estimulación sonora en el ratón, en las ratas o en el cobaya fue semejante fenomenologicamente, con mínimas diferencias, en lo que respecta al partón cuantitativo de los componentes convulsivos. Este sugiere que los tres tipos de animal comparten propiedades comunes de extrema susceptibilidad a la estimulacion audiogénica causada por la administration de metaphit. Erwachsene männliche Mäuse, Ratten und Meerschweinchen wurden einer intensiven Geräuschstimulation durch eine elektrische Glocke (100 dB, 12 kHz für 60 Sek.) nach einer einzelnen intraperitonealen Injektion von Metaphit (50 mg/kg) unterwor‐fen. Bei einem Test 24 Stunden später wurden audiogene Anfälle beobachtet. Keine der mit Salzlösung injizierten Kontrolltiere hatte Anfälle. Die EEG‐Untersuchungen zeigten paroxysmale Aktivität und Spike‐Wave Komplexe in den kortikalen und hip‐pokampalen Ableitungen mit zunehmender Frequenz und Amplitude. Verhaltensmäßig zeigten sich myoklonische Zuckungen im Gesicht, Ohren und Nacken ohne Korrelation zwischen EEG und den motorischen Phänomenen. Die auditorische Stimulation war notwendig, um die voile Sequenz der Anfälle zu erzeugen, die in einem milden Rennen bestand mit anschließender klonischer und dann tonischer Extension. Zum Zeitpunkt der Anfälle erschienen repetitive hochamplitudige Spike‐Waves im EEG, die von einer deutlichen EEG‐ und Verhaltensdepression gefolgt waren. Keines der Tiere starb wahrend oder kurz nach den Anfällen. Die Anfälle nach Tonstimulation bei Mäusen, Ratten und Merrschweinchen ähnelten einander mit kleinen Unterschieden im quantitativem Muster. Dies legt nahe, daß alle drei Tierarten eine gemeinsame Eigenschaft für die extreme Empfindlichkeit auf audiogene Stimulation nach Metaphit‐Gabe besitzen. Copyright © 1991, Wiley Blackwell. All rights reserved

Summary: Adult male mice, rats, and guinea pigs were subjected to intense sound stimulation of an electric bell (100 dB, 12 kHz for 60 s) after a single intraperitoneal (i.p.) injection of metaphit (1‐(1‐(3 isothiocyanatophenyl)‐cyclohexyl)piperidine) (50 mg/kg). When the animals were tested 24 h after administration of metaphit, audiogenic seizures were observed. None of the control saline‐injected animals had convulsions. EEG recordings demonstrated the appearance of paroxysmal activity and spike‐wave complexes in the trace from cortical and hip‐pocampal electrodes, with frequency and amplitude increasing with time. Behaviorally, myoclonic jerks of facial muscles, ears, and neck appeared, but no correlation was noted between EEG and the motor phenomena. Auditory stimulation was necessary to elicit the full‐blown sequence of seizure responses consisting of wild running followed by clonic and then tonic extension. At the time of seizures, repetitive high‐amplitude spikes and waves appeared in the EEG, followed by profound EEG and behavioral depression. None of the animals died during or immediately after seizures. The seizure response to sound stimulation of mice, rats, and guinea pigs was phe‐nomenologically similar, with minor differences in quantitative pattern of convulsive components, which suggests that all three animal species share the common property of extreme susceptibility to audiogenic stimulation caused by metaphit administration. Des souris, rats et cobayes adultes mâles ont été exposés à une stimulation sonore intense par sonnerie électrique (100 dB, 12 kHz pendant 60 s) apres injection intrapéritonéale unique de metaphit (50 mg/kg). Des crises audiogéniques ont été observers 24 heures après 1'administration de metaphit. Aucun des animaux contrôles traités par sérum physiologique n'a présenté de convulsion. Les énregistrements électroencéphalographiques (EEG) ont montré l'apparition d'une activité paroxystique et de complexes de PO sur les électrodes corticales et hippocampiques, avec une fréquence et une amplitude qui augmentaient avec le temps. Sur le plan comportemental, les auteurs ont noté l'apparition de secousses myocloniques des muscles faciaux, des oreillś et du cou, mais n'ont pas observé de corrélation entre l'EEG et les phénomènes moteurs. Une stimulation auditive a été nécessaire pour provoquer une séquence critique compléte, qui a consisté en une course folle suivie d'une extension clonique puis tonique. Au moment des crises, des pointes ondes de grande amplitude sont apparues sur l'EEG, suivies d'une dépression EEG et comportementale profond. Aucun des animaux n'est mort pendant ou immédiatement après les crises. La réponse critique à la stimulation sonore des souris, rats et cobayes a été semblable sur le plan phénoménologique, avec des differences mineures dans l'organisation quantitative des composantes critiques. Ceci suggère que les trois espèces animales ont en commun une propriété de susceptibilityé extréme à la stimulation audiogénique après administration de metaphit. Tras la inyección única intraperitoneal de metaphit (50 mg/kg) ratones macho adultos, ratas y cobayas fueron sometidos a una estimulación sonora muy intensa mediante una campana eléctrica (100 dB, 12 kHz durante 60 s). Cuando se estudiaron 24 horas depués de la administración de metaphit, se observaron ataques audiogénicos. Ninguno de los animales control inyectados con salino tuvieron convulsiones. Los registros electroence‐falográficos (EEG) demostraron la aparición de actividad paroxística y complejos punta‐onda en los trazados de los electro‐dos corticales e hipocampicos con un incremento, en el tiempo, de la frecuencia y de la amplitud. Observando el compor‐tamiento, se detectaron mioclonías de la musculature facial, orejas y cuello pero no se observó ninguna correlación entre el EEG y estos fenómenos motores. La estimulación auditiva fue nece‐saria para conseguir la secuencia completa de ataques que consistía en carrera desordenada seguida de movimientos clónicos y, después, de extensión tónica. En el momenta de las convulsiones, en el EEG aparecieron puntas y ondas repetitivas de alta amplitud seguidas de depresión profunda del EEG y del compor‐tamiento. Ninguno de los animales murio durante o inmediatamente después de los ataques. Las respuestas de ataques a la estimulación sonora en el ratón, en las ratas o en el cobaya fue semejante fenomenologicamente, con mínimas diferencias, en lo que respecta al partón cuantitativo de los componentes convulsivos. Este sugiere que los tres tipos de animal comparten propiedades comunes de extrema susceptibilidad a la estimulacion audiogénica causada por la administration de metaphit. Erwachsene männliche Mäuse, Ratten und Meerschweinchen wurden einer intensiven Geräuschstimulation durch eine elektrische Glocke (100 dB, 12 kHz für 60 Sek.) nach einer einzelnen intraperitonealen Injektion von Metaphit (50 mg/kg) unterwor‐fen. Bei einem Test 24 Stunden später wurden audiogene Anfälle beobachtet. Keine der mit Salzlösung injizierten Kontrolltiere hatte Anfälle. Die EEG‐Untersuchungen zeigten paroxysmale Aktivität und Spike‐Wave Komplexe in den kortikalen und hip‐pokampalen Ableitungen mit zunehmender Frequenz und Amplitude. Verhaltensmäßig zeigten sich myoklonische Zuckungen im Gesicht, Ohren und Nacken ohne Korrelation zwischen EEG und den motorischen Phänomenen. Die auditorische Stimulation war notwendig, um die voile Sequenz der Anfälle zu erzeugen, die in einem milden Rennen bestand mit anschließender klonischer und dann tonischer Extension. Zum Zeitpunkt der Anfälle erschienen repetitive hochamplitudige Spike‐Waves im EEG, die von einer deutlichen EEG‐ und Verhaltensdepression gefolgt waren. Keines der Tiere starb wahrend oder kurz nach den Anfällen. Die Anfälle nach Tonstimulation bei Mäusen, Ratten und Merrschweinchen ähnelten einander mit kleinen Unterschieden im quantitativem Muster. Dies legt nahe, daß alle drei Tierarten eine gemeinsame Eigenschaft für die extreme Empfindlichkeit auf audiogene Stimulation nach Metaphit‐Gabe besitzen. Copyright © 1991, Wiley Blackwell. All rights reserved

[No abstract available]

[No abstract available]

The aim of this study was to investigate the transport of tiazofurin (2-β-D-ribofuranosyl thiazole-4-carboxamide) across the blood-brain barrier (BBB) using brain vascular perfusion and capillary depletion method in the guinea pig. Values for volume of distribution of [3H] tiazofurin in brain increased slowly and almost linearly in time, from 1% of its plasma concentration at 1 min to 5% after 15 min of perfusion. Unidirectional transport constant K(in) was 2.61 ± 0.21 x 10-3 ml/min/g. According to these results, it is evident that tiazofurin slowly penetrates the BBB. Addition of unlabeled tiazofurin to the perfusing medium caused a significant decrease in the uptake of [3H] labeled tiazofurin (K(in) = 0.77 ± 0.1 x 10-3 ml/min/g). Therefore, penetration of tiazofurin from blood into brain seems to be a saturable process. Presence of potential inhibitors of tiazofurin blood-to-brain transport (adenosine and dipyridamole) did not cause complete inhibition of tiazofurin brain uptake. Thus, it could be assumed that transport of tiazofurin from blood into brain is only partially mediated by the nucleosides transport system. The results obtained using capillary depletion method show that tiazofurin that passes across the BBB is accumulated mostly in the brain tissue and not in brain capillaries endothelial cells.

The aim of this study was to investigate the transport of tiazofurin (2-β-D-ribofuranosyl thiazole-4-carboxamide) across the blood-brain barrier (BBB) using brain vascular perfusion and capillary depletion method in the guinea pig. Values for volume of distribution of [3H] tiazofurin in brain increased slowly and almost linearly in time, from 1% of its plasma concentration at 1 min to 5% after 15 min of perfusion. Unidirectional transport constant K(in) was 2.61 ± 0.21 x 10-3 ml/min/g. According to these results, it is evident that tiazofurin slowly penetrates the BBB. Addition of unlabeled tiazofurin to the perfusing medium caused a significant decrease in the uptake of [3H] labeled tiazofurin (K(in) = 0.77 ± 0.1 x 10-3 ml/min/g). Therefore, penetration of tiazofurin from blood into brain seems to be a saturable process. Presence of potential inhibitors of tiazofurin blood-to-brain transport (adenosine and dipyridamole) did not cause complete inhibition of tiazofurin brain uptake. Thus, it could be assumed that transport of tiazofurin from blood into brain is only partially mediated by the nucleosides transport system. The results obtained using capillary depletion method show that tiazofurin that passes across the BBB is accumulated mostly in the brain tissue and not in brain capillaries endothelial cells.