RESUMO
Cerebral high-energy metabolites and metabolic end products were measured during and following total cerebral ischemia in the rat. During cerebral ischemia, lactate accumulation was greatest in the hippocampus, followed by the cerebral cortex and striatum. Following reperfusion, the rate of lactate clearance was slower in the hippocampus than in the other two regions. Regional CBF, cerebral plasma volume (CPV), and calculated mean transit time (MTT) were determined following reflow of ischemic tissue. During hyperemia, CPV, used as an indicator of capillary volume, increased concomitantly with CBF while the MTT remained near the control value, suggesting that the linear flow rate through the vasculature was unchanged. During hypoperfusion, CPV returned to control values, but there was a significant increase in MTT that would result from a decreased linear velocity. The finding of normal tissue energy charge, pHi, and concentration of other metabolites during hypoperfusion shows that hypoperfusion does not result in CBF-metabolic mismatch.
Assuntos
Isquemia Encefálica/fisiopatologia , Encéfalo/metabolismo , Circulação Cerebrovascular/fisiologia , Metabolismo Energético , Volume Plasmático , Trifosfato de Adenosina/metabolismo , Animais , Velocidade do Fluxo Sanguíneo , Encéfalo/irrigação sanguínea , Encéfalo/patologia , Isquemia Encefálica/patologia , Córtex Cerebral/metabolismo , Corpo Estriado/metabolismo , Parada Cardíaca Induzida , Hipocampo/metabolismo , Hipocampo/patologia , Lactatos/metabolismo , Ácido Láctico , Masculino , Fosfocreatina/metabolismo , Ratos , Ratos EndogâmicosRESUMO
Apoptosis or programmed cell death may be involved in neuronal death in the cerebral cortex after a permanent focal ischemic insult. Studies indicate that protein p53 is a major determinant of the cellular mechanism that leads to programmed cell death. Wild-type C57 mice and two groups of transgenic C57 mice, one homozygous and the other heterozygous for a p53 null gene, were subjected to middle cerebral artery occlusion. As expected, the wild-type mice had a large, consistent infarct volume (22.11 +/- 4.59 mm3; n = 10). Both transgenic groups had significantly less ischemic damage than the wild-type control group. However, unexpectedly, the heterozygous group had the least amount of ischemic damage (16.12 +/- 1.71 mm3, n = 11; 27% reduction in infarct size). The ischemic damage in the homozygous group (18.72 +/- 3.48 mm3, n = 9) was significantly less than in the wild-type control (15% reduction in infarct size) but significantly more than in the heterozygous group. Thus, although the absence of p53 expression was protective, greater protection was afforded by reduced expression of p53. These data suggest that attenuated p53 expression may be protective after an ischemic event.
Assuntos
Isquemia Encefálica/genética , Isquemia Encefálica/patologia , Encéfalo/patologia , Deleção de Genes , Proteína Supressora de Tumor p53/genética , Animais , Apoptose/fisiologia , Heterozigoto , Homozigoto , Camundongos , Camundongos Endogâmicos C57BL , Camundongos TransgênicosRESUMO
The authors describe their experience with a baboon model of reversible cerebral ischemia. Middle cerebral artery occlusion was achieved by external compression with an implantable, inflatable balloon cuff in awake, unanesthetized baboons. Selective cerebral angiography confirmed consistent, reliable occlusion. Computed tomography demonstrated early density changes after ischemia, which were reversible with reperfusion. Neurological evaluation demonstrated a "recruitment response" of increasingly persistent deficit with repeated occlusion. Permanent deficits were noted after extensive angiography during periods of occlusion. This was accompanied by the dropout of small vessels in the middle cerebral artery distribution. The results of pathological examinations were consistent with the clinical examinations. No gross or microscopic changes were noted after repeated occlusions that caused deficits like those of transient ischemic attacks. Consistent infarctions were noted in animals with permanent deficits after permanent occlusion or after repeated occlusion and extensive angiography.
Assuntos
Isquemia Encefálica/fisiopatologia , Modelos Animais de Doenças , Animais , Encéfalo/fisiopatologia , Isquemia Encefálica/diagnóstico por imagem , Isquemia Encefálica/patologia , Angiografia Cerebral , Doença Crônica , Masculino , Papio , Tomografia Computadorizada por Raios XRESUMO
The authors have studied the therapeutic effect of barbiturate coma following middle cerebral artery (MCA) occlusion in primates. The relationship of the efficacy of barbiturate protection to the presence or absence of recirculation was examined. Barbiturate therapy was begun 30 minutes after MCA occlusion. The findings were as follows: 1) barbiturate-induced coma, with its attendant monitoring, was safely tolerated by primates for 96 hours; 2) 6 hours of MCA occlusion followed by recirculation resulted in a neurological deficit that was worse than the neurological deficit produced by permanent MCA occlusion; 3) barbiturate-induced coma for 96 hours, initiated 30 minutes after the onset of MCA occlusion, in the absence of reperfusion, was in fact detrimental; 4) barbiturate-induced coma for 96 hours, initiated 30 minutes after MCA occlusion, with the establishment of reperfusion at 6 hours, provided nearly complete protection from ischemic damage.
Assuntos
Barbitúricos/uso terapêutico , Isquemia Encefálica/terapia , Coma/induzido quimicamente , Animais , Arteriopatias Oclusivas/terapia , Doenças Arteriais Cerebrais/terapia , Pressão Intracraniana/efeitos dos fármacos , Ataque Isquêmico Transitório/terapia , Masculino , PapioRESUMO
Reversible, total cerebral ischaemia of eight minutes duration was produced in a closed-chest dog model. Before, and at intervals after, this insult regional cerebral blood flow was determined by radiolabelled microsphere injection; and cerebral cortical capillary mean transit time was determined by reflection spectrophotometry. From these two measured parameters, cerebral cortical blood volume was calculated. After one hour of reperfusion following eight minutes of total cerebral ischaemia; cerebral blood flow was half of pre-ischaemic blood flow and mean transit time was increased by half. These results indicate that the delayed hypoperfusion following total cerebral ischaemia is accompanied by a decreased cerebral cortical blood volume mediated by vasoconstriction.
Assuntos
Isquemia Encefálica/fisiopatologia , Encéfalo/irrigação sanguínea , Animais , Velocidade do Fluxo Sanguíneo , Córtex Cerebral/irrigação sanguínea , Cães , Fluxo Sanguíneo Regional , VasoconstriçãoRESUMO
Barbiturate administration for protection from focal ischemia was evaluated in baboons. All animals were monitored for 96 hours in an intensive care unit during various regimens of pentobarbital administration. Intermittent bolus injections of barbiturate yielded inconsistent electroencephalographic responses and produced the most cardiovascular instability. Continuous barbiturate infusion safely allowed the greatest amount of barbiturate to be employed with the most stable electrophysiological and cardiovascular response.
Assuntos
Barbitúricos/administração & dosagem , Isquemia Encefálica/fisiopatologia , Coma/fisiopatologia , Animais , Barbitúricos/sangue , Pressão Sanguínea/efeitos dos fármacos , Isquemia Encefálica/prevenção & controle , Débito Cardíaco/efeitos dos fármacos , Eletroencefalografia , Infusões Parenterais , Masculino , PapioRESUMO
The procedure used to obtain cerebral tissue for analysis of protein kinase C (PKC) activity may affect the subcellular distribution of the enzyme. We compared different methods of tissue preparation and found that the proportion of PKC activity associated with the particulate fraction of the cerebral cortex was only 30% when the brain was frozen in situ while the animal was on life support or after decapitation followed by delayed freezing. Other methods of obtaining cerebral tissue resulted in 49-56% of the PKC activity in the particulate fraction. Freezing per se had no apparent effect on the activity or subcellular distribution of PKC. In addition, whenever the particulate PKC activity was high (greater than 48%), there was also a significant increase in the proportion of particulate protein (from 51 to approximately 63%, p less than 0.05).
Assuntos
Córtex Cerebral/enzimologia , Proteína Quinase C/metabolismo , Difosfato de Adenosina/metabolismo , Trifosfato de Adenosina/metabolismo , Animais , Córtex Cerebral/ultraestrutura , Congelamento , Concentração de Íons de Hidrogênio , Masculino , Fosfocreatina/metabolismo , Ratos , Ratos Endogâmicos , Frações Subcelulares/enzimologiaRESUMO
Intracellular pH was determined by neutral red color histophotometry in cerebral tissue from rats subjected to 10 minutes of cardiac arrest and from rats that had recovered for 1 and 6 hours following 8-10 minutes of total cerebral ischemia (TIA). Tissue concentrations of ATP, lactate and glucose were measured corresponding to the pH determinations. As expected, tissue ATP was depleted while tissue lactate was markedly elevated after 10 minutes of ischemia without reflow in the cerebral cortex, striatum and hippocampus. However, both metabolites were near control following 1 and 6 hours of recovery in all three regions. Tissue glucose was not significantly different from control following 1 and 6 hours of reperfusion. During ischemia, the intracellular pH dropped to 6.5-6.7 in all three regions (p less than 0.05). But, since the initial pH of the hippocampus was 7.79 while that of the cerebral cortex and striatum was approximately 7.02, the net drop in pHi the hippocampus was greater than in the other two regions. Following 1 hour of reperfusion, a trend towards tissue alkalosis was observed in the cerebral cortex and striatum.
Assuntos
Encéfalo/metabolismo , Parada Cardíaca/metabolismo , Trifosfato de Adenosina/análise , Animais , Glucose/análise , Hipocampo/fisiologia , Concentração de Íons de Hidrogênio , Lactatos/análise , Ácido Láctico , Masculino , Vermelho Neutro , Ratos , Ratos Endogâmicos , RessuscitaçãoRESUMO
The possible activation of protein kinase C (PKC) during total cerebral ischemia was investigated in the rat. Translocation of PKC activity from the soluble to the particulate fraction was used as an index of PKC activation. There was a drop in the proportion of particulate PKC activity from 30% for controls to 20% by 30 min of ischemia (p less than 0.01). By 20 min of cardiac arrest, there was a 40% decline of the total cellular PKC activity (p less than 0.01). This was not accompanied by an increase in activator-independent activity, a finding indicating PKC was not being converted to protein kinase M. These data suggest that PKC was not activated during ischemia, but rather that ischemia causes a reduction in cellular PKC activity. Translocation of PKC activity to the particulate fraction was not observed in the cerebral cortex or hippocampus of reperfused brain for up to 6 h of recovery following 11-13 min of total cerebral ischemia. The level of total, soluble, and particulate PKC activity in the cerebral cortex was reduced (p less than 0.05), corresponding to the decrease observed by 15 min of ischemia without reflow. A similar decline in activity was also observed in the hippocampus. No increase in activator-independent activity was observed. These data suggest that PKC was inhibited during cerebral ischemia and that this reduced level of PKC activity was maintained throughout 6 h of recovery. We conclude that pathological activation of PKC was not responsible for the evolution of ischemic brain damage.
Assuntos
Isquemia Encefálica/enzimologia , Proteína Quinase C/metabolismo , Animais , Isquemia Encefálica/fisiopatologia , Córtex Cerebral/enzimologia , Circulação Cerebrovascular , Parada Cardíaca/enzimologia , Hipocampo/enzimologia , Masculino , Ratos , Ratos Endogâmicos , Reperfusão , Fatores de TempoRESUMO
This study was conducted to determine if regional cerebral flow during the first day after total cerebral ischemia was correlated with neurologic deficit and eventual survival. Dogs were subjected to 11 min of total cerebral ischemia (TCI) produced by an arterial and venous double balloon occlusion method. Recovery was allowed for up to 7 days after reperfusion, whereupon it was reassessed in survivors. Blood flow, determined by the radiolabeled microsphere method, was determined before TCI and at times up to 24 h after reperfusion. Blood flow during reperfusion after TCI followed the expected pattern of immediate hyperperfusion followed by prolonged hypoperfusion. TCI of 11 min duration resulted in a 50% mortality rate by 1 week. No positive correlation between magnitude or duration of hypoperfusion and neurologic deficit or mortality was found. It was concluded that improved postischemic blood flow cannot be used as a criterion for assessing drug therapy without reference to metabolic demand. The observation of a statistical correlation between dogs that survived and lower hematocrit was reported. It was suggested that the prolonged hypoperfusion encountered after TCI was not pathological, but rather served as a mechanism to limit oxygen exposure to the brain during a vulnerable period and, thus, was part of a controlled attempt at recovery of function by the central nervous system.
Assuntos
Isquemia Encefálica/fisiopatologia , Encéfalo/fisiopatologia , Circulação Cerebrovascular , Animais , Isquemia Encefálica/sangue , Isquemia Encefálica/mortalidade , Cães , Hematócrito , Fatores de TempoRESUMO
The use of a transthoracic bioimpedance monitor to determine cardiac output was evaluated in critically ill children. The children ranged in age from 10 months to 8 yr and their height and weight ranged from the third to the 97th percentile. Each child had a thermodilution catheter in place to monitor cardiac output. The bioimpedance monitor used in this study, the NCCOM-3, required the input of a constant (L), which was obtained for each individual patient by adjusting the L setting until cardiac output measured by bioimpedance (COBI) was within 10% of cardiac output measured by thermodilution (COTD). This method of determining L was superior to using either measured thoracic length or the manufacturer's guidelines to obtain L and resulted in an excellent correlation between COTD and COBI (r = .94; p less than .05; n = 59). In children less than 125 cm in height, measured thoracic length alone was inadequate to use for L but provided a good approximation of L when multiplied by 1.25. This study suggests that the use of transthoracic bioimpedance to determine cardiac output compares favorably with thermodilution techniques and it is noninvasive.
Assuntos
Débito Cardíaco , Cardiografia de Impedância , Cuidados Críticos , Pletismografia de Impedância , Criança , Pré-Escolar , Humanos , Lactente , Masculino , Estatística como Assunto , TermodiluiçãoRESUMO
Protein kinase C (PKC) activity was investigated in a model of focal stroke in the rat. Following 6 h of left middle cerebral artery occlusion, rat brains were frozen in situ. In the peripheral ischemic zone, total PKC activity declined by close to two-thirds (1.07 +/- 0.35 vs 2.77 +/- 0.12 nmol/min/mg protein; p less than 0.05, n = 4), and the proportion of total activity associated with the particulate fraction decreased from 33.3 +/- 1.5% to 16.2 +/- 1.4% (p less than 0.01, n = 4). Thus, overall particulate PKC activity in the ischemic zone was less than 20% of control. The cerebral energy metabolite profile of tissue from the ipsilateral hemisphere, corresponding to the region where samples were obtained for PKC activity assay, suggests that this tissue may have been part of the ischemic penumbra before further deterioration.
Assuntos
Isquemia Encefálica/enzimologia , Proteína Quinase C/metabolismo , Trifosfato de Adenosina/metabolismo , Animais , Ativação Enzimática , Lactatos/metabolismo , Ácido Láctico , Masculino , Ratos , Ratos Endogâmicos SHRRESUMO
BACKGROUND AND PURPOSE: Lamotrigine (LTG) is an anticonvulsant drug whose mechanism of action may involve the inhibition of glutamate release by blocking voltage-dependent sodium channels. Glutamate neurotoxicity may contribute to cerebral ischemic damage after recovery from cardiac arrest. Thus, LTG may prevent the brain damage associated with global cerebral ischemia by reducing the release of glutamate from presynaptic vesicles during the ischemic insult or the early recovery period. METHODS: LTG was studied in cardiac arrest-induced global cerebral ischemia with reperfusion in rats. In the first set of experiments, LTG (100 mg/kg, p.o.) was administered before induction of ischemia; and in the second experiment, LTG (10 mg/kg, i.v.) was given 15 minutes after ischemia and a second dose (10 mg/kg,i.v.) was given 5 hours later. RESULTS: In both experiments LTG reduced the damage to the hippocampal CA1 cell population by greater than 50%. Neuroprotection was not associated with changes in brain temperature or plasma glucose concentration. Plasma concentrations of LTG ranged between 8 and 13 micrograms/mL. Patients taking LTG as a monotherapy for epilepsy typically have plasma levels of LTG in the 10 to 15 micrograms/mL range. CONCLUSIONS: These data suggest that LTG may be effective in preventing brain damage after recovery from cardiac arrest. Patients on LTG monotherapy for epilepsy have plasma concentrations very similar to those found to be neuroprotective in this study. Although difficult to extrapolate, our data suggest that LTG at neuroprotective doses may be well tolerated by humans.
Assuntos
Anticonvulsivantes/farmacologia , Isquemia Encefálica/etiologia , Isquemia Encefálica/patologia , Parada Cardíaca/complicações , Hipocampo/efeitos dos fármacos , Hipocampo/patologia , Fármacos Neuroprotetores/farmacologia , Triazinas/farmacologia , Animais , Encéfalo/metabolismo , Lamotrigina , Concentração Osmolar , Ratos , Ratos Endogâmicos F344 , Triazinas/sangue , Triazinas/metabolismoRESUMO
Focal cerebral ischemia in the rat was induced by left middle cerebral artery occlusion. The area of ischemia was determined by infusion of a qualitative perfusion indicator, neutral red. The temporal evolution of alterations in regional energy metabolism was assessed by direct microquantitative histochemical analysis of high-energy phosphates, glucose, glycogen, and lactate content of the tissue. Perfusion analyses demonstrated a perifocal region of diminished, but not absent perfusion up to 6 hr after occlusion. By 24 hr, there was an abrupt demarcation between perfused and nonperfused regions. Profound metabolic alterations were seen as early as 20 min after occlusion. Although there was an area of intermediate metabolic derangement in the more medial portions of the lateral ipsilateral cortex up to 6 hr, by 24 hr there was an abrupt transition from normal to abnormal cortex. No evidence of metabolic recovery was seen in this model of permanent occlusion.
Assuntos
Metabolismo Energético , Ataque Isquêmico Transitório/metabolismo , Trifosfato de Adenosina/metabolismo , Animais , Glucose/metabolismo , Ataque Isquêmico Transitório/fisiopatologia , Lactatos/metabolismo , Ácido Láctico , Masculino , Ratos , Ratos EndogâmicosRESUMO
We examined the consequences of reflow on metabolic recovery following increasing periods of focal ischemia. The middle cerebral artery of 21 Sprague-Dawley rats was occluded with a snare ligature for 1, 2, or 6 hours followed by 5, 4, or 0 hours of reflow, respectively (seven rats in each group). All animals were injected with neutral red for visual confirmation that the affected regions were reperfused. The brains were frozen in situ, and the concentrations of adenosine triphosphate, phosphocreatine, glycogen, and lactate were determined in those areas corresponding to the normally perfused medial ipsilateral cortex, the perifocal region, and the ischemic focus. Values for the 6 hours' occlusion with no reflow group served as a control to demonstrate restoration of metabolite concentrations. In both groups with reflow, the levels of high-energy phosphates were greater than control, but this effect of reflow was primarily significant for the group with 1 hour's occlusion (p less than 0.05). The levels of glycogen and lactate provided additional evidence that the extent of metabolite restoration was graded; following 2 hours of occlusion, metabolite recovery was compromised (p less than 0.05). Our data strongly support the concept that the window of opportunity for effective treatment of focal ischemia by reperfusion is narrow (of short duration).
Assuntos
Arteriopatias Oclusivas/metabolismo , Encéfalo/metabolismo , Artérias Cerebrais , Trifosfato de Adenosina/metabolismo , Animais , Arteriopatias Oclusivas/fisiopatologia , Circulação Cerebrovascular , Glicogênio/metabolismo , Lactatos/metabolismo , Ácido Láctico , Masculino , Concentração Osmolar , Fosfocreatina/metabolismo , Ratos , Ratos Endogâmicos , Reperfusão , Fatores de TempoRESUMO
The ability of dynamic, contrast-enhanced, magnetic susceptibility-weighted scanning to delineate early experimental acute cerebral infarction was compared with that of heavily T2-weighted and diffusion-weighted spin echo scanning. Spontaneously hypertensive rats, which had undergone right middle cerebral artery occlusion, were studied from 15 min to 3 h post ligation on a 1.5-T clinical whole-body imager. In contrast to the diffusion- and T2-weighted spin echo scans, the dynamic, contrast-enhanced technique clearly and consistently delineated the nonperfused regions as early as 15 min post ligation.
Assuntos
Edema Encefálico/diagnóstico , Isquemia Encefálica/diagnóstico , Meios de Contraste , Doença Aguda , Animais , Dextranos , Combinação de Medicamentos , Óxido Ferroso-Férrico , Gadolínio , Gadolínio DTPA , Ferro , Imageamento por Ressonância Magnética/métodos , Nanopartículas de Magnetita , Meglumina , Compostos Organometálicos , Óxidos , Ácido Pentético , Polilisina , Ratos , Ratos Endogâmicos SHR , Fatores de TempoRESUMO
The metabolic characteristics of the penumbral region were examined in spontaneously hypertensive rats one hour after permanent middle cerebral artery occlusion. The effect of hyperglycemia on this region was examined by providing a glucose load prior to occlusion. The depressed concentrations of adenosine triphosphate and elevated levels of lactate in the penumbral region were similar to those found in the ischemic focus. The purported neuroprotective effect of hyperglycemia in the penumbral region was not reflected in an increased high-energy phosphate level in the penumbral region. The rapid deterioration of the metabolic status of this region in this strain of rat suggests that the increased consistency of infarction may come at the expense of the penumbral region, and thus this model may not be well suited for the study of metabolic changes and perhaps even therapeutic intervention.
Assuntos
Infarto Cerebral/metabolismo , Hipertensão/metabolismo , Trifosfato de Adenosina/metabolismo , Animais , Glicemia/metabolismo , Pressão Sanguínea/fisiologia , Encéfalo/metabolismo , Dióxido de Carbono/metabolismo , Artérias Cerebrais , Frequência Cardíaca/fisiologia , Hiperglicemia/metabolismo , Lactatos/sangue , Masculino , Consumo de Oxigênio/fisiologia , Ratos , Ratos Endogâmicos SHRRESUMO
Conflicting reports have appeared in the literature regarding the effect of the opiate antagonist naloxone on ischemic neurologic deficits. We report the results of a study using naloxone in our model of focal cerebral ischemia in the awake primate. A total of 14 adult baboons were subjected to six-hour occlusion of the left middle cerebral artery (MCA). Seven animals served as controls and seven received treatment with naloxone (5 mg/kg) beginning 30 min after MCA occlusion and continuing until two hours after reperfusion. All animals developed profound hemiparesis and homonymous hemianopsia within seconds of inflating the MCA occluder. Acutely, therapy with naloxone partially reversed ischemic neurologic deficits in five of the seven treatment animals. Within minutes of receiving the loading dose of naloxone, responding animals were more alert and demonstrated improvements in motor function. Naloxone did not affect mortality: Three animals in the treatment group and two in the naloxone group died secondary to malignant intracranial pressure within 48 hours of the ischemic episode. In animals surviving the ischemic insult however, treatment with naloxone significantly improved neurologic outcome at 10 days (p less than 0.05). Neuropathologic examinations in these animals revealed amelioration of ischemic tissue damage, with three of the five suffering only small focal areas of infarction. (All control animals suffered large infarcts of the MCA territory.) Our results verify that naloxone can reverse ischemic deficits, and more importantly may improve the outcome from focal ischemic insults.
Assuntos
Ataque Isquêmico Transitório/tratamento farmacológico , Naloxona/uso terapêutico , Animais , PapioRESUMO
BACKGROUND: The dose-response effects of pretreatment with lamotrigine (a phenyltriazine derivative that inhibits neuronal glutamate release) in a porcine cerebral ischemia model during cardiopulmonary bypass were studied. METHODS: Sagittal sinus catheters and cortical microdialysis catheters were inserted into anesthetized pigs. Animals undergoing normothermic cardiopulmonary bypass were pretreated with lamotrigine 0, 10, 25, or 50 mg/kg (n = 10 per group). Fifteen minutes of global cerebral ischemia was produced, followed by 40 min of reperfusion and discontinuation of cardiopulmonary bypass. Cerebral oxygen metabolism was calculated using cerebral blood flow (radioactive microspheres) and arterial-venous oxygen content gradients. Concentrations of microdialysate glutamate and aspartate were quantified; electroencephalographic signals were recorded. After cardiopulmonary bypass, blood and cerebrospinal fluid were sampled for S-100B protein, and a biopsy was performed on the cerebral cortex for metabolic profile. RESULTS: Lamotrigine caused dose-dependent reductions in systemic vascular resistance so that additional fluid was required to maintain venous return. Concentrations of glutamate and aspartate did not change during reperfusion after 50 mg/kg lamotrigine in contrast to fivefold and twofold increases, respectively, with lower doses. There were no intergroup differences in cerebral metabolism, electroencephalographic scores, cortical metabolites, brain lactate, or S-100B protein concentrations in the cerebrospinal fluid and blood. CONCLUSIONS: Lamotrigine 50 mg/kg significantly attenuated excitatory neurotransmitter release during normothermic cerebral ischemia during cardiopulmonary bypass without improving other neurologic parameters. Lamotrigine caused arterial and venous dilation, which limits its clinical usefulness.
Assuntos
Analgésicos/farmacologia , Isquemia Encefálica/metabolismo , Ponte Cardiopulmonar , Ácido Glutâmico/metabolismo , Triazinas/farmacologia , Animais , Relação Dose-Resposta a Droga , Lamotrigina , Oxigênio/metabolismo , SuínosRESUMO
Tumor necrosis factor-alpha (TNF)-converting enzyme (TACE) cleaves the precursor form of TNF, allowing the mature form to be secreted into the extracellular space. GW3333, a dual inhibitor of TACE and matrix metalloproteinases (MMPs), was compared with an anti-TNF antibody to evaluate the importance of soluble TNF and MMPs in rat models of arthritis. Oral administration of GW3333 completely blocked increases in plasma TNF after LPS for up to 12 h. In a model wherein intrapleural zymosan injection causes an increase in TNF in the pleural cavity, GW3333 completely inhibited the increase in TNF in the pleural cavity for 12 h. Under these dosing conditions, the plasma levels of unbound GW3333 were at least 50-fold above the IC(50) values for inhibition of individual MMPs in vitro. In a model wherein bacterial peptidoglycan polysaccharide polymers reactivate a local arthritis response in the ankle, a neutralizing anti-TNF antibody completely blocked the ankle swelling over the 3-day reactivation period. GW3333 administered b.i.d. over the same period also inhibited ankle swelling, with the highest dose of 80 mg/kg being slightly less active than the anti-TNF antibody. In a 21-day adjuvant arthritis model, the anti-TNF antibody did not inhibit the ankle swelling or the joint destruction, as assessed by histology or radiology. GW3333, however, showed inhibition of both ankle swelling and joint destruction. In conclusion, GW3333 is the first inhibitor with sufficient duration of action to chronically inhibit TACE and MMPs in the rat. The efficacy of GW3333 suggests that dual inhibitors of TACE and matrix metalloproteinases may prove therapeutic as antiarthritics.